SI9300217A - Pharmaceutical compositions comprising aryloxyalkylamino and arylthioalkylamino derivatives - Google Patents

Abstract

Use of compounds of formula (I), in which n is 3 to 8; q is 5 to 11; R<1> represents C1-6alkyl or C1-6alkoxy; s is zero, 1 or 2; X represents oxygen or sulphur; and Ar represents phenyl optionally substituted by 1-3 substituents selected from halo, C1-8alkyl, C1-8alkoxy, C1-2alkylenedioxy, trifluoromethyl, trifluoromethyloxy, or a group Ph-(CH2)m-Y-(CH2)p-where Ph is optionally substituted phenyl, m and p are independently 0 to 4 and Y is a bond, O, S, or CH=CH, provided that m + p is not greater than 4, or Ar is an optionally substituted tricyclic heteroaryl group (a) in which Y<1> is Y(CH2)x where x is 0 or 1 and Y is O, S or NR where R is hydrogen or C1-4alkyl, Z is (CH2)r or -CH=CH-, r is 0, 1 or 2 or Ar is the corresponding tricyclic dehydro ring system, and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of conditions where a calcium channel antagonist is indicated. Novel compounds of formula (I), processes for preparing them and pharmaceutical compositions containing them are also described.

Description

SMITHKLINE BEECHAM PLC

Pharmaceuticals containing aryloxyalkylamino and arylthioalkylamino derivatives

The present invention relates to aryloxyalkylamino and arylthioalkylamino derivatives, methods for their preparation, pharmaceutical compositions containing them and their use in the treatment, in particular the treatment of ischemic stroke.

Stroke is the third most common cause of death in the developed world, according to reports. Current ischemic stroke therapies are limited and have many disadvantages, such as the risk of worsening hemorrhage. Therefore, there is a need for new and improved treatments for ischemic stroke.

EP-A-103252 describes a wide class of aryloxyalkylamino derivatives. These compounds are said to have utility as herbicides.

French patent application no. No. 1601591 describes a class of nitrogen-containing heterocyclic compounds derived from phenoxyalkyl alcohols which are said to be cholesterol lowering agents.

We have now found that certain aryloxyalkylamino and arylthioalkylamino derivatives express activity as calcium channel antagonists.

The present invention thus provides, at a first glance, the use of a compound of formula (I):

(R).

(CH ₂ ) _n N- (CH ₂ ) _q -X-Ar formula (I) wherein n is 3 to 8;

q is 5 to 11;

R ¹ represents C 1-6 alkyl or C 1-4 alkoxy;

is zero, 1 or 2;

X represents oxygen or sulfur; and

Ar represents phenyl which is optionally substituted with 1-3 substituents selected from halo, C ^ alkyl, C ^ alkoxy, C ₁₂ alkylenedioxy example. methylenedioxy, trifluoromethyl, trifluoromethyloxy or the group Ph- (CH ₂ ) _m -Y- (CH ₂ ) _p -, where Ph is optionally substituted phenyl, m and p are independently 0 to 4 and Y is a bond of O, S or CH = CH, provided that m + p is not more than 4, or Ar is optionally substituted tricyclic heteroaryl group:

wherein Υ ¹ ΥζίΖΗ ^, where x is 0 or 1, and YO, S or NR, games, R is hydrogen or C _{r 4} alkyl, Z is (CH? or -CH = CH-, r is 0,1, or 2, whether Ar is a suitable tricyclic dehydro ring system, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of conditions associated with the accumulation of calcium in mammalian brain cells.

Preferably n is 4,5 or 6, most preferably 5.

Preferably q is 6 to 9, most preferably 7.

When s is other than zero, R ¹ preferably represents C 1-6 alkyl such as methyl.

X preferably represents oxygen.

When Ar is substituted by the group Ph (-CH ₂ ) _m Y (CH ₂ ) _p -, Y is preferably oxygen or bond. When Y is oxygen, p is preferably 0 and m is preferably 0 or 1. When Y is a bond, the sum of m + p is preferably 1 or 2. When Y is CH = CH, m and p are preferably both zero.

Preferably, Ar is phenyl mono-substituted with phenoxy, benzyl, benzyloxy or halo; halo phenyl disubstituted; or Ar is 2-dibenzofuranyl. Most preferably, Ar is phenyl substituted with benzyl or benzyloxy.

Examples of tricyclic heteroaryl groups include dibenzofuranyl, dibenzothienyl, carbazole, N-methylcarbazole, acridine, and dibenzoxepine. The tricyclic moiety may be bonded to the residue of formula (I) via any suitable ring atom.

Suitable substituents for Ph and tricyclic heteroaryl groups include, e.g. 1 to 3 substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C _1-4 alkoxy.

The alkyl groups present in the compounds of formula (I), alone or as part of another group, may be straight or branched. Thus, a C 1-6 alkyl group may be e.g. methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof, such as isopropyl, t-butyl or sec-pentyl.

It should be borne in mind that for use in medicine salts of compound (I) must be pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts, such as hydrochloride, hydrobromide, sulfate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, methanesulfonate, or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non-pharmaceutically acceptable salts can be used e.g. in the isolation of the final product and are included within the scope of the present invention.

It will be appreciated that the compounds of formula (I) may contain one or more asymmetric centers. Such compounds exist as optical isomers (enantiomers). Both pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of both are included within the scope of the present invention. Furthermore, within the scope of the present invention, all possible diastereomeric forms (pure enantiomers and mixtures thereof).

Certain compounds of formula (I) are believed to be novel. Thus, in a further aspect, the present invention relates to a compound of formula (ΙΑ):

formula (IA) wherein n, q, R ¹ , s and X are as defined for formula (I) and Ar ¹ is optionally substituted tricyclic heteroaryl group as defined for formula (I);

or its salt.

In a still further aspect, the present invention also relates to a compound of formula (ΙΒ):

(R k (CH ₂ ) n N- (CH ₂ ) ₇ XAr 'formula (IB) wherein R ¹ , s, n and X are as defined for formula (I) and Ar ² represents phenyl optionally substituted by a group A Ph- (CH ₂ ) _m Y (CH ₂ ) _p - or tricyclic heteroaryl group as defined for formula (I), or a salt thereof.

In the compounds of formula (IB), n is preferably from 4 to 6, most preferably 5. X is preferably oxygen. When s is other than zero, R ¹ preferably represents CMalkyl. Ar ² preferably represents phenyl substituted with the group Ph (CH ₂ ) _m Y (CH ₂ ) _p -. Most preferably, Ar ² represents phenyl substituted with phenoxy, benzyl or benzyloxy. In general, the phenyl substituent will preferably be at the 4-position of the phenyl ring relative to group X.

The compounds of formulas (IA) and (IB) represent novel and preferred choices based on their activity as calcium channel antagonists.

Specific compounds of the invention which are considered to be novel compounds include:

7-phenoxy-1-piperidmoheptane,

7- (4-fluorophenoxy) -1-piperidinoheptane,

7- (2,4-dichlorophenoxy) -1-piperidmoheptane,

7- (4-phenoxyphenoxy) -1-piperidinoheptane,

7- (3-phenoxyphenoxy) -1-piperidinoheptane,

7- (2-dibenzofuranyloxy) -1-piperidinoheptane,

7- (4-benzyloxyphenoxy) -1-piperidinoheptane,

7- (4-benzyloxyphenoxy) -1-pyrrolidinoheptane,

N- [7- (4-Benzyloxyphenoxy) heptyl] -hexamethyleneimine,

9- (3,4-dichlorophenoxy) -1-piperidinoneone,

9- (4-benzyloxyphenoxy) -1-piperidinoneone,

8- (4-benzfloxyphenoxy) -1-piperidooctane,

8- (4-phenoxyphenoxy) -1-piperidino-octane,

6- (4-benzyloxyphenoxy) -1-piperidinohexane,

7- {4- [2- (4-chlorophenyl) ethyl] phenoxy} -1-piperidinoheptane, trans-7- [4- (2-phenylethenyl) phenoxy] -1-piperidinoheptane,

7- [4- (2-phenylethyl) phenoxy] -1-piperidinoheptane,

7- (4-benzylphenoxy) -1-piperidinoheptane,

7- (2-benzylphenoxy) -1-piperidinoheptane,

7- (4-methoxyphenoxy) -1-piperidinoheptane,

7- (4-tert-butylphenoxy) -1-piperidinoheptane,

7- (3,4-methylenedioxyphenoxy) -1-piperidinoheptane,

7- [4- (3,4-Dichlorobenzyloxy) phenoxy] -1-piperidinoheptane,

7- [4- (4-methoxybenzyloxy) phenoxy] -1-piperidinoheptane,

7- [4- (4-fluorobenzyloxy) phenoxy] -1-piperidinoheptane,

N- [7- (4-Benzyloxyphenoxy) heptyl] -2-methylpiperidine,

N- [7- (4-Benzfloxyphenoxy) heptyl] -3-methylpiperidine,

N- [7- (4-Benzyloxyphenoxy) heptyl] -4-methylpiperidine,

N- [7- (4-Benzyloxyphenoxy) heptyl] -2,6-dimethylpiperidine,

N- [7- (4-Benzyloxyphenoxy) heptyl] -4-methoxypiperidine

5- (4-Benzyloxyphenoxy) -1-piperidimopentane, and pharmaceutically acceptable salts thereof.

The compounds of the present invention can be prepared by methods analogous to those known in the art. The present invention therefore relates to a further view of a process for the preparation of a new compound of formula (I), in particular a compound of formula (IA) or (IB), which includes:

(a) metabolism of a compound of formula (II):

(CH ₂ ) _n N- {CH ₂ ) _q -L

formula (Π) in which n, R ¹ , s and q are as defined in formula (IA) and L ¹ is a nucleophile interchangeable group with a compound of formula (III):

ΑΗ-ΧΗ formula (ΠΙ) in which X is as defined in formula (IA) and Ar ³ represents Ar ¹ when q is as defined in formula (IA), or Ar ² when q is 7;

(b) metabolism of the compound of formula (IV): ΑΑΧ-ρΗ ^ -Ι?

formula (IV) wherein X and q are as defined for formula (IA), Ar ³ is as defined for formula (III) and L ^{2 is a} leaving group, with a compound of formula (V):

<^ X ^{iR, s} (CH ₂ ) n NH formula (V) wherein n, R ¹ and s are as defined in formula (IA); or (c) reduction of an amide of formula (VI) or (VII):

£ - 3 (CH ₂ ) _n ., N ^ CH ₂ ) _q XAr ³ is formula (VI)

(R \

O II formula (VII) wherein R ¹ , s, n, q, X and Ar ³ are as defined above;

(d) reductive amination of an aldehyde of formula (VIII):

OHC- (CH ₂ ) _ql XAr ³ formula (VIII) wherein q, X and Ar ³ are as defined in yarn in the presence of a compound of formula (V) as defined above.

(e) For the preparation of a compound wherein Ar ³ represents phenyl substituted with Ph (CH ₂ ) _m O-, alkylation of a compound of formula (IX):

wherein R ¹ , s, n, q and X are as defined in yarn; with an alkylating agent of formula (X):

PhCCHj) ^ * formula (X) wherein Ph, m and ^L1 are as hereinbefore defined.

(f) To prepare a compound wherein n is 5, reduction of a pyridine derivative of formula (XI):

formula (XI) wherein R ¹ , s, q, X and Ar ³ are as defined in yarn and A 'is against an anion;

g) the internal conversion of one compound of formula (I) into a different compound of formula (I) e.g. reduction of a compound where Y represents CH = CH to a compound where Y represents -CHgCH, -;

followed by salt formation if desired.

In process (a), the reaction between a compound of formula (Π) and a compound of formula (III) can be carried out under standard conditions. E.g. when L ¹ is hydroxy, the reaction is carried out in the presence of diethyl azodicarboxylate and triphenylphosphine. Such a reaction is known as the Mitsunobu reaction (as described in Synthesis 1981, 1). This reaction can optionally be carried out in the presence of a solvent such as tetrahydrofuran. Alternatively, the departure group L ^{1 may be} e.g. a halogen atom or a sulfonyloxy group e.g. methanesulfonyloxy or p-toluenesulfonyloxy. In this case, the reaction may be carried out in the absence or presence of a solvent such as dimethylformamide or methylethylketone, in the presence of a base such as sodium hydride or potassium carbonate and at a temperature in the range of 0 to 200 ° C.

The metabolism of a compound of formula (IV) with a compound of formula (V) according to process (b) can be carried out in a conventional manner, e.g. using excess amine as a solvent or alternatively, using an organic solvent such as ethanol or dimethylformamide. The leaving group L ² may be e.g. a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy, or a sulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy. The metabolism is preferably carried out in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide.

The reduction of the amide according to process (c) can be carried out using a suitable reducing agent such as lithium aluminum hydride.

In process (d), reductive amination of the aldehyde (VIII) can be carried out using a reducing agent such as sodium cyanoborohydride in the presence of a compound of formula (V) according to methods well known in the art.

In process (e), the metabolism of compounds (IX) and (X) can be carried out in an analogous manner as the procedure (a) described above.

The reduction of the pyridinium derivative (XI) by process (f) can be carried out e.g. by hydrogenation, using a noble metal catalyst such as palladium on charcoal, platinum or platinum oxide (Adams catalyst), suitably in a solvent such as alcohol, e.g. ethanol.

Internal conversion reactions according to process (g) can be performed using standard procedures. Thus, e.g. conversion of compound (I) where Y represents -CH = CH- to compound (I) where Y represents -CH ^ CH ^ is carried out by catalytic hydrogenation.

The compound of formula (II) can be prepared under standard alkylation conditions by metabolizing a compound of formula (XII):

v <ay, -L>

formula (XII) wherein L ¹ , L ² and q are as defined in yarn, with a compound of formula (V) as defined in yarn. The reaction is suitably carried out under analogous conditions, such as those described above for process (b).

It is to be appreciated that in the compounds of formula (XII), the leaving groups L ¹ and L ^{2 are} preferably selected such that the compound of formula (V) reacts selectively with L ² . E.g. in the compound of formula (ΧΠ), L ^{1 is} suitably hydroxy and L ^{2 is} suitably halo.

The compounds of formula (III) are commercially available or can be prepared using standard procedures well known in the art.

Compounds of formula (IV) can be prepared by metabolizing a compound of formula (III) as defined by yarn with a compound of formula (XII) as defined by yarn. In this metabolism, both L ¹ and L ^{2 can be} identical, e.g. Hello. The metabolism is appropriately carried out in the presence of a weak base such as potassium carbonate. Alternatively, the metabolism can be carried out under phase transfer conditions using a strong base such as potassium hydroxide.

The compounds of formula (V) and (XII) are commercially available or can be prepared by standard procedures.

The compounds of formula (VI) can be prepared by the general procedures (a) and (b) described herein using the appropriate amide corresponding to formula (II) or (V).

Compounds of formula (VII) can be prepared by acylation of a compound of formula (V), e.g. with an appropriate acid chloride or ester which can itself be prepared from a compound of formula (ΙΠ) by metabolism with a suitable commercially available bromoalkyl ester or acid, followed, if necessary or desired, by conversion to acid chloride. Alternatively, compound (VII) can be prepared by a process analogous to process (a). An aldehyde of formula (VIII) can be prepared e.g. by reducing the corresponding nitrile, using a reducing agent such as disobutylaluminum hydride in the presence of an inert solvent such as toluene. Applied reductive animation of the aldehyde is carried out in situ, i.e. the compound of formula (I) is obtained from the nitrile in a one-pot reaction without isolation of the aldehyde intermediate. The nitrile itself can be prepared by reacting a compound of formula (IV), wherein L ^{2 is} halo, with potassium cyanide. Compounds (VIII) can also be prepared by other standard procedures, such as ester reduction or alcohol oxidation. The compounds of formula (IX) can be prepared by methods analogous to any of the processes (a) - (d) described herein. Alternatively, compound (IX) can be obtained by catalytic hydrogenation of the corresponding compound of formula (I), wherein Ar represents a benzyloxyphenyl group. This then provides a further process of converting a compound of formula (I) into a different compound of formula (I).

The compounds of formula (XI) can also be prepared in a similar manner to the procedures (a) (d) described above.

When a compound of formula (IA) or (IB) is obtained as a mixture of enantiomers, they can be separated by conventional methods such as crystallization in the presence of an isomer separator, or chromatography, e.g. using a chiral HPLC column.

It should be appreciated that while the intermediates of formulas (II) to (XII) are defined according to formulas (IA) and (DB), the above processes can be used to prepare any new compounds within the scope of formula (I) and to submit the invention extends to the preparation of such compounds.

The present invention also contains any of the novel intermediates described herein, in particular those of formulas (II), (IV), (VI), (VII), (IX) and (XI).

The compounds of the present invention have been found to express a highly blocking action of calcium influx, e.g. in neurons. The compounds as such are expected to be useful in the treatment of conditions and diseases associated with calcium accumulation in mammalian brain cells, especially humans. E.g. the compounds are expected to be useful in the treatment of anoxia, ischemia, including e.g. stroke, migraine, visceral pain, epilepsy, traumatic head injury or traumatic spinal injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, mood disorders and drug addiction withdrawal, such as withdrawal of addiction ethanol.

Particularly preferred compounds of the present invention are 7- (4-benzylphenoxy) -1-piperidinoheptane and 7- (4-benzyloxyphenoxy) -1-piperidinoheptane (which may also be called) 1- [7- (4-benzylphenoxy) heptyl] piperidine and 1- [7- (4-Benzyloxyphenoxy) heptylpiperidine) and their pharmaceutically acceptable salts. These compounds effectively inhibit Ca ²⁺ current especially in neural channels. The compounds also demonstrate neuroprotective effects in various animal models of ischemia when administered after ischemia.

The present invention also relates to a method for treating conditions or diseases that are associated (e.g., caused or exacerbated by) calcium accumulation in mammalian brain cells, comprising administering to the patient in need thereof effective amounts of a compound of formula (I), as defined by yarn or pharmaceutically acceptable salts thereof.

So e.g. the present invention relates to a method for treating anoxia, ischemia, which includes e.g. stroke, migraine, visceral pain, epilepsy, traumatic head injury or traumatic spinal injury, AIDS-related dementia, neuro-13 generative diseases such as Alzheimer's disease and age-related memory disorders, mood disorders and drug dependency withdrawal, such as withdrawal of addiction ethanol, which involves administering to a patient in need of this treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

For medical use, the compounds of the present invention are typically administered in standard pharmaceutical compositions. The present invention therefore relates to a further view of pharmaceutical compositions comprising a novel compound of formula (I), such as a defined yarn or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

The compounds of the present invention can be administered by any conventional method, e.g. oral, parenteral, buccal, rectal or transdermal administration, and pharmaceutical compositions are suitably adapted. Parenteral administration is generally preferred.

The compounds of formula (I) and their pharmaceutically acceptable salts, which are active when administered orally, can be formulated as liquids or solids, e.g. syrups, suspensions or emulsions, tablets, capsules or lozenges.

The liquid preparation generally consists of a suspension or solution of a compound or pharmaceutically acceptable salt in a suitable liquid carrier (s) e.g. ethanol, glycerin, a non-aqueous solvent, e.g. polyethylene glycol, oils or water with a suspending agent, preservative, flavoring or coloring agent.

The tablet formulation can be prepared using any suitable pharmaceutical carrier (s) that is routinely used to prepare solid preparations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

The capsule-shaped composition can be prepared using routine encapsulation procedures. E.g. pellets containing the active ingredients can be prepared using standard carriers and then filled into hard gelatin capsules; alternatively, the dispersion or suspension may be prepared using any suitable pharmaceutical carrier (s), e.g. aqueous gums, celluloses, silicates or oils, and the dispersion or suspension is then filled into soft gelatin capsules.

The compounds of the present invention may also be administered parenterally, by bolus injection or continuous infusion. Typical parenteral compositions consist of a solution or suspension of a compound or pharmaceutically acceptable salt in a sterile aqueous vehicle or a parenterally acceptable oil, e.g. polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution may be lyophilized 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 a unit dosage form, such as a tablet, capsule or ampoule.

Each oral dosage unit contains preferably from 1 to 250 mg (and for parenteral administration preferably contains from 0.1 to 0.60 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.

The daily dosage regimen for an adult patient may be e.g. an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or intravenous, subcutaneous or intramuscular doses between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base, the compound being administered 1 to 4 times daily. Alternatively, the compounds of the present invention may be administered by continuous intravenous infusion, preferably at doses up to 400 mg per day. Therefore, the total daily dose for oral administration may be in the range of 1 to 2000 mg and the total daily dose for parenteral administration may be in the range of 0.1 to 400 mg. The compounds may be administered during a continuous treatment period, e.g. 1 week or more.

If desired, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered in combination or simultaneously with one or more other therapeutic agents, e.g. a thrombolytic agent such as an anistreplase, streptokinase or tissue plasminogen activator, an excitable amino acid antagonist such as an NMDA antagonist; free radical inhibitor; or calpain inhibitor.

BIOLOGICAL INFORMATION

In vitro

Measurement of Ca ²⁺ current

Cell preparations

Sensory neurons from the dorsal spinal ganglia are distinguished from one-day-old pup rats (Forda et al, Developmental Brain Research, 22 (1985), 55-65). The cells were placed on a cover glass and used within three days to allow efficient voltage accumulation of Ca ²⁺ currents.

Solutions

The pipette (internal solution) contained in mM: CsCl, 130; HEPES ([4- (2-hydroxyethyl) piperazino-ethanesulfonic acid), 10; EGTA (ethylenebis (oxyethylenitrile) -tetra acetic acid), 10; MgCl ₂ , 4; ATP (adenosine-5'-triphosphate), 2; charged to pH 7.2 with CsOH. The cells were buried in normal Tyrodes solution before full cellular registration was established, when the bath solution was changed to allow Ca ²⁺ streams to be isolated. The external solution for recording Ca ²⁺ channel flows contains in mM: BaCl ₂ , 10; TEA-C1 (tetra ethyl ammonium chloride), 130; glucose, 10; HEPES, 10; MgCl ₂ , 1; purified to pH 7.3 with TEA-OH (tetra ethyl ammonium hydroxide). Barium is used as a charge carrier, which as such helps in current isolation and eliminates calcium-dependent current deactivation. The compounds were dissolved in DMSO (dimethylsulfoxide) to make a 20 mM stock solution. At the drug concentration, the vehicle used (0.1%) had no significant effect on Ca ²⁺ currents. All experiments were performed at 21 to 24 ° C. Whole cell currents were recorded using List EPC-7 enhancers and harvested, digitized for later analysis using a PC based program similar to that described for yarns (Benham & Tsien, Journal of Physiology (1988), 404,767-784).

Ca ²⁺ flows

Peak voltage input Ca ²⁺ channel currents up to 10 nA from dorsal root ganglia neurons are recorded using 10 mM Ba ²⁺ as a charge carrier.

Currents are called from the existing potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential is at the peak of the current-to-voltage ratio, and a specific block at this point reduces all errors due to the accumulation of existing potential. Some cells show a slow drop in current, as we usually register when recording Ca ²⁺ currents. The velocity drop is measured under control conditions and extrapolated beyond the drug delivery time to obtain a control value to compare it with the flow affected by the drug. The block of 20 μΜ of drug was determined 3 minutes after drug administration.

The compounds of the invention give a percentage inhibition of the plateau of Ca ²⁺ current in the range of 35-100%.

In vivo

Test compound A = 7- (4-Benzyloxyphenoxy) -1-piperidinoheptane hydrochloride

Test compound B = 7- (4-benzylphenoxy) -1-piperidinoheptane hydrochloride

BCAO jumper model

Male Mongolian jumpers weighing between 60-80 g were anesthetized with halothane, placed on a heated mat and clogged the carotid artery. After reperfusion, the animals were sewn and placed in an incubator maintained at body temperature until recovery. The animals were then caged and locomotor activity determined on the fourth day after surgery using an automated locomotor activity monitoring system. The dosing protocol in these experiments is 30 minutes after ischemia, then twice daily for 3 days, with injections via the intraperitoneal route. We perform two sets of experiments. In the first, the duration of the occlusion is 8 minutes and test compound A is administered at 10 mg.kg ' ¹ or 3 mg.kg ⁴ , using the above dosing regimen. In the second experiment, 10 minutes of occlusion, and 30 mg.kg ^"1 of the test compounds A and B administered 30 minutes after - ischemia, followed by 10 mg.kg ⁴ 2 times daily for 3 days.

During the 8 minute period of the ischemic experiment, test compound A at 10 mg.kg ⁴ causes a significant reversal of histological damage in the CA1 region of the hippocampus seen in animals treated with the ischemic carrier. This dose also causes a slight but statistically insignificant reversal of ischemically-induced hyperlocation. A higher dose of test compounds A and B used in the second experiment results in a significant reversal of locomotor deficiency caused by a 10 minute ischemia period, but does not produce a statistically significant effect on histology.

Rat model with Bengal pink

Lister Hooded male rats (250-280 g) anesthetized with halothane were placed in a stereotaxic box. The rectal temperature was maintained at 39 ° C. The skull is exposed and a forked optical fiber guide (3.0 mm diameter) from a 300 w xenon arc lamp is mounted on the skull at the bregma in the anterior - posterior plane in the holder designed to center the 2.5 mm light guide heads to the left and right from the middle. The Bengal pink (20 mg.kg ' ¹ ) is initiated into the lateral tail vein. The skull was illuminated for 5 min, then the wound was sutured and the anesthesia was discontinued.

The test compounds are administered intraperitoneally 30 mg.kg ' ¹ 10 minutes after surgery, followed by a further dose of 10 mg.kg' ¹ 1 hour after surgery and then twice daily for 3 days. A 75% reduction in wound volume for Compound A is observed.

The above doses of compounds A and B tested do not show adverse toxicological effects.

Cardiovascular screening

Male Lister Hooded rats were anesthetized with sodium pentobarbitone (60 mg.kg ' ¹ intraperitoneally). We measure the effects on diastolic blood pressure and heart rate via drug infusion. Test compound A (10 mg.kg ¹ ) dissolved in 10% HPCD) was infused over 30 minutes. Minor pectoral effects similar to those observed in solvent-treated animals are observed, together with minor reductions in heart rate. These results indicate that the compound has no significant cardiovascular effects at the dose tested. The compounds of formula (I) have been found to exhibit good brain-penetrant properties.

Pharmaceutical preparations

1. Preparation for intravenous infusion of the compound of formula (I) sodium hydroxide / hydrochloric acid polyethylene glycol propylene glycol alcohol water

2. Bolus injection preparation Compound of Formula (I) Sodium hydroxide or hydrochloric acid polyethylene glycol alcohol water

Toxicity adjusters, dextrose or mannitol may be added

3. Tablet for oral administration of compounds of formula (I) lactose starch crospovidone microcrystalline cellulose magnesium stearate

0.1-60 mg to pH approx. 7 0-30 ml 0-30 ml 0-10ml to 100 ml

0.1 - 60 mg to pH approx. 7

0-2,5 ml

- 2.5 ml to 5 ml e.g. sodium chloride mg / tablet

153

255

EXAMPLES

Intermediate preparations

1) 7-piperidinoheptanol

7-Bromoheptanol (5.0 g) was added 30 minutes to piperidine (20 ml), which was stirred at room temperature. The resulting mixture was allowed to stand for 60 hours and then dissolved in chloroform. This solution is washed with dilute sodium hydroxide solution, a brine containing a few drops of dilute sodium hydroxide solution, and dried over magnesium sulfate. The solvent was removed and the Kugelrohr residue was distilled to give the title compound as a solid (4.53 g) of soil. 37-39 ° C.

2) 1-bromo-7- (2-dibenzofuranyloxy) heptane

A mixture of 1,7-dibromoheptane (8.5 g), 2-hydroxydibenzofuran (4.66 g), potassium carbonate (6.91 g) and butan-2-one (100 ml) was heated at reflux temperature for 18 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was separated, washed with brine, dried over magnesium sulfate and the solvent removed. The residue was suspended in boiling hexane (100 ml) and filtered, and the filtrate was allowed to cool. The precipitate was collected by filtration to give the title compound (1.89 g) of soil. 65-70 ° C, which is used without further purification. The filtrate was evaporated to give another portion of the title compound (5.82 g).

3) 7- (4-Benzyloxyphenoxy) -1-bromoheptane

1,7-Dibromoheptane (12.9 g) was added dropwise to a stirred solution of 4-benzyloxyphenol (10 g), sodium hydroxide (2.5 g), benzyltriethylammonium chloride (0.4 g) and water (30 ml). The mixture was stirred at 50 ° C for 18 hours, water (50 ml) was added and the solution was extracted with dichloromethane (2 x 100 ml). The combined dichloromethane extracts were dried over magnesium sulfate, the solvent removed and the residue chromatographed on silica gel eluted with hexane / dichloromethane to give the title compound (4.25 g) as a solid. Tal. 56-59 ° C.

4) 6-piperidinohexanol

The title compound is prepared in a similar manner to intermediate 1 starting from

6-bromohexanol (10.0 g). Kugelrohr distillation (oven temperature 150 ° C at 13.33 Pa) gives the title compound as a clear oil, (9.07 g).

5) 8-piperidino-octanol

The title compound is prepared in a similar manner to intermediate 1 starting from

8- bromooctanol (10.0 g). Kugelrohr distillation (oven temperature 160 ° C at 13.33 Pa) gives the title compound as a white solid (9.06 g) of soil. 45-47 ° C.

6) 9-piperidinonanol

The title compound is prepared in a similar manner to intermediate 1 starting from

9- bromononanol (5.0 g). Kugelrohr distillation (oven temperature 180 ° C at 6.67 Pa) gives the title compound as a white solid, (4.632 g) soil, 53-55 ° C.

7) 7- (4-hydroxyphenoxy) -1-piperidinoheptane

A mixture of 7- (4-benzyloxyphenoxy) -1-piperidmoheptane (13.28 g), 5% palladium on carbon (0.5 g) and ethanol (250 ml) was shaken under a hydrogen atmosphere at 344,738 kPa for 16 h. The catalyst was removed by filtration and the filtrate was evaporated. The residue was recrystallized from acetonitrile to give the title compound as a white crystalline solid (8.438 g), m.p. 106-106.5 ° C.

Found: C, 74.03; H, 9.81; N 4.93% (C ₁₈ H ₂₉ NO ₂ .Ha) calcd: C 74.18; H, 10.03; N 4,81%

8) 1- [7- (4-Benzyloxyphenoxy) heptyl] -4-methoxypyridinium bromide

A solution of 4-methoxypyridine (3.21 g) and 7- (4-benzyloxyphenoxy) -1-bromoheptane (11.09 g) in ethanol (100 ml) was refluxed for 55 hours. The solvent was removed, the residue treated with ether and the resulting solid collected and recrystallized from acetonitrile to give the title compound (5.23 g), which was used without further purification.

9) 5- (4-Benzyloxyphenoxy) -1-bromopentane

1,7-dibromoheptane in intermediate preparation 3 substitutions for 1,5-dibromopentane (12.64 g) and the use of appropriate molar ratios of the other reagents gave the title compound, (11.60 g) m.p. 45-46 ° C, which is used without further purification.

10) 6- (4-Benzyloxyphenoxy) -1-bromohexane

A mixture of 4-benzyloxyphenol (17.47 g), 1,6-dibromohexane (26.9 ml), benzyltrimethylammonium chloride (1.03 g), sodium hydroxide, water (400 ml) and dichloromethane (45 ml) was stirred and heated to 60 ° C and then refluxed for 6 hours. The cooled mixture was extracted with dichloromethane. The dichloromethane extracts were washed with water, dried over sodium sulfate and the solvent removed. The residue was recrystallized 2 times from hexane to give the title compound (17.83 g), m.p. 74-76 ° C.

Found: C 63.07; H, 6.25; Br 21.68% (C ^ H ^ BrOJ calc .: C 62.82; H 6.38; Br 22.00%

11) 7- (4-Benzyloxyphenoxy) heptannitrile

A mixture of 6- (4-benzyloxyphenoxy) -1-bromohexane (10.00 g), potassium cyanide (1.79 g) and dimethyl sulfoxide was stirred and heated at 60 ° C for 16 hours. Pour the cooled mixture into water (1 L). The precipitate was collected, washed with water and recrystallized from toluene / hexane to give the crude title compound (7.82 g).

EXAMPLES

7-Phenoxy-1-piperidinoheptane hydrochloride

A solution of 7-piperidinoheptanol (1.0 g), phenol (0.48 g), triphenylphosphine (1.31 g) in tetrahydrofuran (50 ml) was treated with diethyl azodicarboxylate (0.87 g). The resulting solution was stirred at room temperature for 18 hours, the solvent was removed and the residue was chromatographed on silica gel eluting with methanol / dichloromethane. The resulting oil was dissolved in ethyl acetate (50 ml) and treated with ether hydrogen chloride. The precipitate was collected by filtration and recrystallized (methanol / ethyl acetate) to give the title compound (0.645 g) as white needles, m.p. Mp 154-155 ° C.

Found: C, 69.37; H, 9.62; N, 4.28; Cl 11.11% (C ₁₈ H ₂₉ NO.HC1) calcd: C 69.32; H, 9.70; N, 4.49; Cl 11,37%

EXAMPLE 2

7- (4-fluorophenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (1.5 g), 4-fluorophenol (0.84 g), triphenylphosphine (1.97 g) and diethyl azodicarboxylate (1.30 g). Chromatography on silica gel eluted with methanol / dichloromethane and treated with ether hydrogen chloride followed by recrystallization from ethyl acetate / methanol to give a white solid, (1.27 g), m.p. 126-127 ° C.

Found: C 65.11; H, 8.49; N, 4.19; Cl 10.83% (C ^ H ^ FNO.HCl) calcd: C 65.54; H, 8.86; N, 4.25; Cl 10,75%

EXAMPLE 3

7- (2,4-Dichlorophenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidino heptanol (1.0 g), 2,4-dichlorophenol (0.81 g), triphenylphosphine (1.131 g) and diethylazodicarboxylate (0.87 g) . Chromatography on silica gel eluted with methanol / dichloromethane and treatment with ether hydrogen chloride gave a white solid, which was recrystallized from acetonitrile, m.p. 176-178 ° C.

Found: C, 56.54; H, 7.03; N, 4.00; Cl 28.39% (C 18 H 16 NO 2 HCl) calcd: C 56.78; H, 7.41; N, 3.68; Cl 27,93%

EXAMPLE 4

7- (3,4-Dichlorophenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from

7-piperidinoheptanol (1.0 g), 3,4-dichlorophenol (0.81 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Chromatography on silica gel eluted with

2 $ with methanol / dichloromethane and treatment with ether hydrogen chloride to give a white solid recrystallized from methanol / ethyl acetate (1.27 g), m.p. 139-141 ° C.

Found: C, 56.62; H, 7.06; N, 3.57; CI 27.64% (C ₁₈ H ₂₇ O ₂ NO.HCl) calcd: C 56.78; H, 7.41; N, 3.68; CI 27,93%

EXAMPLE 5

7- (4-Phenoxyphenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (1.0 g), 4-phenoxyphenol (0.93 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Chromatography on silica gel eluted with methanol / dichloromethane and treatment with ether hydrogen chloride gave a white solid recrystallized from methanol / ethyl acetate (1.23 g), m.p. 176-178 ° C.

Found: C 71.13; H, 8.20; N, 3.42; CI 8.80% (C ^ H ^ NO ^ Ha) calcd: C 71.35; H, 8.48; N, 3.47; CI 8.77%

EXAMPLE 6

7- (3-phenoxyphenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (1.0 g), 3-phenoxyphenol (0.93 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Chromatography on silica gel eluted with methanol / dichloromethane and treatment with ether hydrogen chloride gave a white solid recrystallized from methanol / ethyl acetate (0.884 g), m.p. 100-101 ° C.

Found: C 71.23; H, 8.31; N, 3.60; CI 8.94% (C ^ H ^ NO ^ Ha) calcd: C 71.35; H, 8.48; N, 3.47; CI 8.77%

EXAMPLE Ί

7- (2-Dibenzofuranyloxy) -1-piperidinoheptane hydrochloride

Crude 1-bromo-7- (2-dibenzofuranyloxy) heptane (5.8 g) was added over 20 minutes to piperidine (15 ml), which was stirred at room temperature. The resulting mixture was allowed to stand for 18 hours and then dissolved in chloroform. This solution is washed with dilute sodium hydroxide solution, with brine containing a few drops of dilute sodium hydroxide solution, and dried over magnesium sulfate. The solvent was removed and the residue treated with ether hydrogen chloride and recrystallized from acetonitrile to give the title compound as white needles. (1.925 g), m.p. 127-129 ° C.

Found: C 70.70; H, 7.77; N, 3.37; Cl 9.03% (C ₂₄ H ₃₁ NO _2. HC1.0,25 H ₂ O) calcd: C 70.91; H, 7.81; N, 3.44; Cl 8,72%

EXAMPLE 8

7- (4-Benzyloxyphenoxy) -1-piperidinoheptane hydrochloride

A mixture of 7- (4-benzyloxyphenoxy) -1-bromoheptane (5.0 g), piperidine (2.18 g), potassium carbonate (2.73 g) and ethanol (50 ml) was stirred at reflux for 18 hours. The mixture was filtered and the residue was washed with ethanol. Combine the filtrates. The solvent was removed and the residue partitioned between dichloromethane and dilute sodium hydroxide solution. The dichloromethane layer was separated, dried over magnesium sulfate and the solvent removed to give an oil which was treated with ether hydrogen chloride. Recrystallization from ethyl acetate gave the title compound (1.95 g), m.p. 171-173 ° C.

Found: C 71.25; H, 8.47; N, 3.41; Cl 8.48% (C ₂₅ H ₃₅ NO _2. HC1.0.25 Κ, Ο) calcd: C 71.07; H 8.70; N, 3.30; Cl 8.30%

EXAMPLE 9

7- (4-Benzyloxyphenoxy) -1-pyrrolidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 8, starting from 7- (4-benzyloxyphenoxy) -1-bromoheptane (1.0 g), pyrrolidine (1.13 g), potassium carbonate (1.62 g) and ethanol (25 ml) ). Chromatography on silica gel eluted with methanol / dichloromethane and treatment with ether hydrogen chloride gave a white solid recrystallized from acetone (0.45 g), m.p. Mp 132-134 ° C.

Found: C, 70.89; H, 8.17; N, 3.45; CI 8.49% (C ^ H ^ NO ^ HaO ^ H ₂ O) calcd: C 70.56; H, 8.26; N, 3.42; CI 8.69%

EXAMPLE 10

N- [7- (4-Benzyloxyphenoxy) heptyl] -hexamethylenimine hydrochloride

A mixture of 7- (4-benzyloxyphenoxy) -1-bromoheptane (1.88 g) and 80% sodium hydride (0.17 g) and dimethylformamide was stirred under nitrogen for 5 minutes. Hexamethylenimine (0.563 ml) was added with a syringe and the mixture was stirred at 60 ° C for 4 hours. The solution was treated with water (30 ml) and extracted with dichloromethane. The dichloromethane layer was washed successively with water and dilute hydrochloric acid and then dried over magnesium sulfate, the solvent removed and the residue chromatographed on silica gel eluted with dichloromethane / methanol and recrystallized from acetonitrile to give the title compound (0.738 g). Mp 162-163 ° C.

Found: C 71.92; H, 8.66; N, 3.25; CI 8.15% (C ^ H ^ NO ^ Ha) calcd: C 72.28; H, 8.87; N, 3.24; CI 8.21%

EXAMPLE 11

6- (3,4-Dichlorophenoxy) -1-piperidinohexane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 6piperidinohexanol (1.5 g), 3,4-dichlorophenol (1.32 g), triphenylphosphine (2.12 g) and diethyl azodicarboxylate (1.40 g). Chromatography on silica gel eluted with methanol / dichloromethane followed by treatment with ether hydrogen chloride and recrystallization from methanol / ethyl acetate gave the title compound as white needles, (1.17 g), m.p. Mp 138-139 ° C.

Found: C 55.60; H, 6.83; N, 3.90; Cl · 9.68% (C ^ H ^ C ^ NO.HCl) calcd .: C 55.67; H, 7.14; N, 3.81; C1 '9,66%

EXAMPLE 12

9- (3,4-dichlorophenoxy) -1-piperidinone hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 9-piperidinonanol (1.2 g), 3,4-dichlorophenol (0.84 g), triphenylphosphine (1.38 g) and diethyl azodicarboxylate (0.92 g ). Chromatography on silica gel eluted with methanol / dichloromethane followed by treatment with ether hydrogen chloride and recrystallization from acetonitrile gave the title compound as white needles (1.25 g). Tal. 127128 ° C.

Found: C 58.65; H, 7.73; N, 3.47; Cl 26.21% (C ^ H ^ NO.HCl) calcd: C 58.76; H, 7.89; N, 3.43; Cl 26,01%

EXAMPLE 13

9- (4-Benzyloxyphenoxy) -1-piperidinone hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 9-piperidinonanol (1.2 g), 4-benzyloxyphenol (1.05 g), triphenylphosphine (1.38 g) and diethyl azodicarboxylate (0.92 g). Chromatography on silica gel eluted with methanol / dichloromethane, followed by treatment with ether hydrogen chloride and recrystallization from acetonitrile to give the title compound as white needles, (0.834 g), m.p. 144145 ° C.

Found: C, 72.39; H, 8.86; N, 3.16; Cl 7.88% (C ₂₇ H ₃₉ NO ₂ .HC1) calcd: C 72.70; H, 9.04; N, 3.14; Cl 7,95%

EXAMPLE 14

8- (4-Benzyloxyphenoxy) -1-piperidino-octane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 8-piperidino-octanol (1.3 g), 4-benzyloxyphenol (1.22 g), triphenylphosphine (1.60 g) and diethyl azodicarboxylate (1.06 g). Chromatography on silica gel eluted with methanol / dichloromethane followed by treatment with ether hydrogen chloride and recrystallization from ethyl acetate gave the title compound as white needles, (0.793 g), m.p. 141143 ° C.

Found: C 71.63; H 8.50; N, 3.16; Cl 8.47% (C ^ H ^ NO ^ HCLO ^ H ₂ O) calcd: C 71.54; H, 8.65; N, 3.20; a 8,12%

EXAMPLE 15

8- (4-Phenoxyphenoxy) -1-piperidino-octane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 8-piperidino-octanol (1.3 g), 4-phenoxyphenol (1.12 g), triphenylphosphine (1.60 g) and diethyl azodicarboxylate (1.06 g). Chromatography on silica gel eluted with methanol / dichloromethane followed by treatment with ether hydrogen chloride and recrystallization from ethyl acetate gave the title compound as a white solid, (0.98 g), m.p. 75-76 ° C.

Found: C 71.57; H, 8.41; N, 3.46; Cl 8.11% (C ^ H ^ NO ^ HCl) calcd: C 71.83; H, 8.68; N, 3.35; Cl 8,48%

EXAMPLE 16

6- (4-Benzyloxyphenoxy) -1-piperidinohexane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from

6-piperidmohexanol (1.5 g), 4-benzyloxyphenol (1.62 g), triphenylphosphine (1.12 g) and diethyl azodicarboxylate (1.40 g). Chromatography on silica gel eluted with methanol / dichloromethane followed by treatment with ether hydrogen chloride and recrystallization from ethyl acetate gave the title compound as a white solid, (1.33 g), m.p. 174-175 ° C.

Found: C 71.16; H, 8.24; N, 3.67; Cl 9.2% (C ^ H ^ NO ^ HCl) calcd: C 71.35; H, 8.43; N, 3.46; Cl 8.80%

EXAMPLE 17

7- {4- [2- (4-chlorophenyl) ethyl] phenoxy} -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from

7-piperidinoheptanol (1.0 g), 4- [2- (4-chlorophenyl) ethyl] phenol (1.19 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Chromatography on silica gel eluted with methanol / dichloromethane, followed by treatment with ether hydrogen chloride and recrystallization from acetonitrile gave the title compound as white needles, (0.853 g), m.p. 167169 ° C.

Found: C, 69.87; H, 8.09; N, 3.10; Cl 15.43% (C ₂₆ H ₃₆ ClNO ₂ .HCl) calcd: C 69.32; H, 8.28; N, 3.11; Cl 15,74%

EXAMPLE 18 trans-7- [4- (2-phenylethenyl) phenoxy] -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from

7-piperidinoheptanol (3.0 g), trans-4-hydroxystilbene (3.01 g), triphenylphosphine (3.93 g) and diethyl azodicarboxylate (2.61 g). Chromatography on silica gel eluted with methanol / dichloromethane gave a white solid (4,056 g). A sample of this material (1.75 g) was treated with ether hydrogen chloride to give a white solid, which was recrystallized from ethanol to give the title compound (1.145 g), m.p. 219-220 ° C.

Found: C, 75.02; H, 8.47; N, 3.37; Cl 8.56% (C ₂₆ H ₃₅ NO.Ha) calcd: C 75.43; H, 8.76; N, 3.38; Cl 8,57%

EXAMPLE 19

7- [4- (2-Phenylethyl) phenoxy] -1-piperidinoheptane hydrochloride

A mixture of trans-7- [4- (2-phenylethenyl) phenoxy] -1-piperidnoheptane (2.22 g), 10% palladium on carbon (0.35 g), methanol (50 ml) and ethanol (50 ml) under a hydrogen atmosphere at 344,738 kPa for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. The Os29 thin was dissolved in ethyl acetate and treated with ether hydrogen chloride to give a white solid, which was recrystallized from acetonitrile to give the title compound, (1.253 g), m.p. Mp 165-166 ° C.

Found: C 74.77; H, 9.05; N, 3.32; Q 8.27% (C ^ H ^ NO.HCl) calcd: C 75.06; H, 9.21; N, 3.37; Cl 8,52%

EXAMPLE 20

7- (4-Benzyloxyphenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (1.0 g), 4-benzyloxyphenol (1.14 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Chromatography on silica gel eluted with methanol / chloroform and treatment with ether hydrogen chloride followed by recrystallization from acetonitrile gave the title compound as white needles, (1.94 g), m.p. 173-174 ° C. Found: C 71.70; H 8.50; N, 3.38; Cl 8.26% (C ₂₅ H ₃₅ NO ₂ .HCl) calcd: C 71.83; H, 8.68; N, 3.35; Cl 8,48%

EXAMPLE 21

7- (4-Benzylphenoxy) -1-piperidino-hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (1.0 g), 4-benzylphenol (0.93 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Chromatography on silica gel eluted with methanol / dichloromethane and treatment with ether hydrogen chloride followed by recrystallization from ethyl acetate / methanol gave the title compound as a white solid, (1.94 g), m.p. 95-96 ° C.

Found: C 74.31; H, 8.71; N, 3.42; Cl 8.79% (C ^ H ^ NO.HCl) calcd: C 74.69; H, 9.03; N, 3.48; Cl 8,82%

EXAMPLE 22

7- (2-Benzylphenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (2.0 g), 2-benzylphenol (1.84 g), triphenylphosphine (2.62 g) and diethyl azodicarboxylate (1.74 g). Chromatography on silica gel eluted with methanol / dichloromethane and treatment with ether hydrogen chloride followed by recrystallization from ethyl acetate / methanol gave the title compound as a white solid (1.17 g), m.p. 118-120 ° C.

Found: C, 73.96; H, 8.80; N, 3.71; Cl 8.74% (C ₂₅ H ₃₅ NO.HC1.0.2 H10) calcd: C 74.02; H, 9.04; N, 3.45; Cl 8,74%

EXAMPLE 23

7- (4-Methoxyphenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (1.0 g), 4-methoxyphenol (0.62 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Chromatography on silica gel eluted with methanol / dichloromethane and treatment with ether hydrogen chloride followed by recrystallization from ethyl acetate / methanol gave the title compound as white needles, (1,143 g), m.p. 128-130 ° C.

Found: C, 66.71; H, 9.30; N, 4.15; Cl 10.37% (CjHHjjNOj.Ha) calcd: C 66.74; H, 9.43; N, 4.10; Cl 10,37%

EXAMPLE 24

7- (4-tert-Butylphenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (1.0 g), 4-tert-butylphenol (0.75 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g ). Chromatography on silica gel eluted with methanol / dichloromethane and treated with ether hydrogen chloride followed by recrystallization from methanol / ethyl acetate to give the title compound as a white solid (0.779 g), m.p. 170-171 ° C.

Found: C 71.69; H, 10.00; N, 3.88; Cl 9.57% (C ^ H ^ NO.HCl) calcd: C 71.80; H, 10.41; N, 3.81; Cl 9,63%

EXAMPLE 25

7- (3,4-methylenedioxyphenoxy) -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7-piperidinoheptanol (1.0 g), sesame oil (0.69 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Chromatography on silica gel eluted with methanol / chloroform and treated with ether hydrogen chloride followed by recrystallization from methanol / ethyl acetate to give the title compound as a white solid, (1.16 g), m.p. Mp 141-142 ° C.

Found: C, 63.94; H, 8.18; N, 3.99; Cl 10.38% (C ₁₉ H ₂₉ NO ₃ .Ha) calcd: C 64.11; H, 8.49; N, 3.93; Cl 9,96%

EXAMPLE 26

7- (4- (3,4-Dichlorobenzyloxy) phenoxy] -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 1, starting from 7- (4-hydroxyphenoxy) -1-piperidinoheptane (1.45 g), 3,4-dichlorobenzyl alcohol (1,885 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). The solvent was removed and the residue dissolved in dichloromethane. This solution was washed thoroughly with dilute hydrochloric acid, dried over sodium sulfate and evaporated. Chromatography on silica gel eluting with methanol / dichloromethane and recrystallization from ethanol to afford the title compound as a white solid (0.827 g), m.p. Mp 184-186 ° C.

Found: C, 61.62; H, 6.87; N, 2.98; Cl 21.75% (C ^ H ^ ClgNO ^ HCl) calcd: C 61.67; H, 7.04; N, 2.88; Cl 21,84%

EXAMPLE 27

7- [4- (4-Methoxybenzyloxy) phenoxy] -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 26, starting from 7- (4-hydroxyphenoxy) -1-piperidinoheptane (1.45 g), 4-methoxybenzyl alcohol (0.69 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Recrystallization from acetonitrile gave the title compound as a white crystalline solid (0.519 g), m.p. 172176 ° C.

Found: C, 69.20; H, 8.21; N, 3.23; Cl 7.73% (C ₂₆ H ₃₇ NO ₂ HCl. O ₃ .1H ₂ O) calcd: C 69.40; H, 8.51; N, 3.11; Cl 7,88%

EXAMPLE 28

7- [4- (4-Fluorobenzyloxy) phenoxy] -1-piperidinoheptane hydrochloride

The title compound was prepared in a similar manner to Example 26, starting from 7- (4-hydroxyphenoxy) -1-piperidino-heptane (1.45 g), 4-fluorobenzyl alcohol (0.63 g), triphenylphosphine (1.31 g) and diethyl azodicarboxylate (0.87 g). Recrystallization from acetonitrile gave the title compound as a white crystalline solid (0.782 g), m.p. 167168 ° C.

Found: C 68.37; H, 7.60; N, 3.29; Cl 8.09% (C ₂₅ H ₃₄ FNO ₂ .Ha.0, 1H ₂ O) calcd: C 68.58; H, 8.07; N, 3.20; Cl 8,10%

EXAMPLE 29

N- [7- (4-Benzfloxyphenoxy) heptyl] -2-methylpiperidine hydrochloride

A mixture of 7- (4-benzyloxyphenoxy) -1-bromoheptane (1.88 g), 80% sodium hydride (0.17 g) and dimethylformamide (10 ml) was stirred under nitrogen. 2-methylpiperidine (0.6 ml) was added with a syringe and the mixture was stirred at 60 ° C for 16 hours. The solution was treated with water and the solid collected and extracted with ether. The ether was evaporated, the residue was dissolved in dichloromethane, washed sequentially with water and dilute hydrochloric acid and then dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluted with dichloromethane-methanol and recrystallized from acetonitrile to give the title compound (0.66 g), m.p. 128-129 ° C.

Found: C, 72.08; H, 8.63; N, 3.25; Cl 8.09% (C ₂₆ H ₃₇ NO ₂ .HC1) calcd: C 72.28; H, 8.87; N, 3.24; Cl 8,21%

EXAMPLE 30

N- [7- (4-Benzyloxyphenoxy) heptyl] -3-methylpiperidine hydrochloride

The 2-methylpiperidines in Example 29 were replaced by 3-methylpiperidine and recrystallization of the product from acetonitrile gave the title compound (0.989 g) as a white crystalline solid. Tal. 161-163 ° C.

Found: C 72.20; H, 8.58; N, 3.20; Cl 8.30% (C ₂₆ H ₃₇ NO ₂ .HC1) calcd: C 72.28; H, 8.87; N, 3.24; Cl 8,21%

EXAMPLE 31

N- [7- (4-Benzyloxyphenoxy) heptyl] -4-methylpiperidine hydrochloride

The 2-methylpiperidine in Example 29 was replaced by 4-methylpiperidine and recrystallization of the product from acetonitrile gave the title compound (0.688 g) as a white crystalline solid. Tal. Mp 168-170 ° C.

Found: C 72.20; H, 8.67; N, 3.32; Cl 8.12% (C ₂₆ H ₃₇ NO ₂ .HC1) calcd: C 72.28; H, 8.87; N, 3.24; Cl 8,21%

EXAMPLE 32

N- [7- (4-benzyloxyphenoxy) heptyl] -2,6-dimethylpiperidine hydrochloride

The 2-methylpiperidine in Example 29 was replaced by 2,6-dimethylpiperidine and recrystallization from the ethyl acetate / methanol product gave the title compound (0.16 g) as a white crystalline solid. Tal. 127-128 ° C.

Found: C 71.13; H, 8.63; N, 3.22% (C H ^H OO OHClLOO O) calcd: C 71.26; H, 9.08; N 3.07%

EXAMPLE 33

N- [7- (4-Benzyloxyphenoxy) heptyl] -4-methoxypiperidine hydrobromide

A mixture of 1- [7- (4-benzyloxyphenoxy) heptyl] -4-methoxypyridmium bromide (2.0 g) and Adams catalyst (0.1 g) in ethanol (50 ml) was shaken under a hydrogen atmosphere at 344,738kPa for 24 hours. The mixture was filtered, the residue suspended in dichloromethane, filtered and the filtrate was evaporated. The residue was chromatographed on silica gel eluted with ethyl acetate / methanol and recrystallized from ethanol to give the title compound as a white crystalline solid (0.242 g), m.p. 140-144 ° C.

Found: C, 63.21; H, 7.56; N, 3.18; Br 15.95% (C ^ H ^ NOg.HBr) calcd: C 63.41; H, 7.78; N, 2.84; No 16.22%

EXAMPLE 34

5- (4-Benzyloxyphenoxy) -1-piperidinopentane hydrochloride

A mixture of 5- (4-benzyloxyphenoxy) -1-bromopentane (2.0 g), piperidine (0.43 g), potassium carbonate (0.8 g) and ethanol (50 ml) was stirred at reflux for 18 hours. The mixture was filtered and the residue was washed with ethanol. The filtrates were combined, the solvent removed and the residue partitioned between ether and dilute sodium hydroxide solution. The ether layer was separated, dried over magnesium sulfate, and the solvent removed to give an oil which was treated with ether hydrogen chloride. The solid was collected and recrystallized from ethyl acetate to give a solid, which was further recrystallized from water to give the title compound as a white solid (0.265 g), m.p. 202-204 ° C.

Found: C 68.23; H, 8.00; N, 3.72; Q 8.32% (C ^ NO ^ aO ^ HgO) calcd: C 68.46; H, 8.36; N, 3.46; Cl 8,78%

EXAMPLE 35

7- (4-Benzyloxyphenoxy) -1-piperidinoheptane hydrochloride

A solution of 7- (4-benzyloxyphenoxy) heptannitrile (0.1 g) in toluene (5 ml) under nitrogen was treated with disobutyl aluminum hydride in toluene (0.7 ml, 1.5 mol solution). The mixture was stirred for 16 hours and then piperidine (1 ml) was added. The mixture was stirred for 1 hour then methanol was added and the mixture was stirred for a further 1 hour. Water (1 ml) and sodium cyanoborohydride (1.0 g) were added and the mixture stirred for 3 hours and then poured into water and extracted with dichloromethane. The dichloromethane layer was washed with dilute hydrochloric acid, dried over sodium sulfate and the solvent removed to give a white solid (0.109 g) which was recrystallized to give the title compound as a white solid (0.03 g). The product was identical to the product of Example 8 (HPLC, TLC).

EXAMPLE 36

7- (4-Benzyloxyphenoxy) -1-piperidinoheptanemesylate

The product of Example 8 (1.0 g) was partitioned evenly between ethyl acetate and 0.5N NaOH. The aqueous fraction was re-extracted with ethyl acetate and the combined organic extracts were washed (HgO, brine), dried (anhydrous Na ₂ SO ₄ ) and evaporated to dryness to give a colorless oil. This oil was dissolved in methanol / ethyl acetate and methane sulfonic acid (0.23 g, one equivalent) in methanol was added. The mixture was concentrated and allowed to stand in the refrigerator overnight to give the title compound (0.86 g) as white crystals, m.p. Mp 146-148 ° C.

Found: C, 65.35; H, 7.92; N, 3.01% (C ^ H ^ NOg.CHgSOgH) calcd: C, 65.38; H, 8.23; N 2,93%

EXAMPLE 37

7- (4-Benzyloxyphenoxy) -1-piperidinoheptane tartrate

The product of Example 8 (1.0 g) was uniformly partitioned between dichloromethane and N NaOH. The aqueous fraction was re-extracted with dichloromethane (2 X) and the combined organic extracts were washed (HgO, brine), dried (MgSO ₄ ) and evaporated to dryness to give a colorless oil. This oil was dissolved in boiling methanol and (+) tartaric acid (0.36 g, 1 equivalent) in methanol was added. The mixture was concentrated, hot ethyl acetate was added and further concentrated to give a white crystalline solid (1.15 g). This material was first crystallized from methanol / ethyl acetate and finally from methanol / water to give the title compound (0.52 g) as a white crystalline solid, m.p. 83-84 ° C.

EXAMPLE 38

7- (4-Benzyloxyphenoxy) -1-piperidinoheptane oxalate

A mixture of 7- (4-benzyloxyphenoxy) -1-bromoheptane (1.0 g), piperidine (0.25 g), potassium carbonate (2.00 g) and ethanol (25 ml) was stirred at reflux for 48 hours. The mixture was filtered and the residue was washed with ethanol. The filtrates were combined, the solvent removed and the residue partitioned between dichloromethane and dilute sodium hydroxide solution. The dichloromethane layer was separated, dried over magnesium sulfate and the solvent removed to give an oil which was treated with oxalic acid in methanol / ethyl acetate. The resulting solid was recrystallized from ethyl acetate / methanol to give the title compound (0.49 g) m.p. 161-163 ° C.

found: C 67.67; H, 7.73; N, 3.24;

(C ₂₅ H ₃₅ NO _2. C ₂ H ₂ O ₄ .0.5 E ^ O) calcd: C 67.47; H, 7.97; N 2.91%

Pharmaceutical preparations

The following represent typical pharmaceutical compositions of the present invention that can be prepared using standard procedures.

IV infusion of compounds of formula (I) solvent / complexation buffer

A bolus injection of a compound of formula (I) is a buffer co-solvent

1-40 mg to pH approx. 7 to 100 ml

1-40 mg to pH approx. 7 to 5 ml

Buffer: Suitable buffers include citrate, phosphate, sodium hydroxide / hydrochloric acid

Solvent: Typically water, but may include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.

Tablet Ssoyina 1-40 mg thinner / filler * 50-250 mg binder 5-25 mg disintegrant * 5-50 mg lubricant 1-5 mg cyclodextrin 1-100 mg

* may also include cyclodextrins

Thinner: e.g. microcrystalline cellulose, lactose, starch Binder: e.g. polyvinylpyrrolidone, hydroxypropylmethylcellulose

Disintegrant: e.g. sodium starch glycolate, crospovidone

Oral suspension compound 1-40 mg suspend the asset 0.1-10 mg thinner 20-60 mg preservative 0.01-1.0 mg buffer to a pH of approx. 5-8 co-solvent 0-40 mg aroma 0.01-1.0 mg dye 0.001-0.1 mg Suspend the asset: e.g. xanthan gum, microcrystalline cellulose Thinner: 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

For

SMITHKLINE BEECHAM pic:

. · ^Y and iU'-Λ

PATENT APPLICATIONS

Claims (17)

PATENT APPLICATIONS Use of a compound of formula (I): (R). (CH,) _n N- (CH ₂ ) _q -X-Ar formula (I) wherein n is 3 to 8; q is 5 to 11; R ¹ represents C 1-6 alkyl or C 1-4 alkoxy; s is zero, 1 or 2; X represents oxygen or sulfur; and Ar represents phenyl optionally substituted by 1-3 substituents selected from halo, C 1-6 alkyl, C 1-4 alkoxy, C ₁₂ alkylenedioxy, trifluoromethyl, trifluoromethyloxy, or the group Ph- (CH ₂ ) _m -Y- (CH ₂ ) _p - wherein Ph is optionally substituted phenyl, m and p are independently 0 to 4 and Y is a bond, O, S or CH = CH, provided that m + p is not greater than 4, or Ar is in the given case substituted tricyclic heteroaryl group: in which Υ is ¹ Y (CH ₂ ) _x , where x is 0 or 1 and YO, S or NR, where R is hydrogen or C _M alkyl, Z is (CH ₂ ) _r or -CH = CH-, r is 0 , 1 or 2, whether Ar is a suitable tricyclic dehydro ring system, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of conditions associated with calcium accumulation in mammalian brain cells. Use of a compound according to claim 1, wherein n is 4 to 6. Use of a compound according to claim 1 or 2, characterized in that q is 6 to 9. Use of a compound according to any one of claims 1 to 3, characterized in that it is 0. Use of a compound according to any one of claims 1 to 4, characterized in that X represents oxygen. Use of a compound according to any one of claims 1 to 5, characterized in that Ar is phenyl mono-substituted with phenoxy, benzyl, benzyloxy or halo; phenyl disubstituted by halo but Ar is 2-dibenzofuranyl. Use of a compound according to claim 1, wherein n is 3 to 8; q is 5 to 11; X is oxygen or sulfur; s is 0 and Ar is phenyl optionally substituted by 1-3 substituents selected from halo, C 1-6 alkyl, trifluoromethyl, trifluoromethyloxy or a group Ph- (CH ₂ ) _m -Y- (CH ₂ ) _p -, where Ph optionally substituted phenyl, m and p are independently 0 to 4 and Y is a bond, O or S, provided that m + p is not greater than 4, or Ar is optionally substituted tricyclic heteroaryl group: in which Υ ^{1 is} Y (CH ₂ ) _t , where x is 0 or 1 and YO, S or NR, where R is hydrogen or CMalkyl, Z is or -CH = CH-, r is 0,1 or 2, or Ar is a suitable tricyclic dehydro ring system, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of conditions associated with calcium accumulation in mammalian brain cells. Use according to claim 1 of a compound selected from the group consisting of: 7-phenoxy-1-piperidinoheptane, 7- (4-fluorophenoxy) -1-piperidinoheptane, 7- (2,4-dichlorophenoxy) -1-piperidinoheptane, 7- (3,4-dichlorophenoxy) -1-piperidinoheptane, 7- (4-phenoxyphenoxy) -1-piperidinoheptane, 7- (3-phenoxyphenoxy) -1-piperidinoheptane, 7- (2-dibenzofuranyloxy) -1-piperidinoheptane, 7- (4-benzyloxyphenoxy) -1-piperidinoheptane, 7- (4-benzyloxyphenoxy) -1-pyrrolidinoheptane, N- [7- (4-Benzyloxyphenoxy) heptyl] -hexamethylenimine, 6- (3,4-dichlorophenoxy) -1-piperidinohexane, 9- (3,4-dichlorophenoxy) -1-piperidinoneone, 9- (4-benzyloxyphenoxy) -1-piperidinoneone, 8- (4-benzyloxyphenoxy) -1-piperidino-octane, 8- (4-phenoxyphenoxy) -1-piperidino-octane, 6- (4-benzyloxyphenoxy) -1-piperidinohexane, 7- {4- [2- (4-chlorophenyl) ethyl] phenoxy} -1-piperidinoheptane, trans-7- [4- (2-phenylethenyl) phenoxy] -1-piperidinoheptane, 7- [4- (2-phenylethyl) phenoxy] -1-piperidinoheptane, 7- (4-benzylphenoxy) -1-piperidinoheptane, 7- (2-benzylphenoxy) -1-piperidinoheptane, 7- (4-methoxyphenoxy) -1 -piperidinoheptane, 7- (4-tert-butylphenoxy) -1-piperidinoheptane, 7- (3,4-methylenedioxyphenoxy) -1-piperidinoheptane, 7- [4- (3,4-dichlorobenzyloxy) phenoxy] -1-piperidinoheptane, 7- [4- (4-methoxybenzyloxy) phenoxy] -1-piperidinoheptane, 7- [4- (4-fluorobenzyloxy) phenoxy] -1-piperidinoheptane, N- [7- (4-benzyloxyphenoxy) heptyl] -2-methylpiperidine , N- [7- (4-benzyloxyphenoxy) heptyl] -3-methylpiperidine, N- [7- (4-benzyloxyphenoxy) heptyl] -4-methylpiperidine, N- [7- (4-benzyloxyphenoxy) heptyl] -2, 6-dimethylpiperidine, N- [7- (4-benzyloxyphenoxy) heptyl] -4-methoxypiperidine, or 5- (4-benzyloxyphenoxy) -1-piperidinopentane, or a pharmaceutically acceptable salt thereof. A compound of formula (IA) (R). N- (CH ₂ ) _q -X-Ar formula (IA) wherein n, q, R ¹ , s and X are as defined for formula (I) and Ar ¹ is optionally substituted tricyclic heteroaryl group as defined for formula (I); or its salt. 10. A compound of formula (ΙΒ): (CH ₂ ) _n N- (CH ₂ ) ₇ XAr formula (IB) wherein R ¹ , s, n and X are as defined for formula (I) and Ar ² represents phenyl optionally substituted by the group Ph- (CH ₂ ) _m Y (CH ₂ ) _p - or tricyclic heteroaryl group as defined for formula (I), or a salt thereof. A compound of formula (IB) according to claim 10, characterized in that Ar ² represents phenyl optionally substituted by the group Ph- (CH ₂ ) _m -Y (CH ₂ ) _p - as defined in formula ( I). A compound of formula (IB) according to claim 10 or claim 11, wherein it is zero. 13. A compound selected from the group consisting of: 7-phenoxy-1-piperidinoheptane, 7- (4-fluorophenoxy) -1-piperidinoheptane, 7- (2,4-dichlorophenoxy) -1-piperidinoheptane, 7- (4-phenoxyphenoxy) -1-piperidinoheptane, 7- (3-phenoxyphenoxy) -1-piperidinoheptane, 7- (2-dibenzofuranyloxy) -1-piperidinoheptane, 7- (4-benzyloxyphenoxy) -1-piperidinoheptane, 7- (4-benzyloxyphenoxy) -1-pyrrolidinoheptane, N- [7- (4-benzyloxyphenoxy) heptyl] -hexamethylenimine, 9- (3,4-dichlorophenoxy) -1-piperidinoneone, 9- (4-benzyloxyphenoxy) -1-piperidinoneone, 8- (4-benzyloxyphenoxy) -1-piperidino-octane, 8- (4-phenoxyphenoxy) -1-piperidino-octane, 6- (4-benzyloxyphenoxy) -1-piperidinohexane, 7- {4- [2- (4-chlorophenyl) ethyl] phenoxy} -1-piperidinoheptane, trans-7- [4- (2-phenylethenyl) phenoxy] -1-piperidinoheptane, 7- [4- (2-phenylethyl) phenoxy] -1-piperidinoheptane, 7- (4-benzylphenoxy) -1-piperidinoheptane, 7- (2-benzylphenoxy) -1-piperidinoheptane, 7- (4-methoxyphenoxy) -1-piperidinoheptane, 7- (4-tert-butylphenoxy) -1-piperidinoheptane, 7- (3,4-methylenedioxyphenoxy) -1-piperidinoheptane, 7- [4- (3,4-Dichlorobenzyloxy) phenoxy] -1-piperidinoheptane, 7- [4- (4-methoxybenzyloxy) phenoxy] -1-piperidinoheptane, 7- [4- (4-fluorobenzyloxy) phenoxy] -1-piperidinoheptane, N- [7- (4-Benzyloxyphenoxy) heptyl] -2-methylpiperidine, N- [7- (4-Benzyloxyphenoxy) heptyl] -3-methylpiperidine, N- [7- (4-Benzyloxyphenoxy) heptyl] -4-methylpiperidine, N- [7- (4-Benzyloxyphenoxy) heptyl] -2,6-dimethylpiperidine, N- [7- (4-Benzyloxyphenoxy) heptyl] -4-methoxypiperidine, or 5- (4-Benzyloxyphenoxy) -1-piperidinopentane, or salts thereof. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 9 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition for use in the treatment of conditions related to calcium accumulation in mammalian brain cells, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. A process for the preparation of a compound of formula (I) as defined in any one of claims 9 to 13, characterized in that it includes: (a) metabolizing a compound of formula (II) (R ¹ ), (CH ₂ ) n N- (CH ₂ ) -L formula (II) in which n, R ¹ , s and q are as defined in formula (IA ) and the L ¹ group is a nucleophile interchangeable group with a compound of formula (III): Ar ³ -XH formula (III) wherein X is as defined in formula (IA) and Ar ³ represents Ar ¹ when Q is as defined in formula (IA), or Ar ² when q is 7; (b) metabolizing a compound of formula (IV): AA ^ CH ^ -L ² formula (IV) in which X and q are as defined for formula (IA), Ar ^{3 is} as defined for formula (III) and L ^{2 is a} leaving group, with a compound of formula (V ): <CH ₂ ) 'NH formula (V) wherein n, R ¹ and s are as defined in formula (IA); or (c) reduction of an amide of formula (VI) or (VII): <(R). f — Λ N- (CH ₂ ) _q XAr ³ formula (VI) / R). O (CH ₂ ) n Ν-ίχΟΗ ^ ΧΑτ formula (VII) wherein R ¹ , s, n, q, X and Ar ^{3 are the} angles defined above; (d) reductive amination of an aldehyde of formula (VIII): OHC (CH _{2) q4} XAr ^{3 of} formula (VIII) wherein q, X and Ar ³ are as hereinbefore defined, in the presence of a compound of formula (V) as defined above, (e) for preparing compounds wherein Ar ³ represents phenyl substituted by Ph (CH ₂ ) _m O-, alkylation of a compound of formula (IX): wherein R ¹ , s, n, q and X are as defined in yarn; with an alkylating agent of formula (X): PhtCHjV? Formula (X) wherein Ph, m and ^L1 are as hereinbefore defined; (f) for the preparation of a compound wherein n is 5, reduction of a pyridine derivative of formula (XI): © N— (CH ₂ ) „XAr ³ Αθ formula (XI) wherein R ¹ , s, q, X and Ar ^{3 are} as defined in the yarn and A 'against the anion; (g) the internal conversion of one compound of formula (I) into another compound of formula (I) e.g. reduction of a compound where Y represents CH = CH to a compound where Y represents followed by, if desired, salt formation. 17. A new intermediate of formula (II), (IV), (VI), (IX) or (XI).