JPH10500967A - Phenoxyalkyl-substituted piperidines, pyrrolidines, morpholines and thiomorpholines as calcium channel antagonists - Google Patents

Abstract

(57) [Summary] Formula (I): [Wherein, W is-(CH ₂ ) ₄ ,-(CH ₂ ) ₅ ,-(CH ₂ ) ₂ O (CH ₂ ) ₂ or-(CH ₂ ) ₂ S (CH ₂ ) ₂ ; 6; m to 0 not 3; A is a bond, -CH = CH -, - C≡C- , oxygen, sulfur or NR ^1; R ¹ is hydrogen, C _{1 to 8} alkyl or phenyl C _{1 to 4} alkyl Ar is a group (a): (Wherein, X is -SO ₂ - or -C (CH _{3) 2} - a and, Y and Z each represents hydrogen, fluorine, chlorine, bromine, C _{1 to 4} alkyl, C _{1 to 4} alkoxy or trifluoromethyl Or a salt thereof is a calcium channel antagonist having activity in neurons, and is useful for treating symptoms such as ischemic stroke.

Description

DETAILED DESCRIPTION OF THE INVENTION Phenoxyalkyl-substituted piperidines as calcium channel antagonists , Pyrrolidine, morpholine and thiomorpholine   The present invention relates to a cyclic secondary amine derivative, a method for producing the same, and a medicament containing them. It relates to pharmaceutical compositions and their use in therapy.   Our International Applications WO92 / 02501, WO92 / 02502, WO92 / 2 In 2527 and WO 93/15052, we identified various intermediates as intermediates. Disclosed are cyclic secondary amine derivatives, comprising calcium channel antagonists Their use as described in our international application WO 94/13291. We have now shown a therapeutic activity that is particularly useful as a calcium channel antagonist A small group of related novel compounds was found.   Therefore, the present invention provides, in a first aspect, a compound of formula (I): Wherein W is-(CH_Two)_Four,-(CH_Two)_Five,-(CH_Two)_TwoO (CH_Two)_TwoOr-(CH_Two)_Two S (CH_Two)_Two;   n is 0 to 6;   m is 0 to 3;   A is a bond, -CH = CH-, -C≡C-, oxygen, sulfur or NR¹;   R¹Is hydrogen, C_{1 ~ 8}Alkyl or phenyl C_{1 ~Four}Alkyl;   Ar is a group: (Where X is -SO_Two-Or -C (CH_Three)_TwoAnd Y and Z are each water Element, fluorine, chlorine, bromine, C_{1 ~Four}Alkyl, C_{1 ~Four}Alkoxy or trifluoro Lomethyl) Means Or a salt thereof.   Compounds similar to the compounds of formula (I) wherein Ar is various substituted phenyl groups are described above. Nothing is known from the patent application but has a special Ar group as defined above. The compounds of the invention of the formula (I) therefore represent a novel selection from the prior art.   Compounds of formula (I) and their pharmaceutically acceptable salts can be used, for example, It may be used in the treatment of diseases requiring a channel antagonist, The use of objects forms an important aspect of the present invention.   In the compounds of formula (I), preferably, W is (CH_Two)_FourOr (CH_Two)_FiveIs .   Group-(CH_Two)_nA (CH_Two)_mAr may be substituted on any carbon atom of the ring No. W is (CH_Two)_FourOr (CH_Two)_FiveIf preferred, the substituent is a ring nitrogen. It is α-position to the elementary atom.   The values of n and m and A are the chains (CH_Two)_nA (CH_Two)_mContains at least one atom Should be selected as follows. Generally, the chain-(CH_Two)_nA (CH_Two)_mLength is not 2 And 6 atoms. Preferred values for n and m depend on group A. Hide For example, when A is oxygen, the sum of n + m is 1 to 5, for example, For example, n may be 1 or preferably 2, and m may be zero.   Preferably, A is oxygen or a bond, most preferably oxygen.   Preferably, W is-(CH_Two)_FiveAnd a substituent-(CH_Two)_nA (CH_Two)_mAr is a ring Is α-position to the nitrogen atom. In a preferred class of compounds, A is oxygen Where n is 1 or 2 and m is zero.   A particularly preferred group of compounds of the present invention is represented by formula (IA): Wherein X, Y and Z are as defined above for formula (I), and n is 1 or Is 2. Or a salt thereof.   In the compounds of the formulas (I) and (IA), preferably the group: Is-(CH_Two)_nA (CH_Two)_m4-position to the group.   Preferably, Y is fluoro or chloro and Z is hydrogen or Y And Z are both hydrogen. When Y is fluoro or chloro, it is X 4-position to the group.   The alkyl group present on the compounds of the formula (I) may be on its own or one of the other groups. The part may be linear or branched. Thus, C_{1 ~ 6}Alkyl The groups are, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n -Hexyl or iso-propyl, tert-butyl or sec-pliers And any of the branched isomers thereof, such as   Base: May optionally be as described in co-pending international application PCT / EP93 / 03473. Optionally substituted phenyl C_{1 ~Four}Understood to be a special case of alkyl compounds Let's do it.   W is-(CH_Two)_FiveAnd the group-(CH_Two)_nA (CH_Two)_mAr to piperidine nitrogen Compounds of formula (I) which are in the α-position are particularly preferred. Preferably, A is oxygen and n is 1 or more. Or 2, m is zero.   Particular compounds according to the invention are:   (±) 2- [2- {4- (4-fluorophenylsulfone) phenoxy} ethyl Le] piperidine,   (±) 2- [2- (4- {1-methyl-1- (4-fluorophenyl) ethyl] {Phenoxy) ethyl] piperidine,   (±) 2- [2- {4- (3-fluorophenylsulfone) phenoxy} ethyl Le] piperidine,   (±) 2- [2- (4- {1-methyl-1- (3-fluorophenyl) ethyl] {Phenoxy) ethyl] piperidine,   (±) 2- [2- {4- (4-chlorophenylsulfone) phenoxy} ethyl ] Piperidine,   (±) 2- [2- (4- {1-methyl-1- (4-chlorophenyl) ethyl} Phenoxy) ethyl] piperidine,   (±) 2- [2- {4- (phenylsulfone) phenoxy} ethyl] piperidi ,   (±) 2- [2- (4- {1-methyl-1-phenylethyl} phenoxy) e Chill] piperidine And their salts.   The compounds of the present invention have relatively simple pharmacokinetic characteristics and long-lasting in vivo. It is believed that it will have a duration. Furthermore, the compound of the present invention is effective against metabolic degradation. The present invention is believed to be particularly advantageous because it is resistant. Also, the compound of the present invention Are characterized by having improved solubility.   For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable. It will be understood that it should be. Examples of pharmaceutically acceptable salts are hydrochloride, bromide water Phosphate, sulfate, phosphate, acetate, fumarate, malate, citrate, milk Inorganic and organic acid addition salts such as acid, tartrate, methanesulfonate And pharmaceutically acceptable inorganic or organic acid addition salts. Other pharmaceutically acceptable Unreacted salts, for example oxalates, may be used for the isolation of the final product, Included within the scope.   It is understood that compounds of formula (I) may contain one or more asymmetric carbons. Like. Such compounds will exist as optical isomers (enantiomers). Pure enantiomer, racemic (50% of each enantiomer) and two Mixtures that are not in the same proportion of are both included within the scope of the present invention. Plus, everything Possible diastereomeric forms (pure enantiomers and their mixtures) Are within the scope of the present invention. Further, when A is -CH = CH-, What isomers exist and the present invention relates to all such isomers and their And mixtures thereof.   Methods similar to those known in the art, for example, WO92 / 02501 WO92 / 02502, WO92 / 22527 and WO93 / 15052 The compounds of the invention can be prepared by the general methods described. Thus, the present invention A further further aspect is a method of making a compound of formula (I), wherein (A) A is O, S or NR¹For compounds of formula (I) that are: Wherein W and n are the same as described for formula (I);¹Is O, S or NR¹, R^FourRepresents an N-protecting group] And a compound of formula L (CH_Two)_mAr [wherein, m and Ar represent formula (I) And L represents a leaving group]. ; (B) A is O, S or NR¹For compounds of formula (I) that are: Wherein W, n and R^FourIs the same as described above, and L¹Is replaced by a nucleophilic group Means a group that can be replaced] And a compound represented by the formula HA¹(CH_Two)_mAr [where m and Ar represent the formula (I) Is the same as described for¹Is the same as described for equation (II).] Reaction with the indicated compound; (C) A is NR¹For compounds of formula (I) that are: [Wherein, R^FiveIs a group-(CH_Two)_nN (R¹) C (O) (CH_Two)_m-1Ar or-(CH_Two)_n-1C (O) N (R¹) (CH_Two)_mAr and R^4aIs hydrogen or an N-protecting group; W, n , M and Ar are the same as described above] Reduction of the compound represented by (D) For compounds of formula (I) wherein A is a bond, formula (V): [Where W, R^Four, L¹, M and n are the same as defined above] And a compound of formula X¹Ar [Ar is the same as described with respect to formula (I) Yes, X¹Represents an alkali metal] with a compound represented by the formula: (E) W is (CH_Two)_FiveAnd A is O, S, NR¹Or for compounds that are And the formula (VI): Wherein A, Ar, m and n are the same as defined above;^4aIs hydrogen or N-protecting group And X- means a counter ion. Reduction of the compound represented by (F) For compounds where A is -CH = CH-, formula (VII): [Where W, R^FourAnd n are the same as defined above. And a group (CH_Two)_mReaction with a reagent that serves to introduce Ar; (G) interconversion of one compound of formula (I) into another compound of formula (I), for example -(CH) of the compound in which A is -CH = CH-_Two)_nA (CH_Two)_m-Is part -CH_Two -CH_TwoReduction to a compound comprising- Then, if necessary, the N-protecting group R^FourRemoval, followed by salt formation if desired. When Providing a method comprising:   In process (a), a compound of formula (II) and a compound L (CH_Two)_mBetween Ar The reaction can take place under conditions depending on the nature of the group L and the value of m. For example, m In the case of b, preferably, the compound of the formula (II) reacts with the compound F-Ar As such, L is fluoro. Preferably, the presence of a strong base such as sodium hydride In the presence of inert organics such as dimethylsulfoxide or dimethylformamide The reaction is performed in a solvent. L is halogen, tosylate or mesylate If m is other than zero, a base may be present if desired. The reaction is performed under standard conditions in a solvent that may be used.   Compound of formula (III) and formula HA¹(CH_Two)_mThe reaction with Ar (process b) is¹ And A¹Can be carried out under conditions according to the properties of For example, L¹Is hydroxy A, m is O, A¹Azodicarboxy when is oxygen or sulfur The reaction is carried out in the presence of diethyl phosphate and triphenylphosphine. Such a reaction Is known as the Mitsunobu reaction (Synthesis, 1981, p. 1). Alternatively, the leaving group L¹Is, for example, a halogen atom Or a sulfonyloxy group such as methanesulfonyloxy or p-toluene It may be sulfonyloxy. In this case, in the presence or absence of a solvent, The reaction may be carried out at a temperature ranging from 0 to 200 ° C.   Reduction of compounds of formula (IV) by process (c) is known in the art. Method, for example, using a reducing agent such as lithium aluminum hydride. it can. Conventionally, a compound of formula (IV) is synthesized and compound (IV) itself is isolated. It can be reduced in a "one-pot" reaction.   A compound of formula (V) in process (d) and a compound of formula X¹Reaction of Ar with compound , Under standard conditions known to those skilled in the art to form carbon-carbon bonds. When Can be.   Suitably in a solvent such as an alcohol, for example ethanol, for example, platinum, Process (e) by hydrogenation using a noble metal catalyst such as radium or platinum oxide ) May be used to reduce the compound of formula (VI).   Formulas such as diethylphosphonate Ar (CH_Two)_{m + 1}P (O) (OAlk)_TwoIndicated by Commercially available using Wadsworth-Emmons reagent or Of the formula Ar (CH_Two)_{m + 1}PPh_ThreeX- (here X- is an anion) using a Wittig reagent represented by the following formula: f) may be performed. 15-crown-5 or 18-crown-6 as desired Solvents such as tetrahydrofuran which may contain Clownether In a strong base such as sodium or potassium tert-butoxide The reaction may be performed in the presence.   The interconversion reaction of the process (g) is performed by a method well known in the art. You may go more. Thus, for example, of a compound wherein A is -CH = CH-, (CH_Two)_nA (CH_Two)_m-Is part -CH_Two-CH_TwoConversion to compounds containing- Alternatively, the reduction may be performed.   Protecting group R^FourIs a lower alkyl group such as methyl; benzyl, diphenylmethyl Or an aralkyl group such as triphenylmethyl; and acetyl, trifluoro Roacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert -Includes acyl groups such as butoxycarbonyl or benzyloxycarbonyl I do. In process (e), preferably, the protecting group R^4aIs an alkyl, e.g. Tyl or aralkyl such as benzyl. Such groups are known in the art. It may be removed by well-known methods. 1-chloromethyl chloroformate Alkyl groups such as methyl by treatment with haloalkyl haloformates May be removed by cleavage of an aralkyl group such as a benzyl group by hydrogenolysis. And an acyl group such as benzoyl may be cleaved by hydrolysis. the above Any of compounds (II) to (VII) and the following compound (VIII) Good protecting group R^FourOr R^4aSelect whether it will not be cleaved, or The object participates in any of the reactions intended to participate, and And that its removal does not adversely affect other groups or residues present in the molecule. Should be. Such factors can be easily ascertained by those skilled in the art, The protecting group will be readily apparent to one.   R^FourIs hydrogen from a corresponding compound of formula (I) by methods well known in the art. The compound of I) can be produced. For example, acid chloride or anhydride A suitable acid derivative, or for example di-tert-butyl dicarbonate or Reaction with activated esters such as haloformate such as ethyl chloroformate In response, an acyl group may be introduced.   R^FourThe corresponding compound of formula (II) wherein is hydrogen is commercially available and is known in the literature Or by standard methods, for example, the corresponding hydroxyalkyl-pyri It can be produced by reduction of gin.   Alternatively, A¹Is a compound of formula (II) wherein is oxygen [Where W, R^FourAnd n are the same as described above. Can be produced by reduction of the compound represented by In this example, R^FourIs , Should be a group such as an alkyl that is not cleaved by a reduction reaction.   L¹The compound of formula (III) wherein is OH has been described with respect to the compound of formula (II) Can be manufactured as L¹Is a halogen atom or mesyloxy or tosyl The compound of formula (III), which is an oxy group, is converted in a conventional manner to the corresponding alcohol. Can be manufactured from   A¹Is NR¹Is converted to a group-(CH_Two)_mAcylation corresponding to Ar Agents such as the acid chloride ClOC (CH_Two)_m-1By reacting with Ar, R^FiveIs based − (CH_Two)_nN (R¹) C (O) (CH_Two)_m-1Producing a compound of formula (IV) which is Ar Can be.   For example, R^FiveIs-(CH_Two)_n-1CO_TwoA corresponding compound or acid halide which is H, An ester or a derivative thereof such as an anhydride and a compound of the formula HN (R₁) (CH_Two)_mIndicated by Ar Reaction with an amine^FiveIs a group-(CH_Two)_n-1C (O) N (R¹) (CH_Two)_mIn Ar Certain compounds of formula (IV) may be prepared. When using the acid itself, a coupling agent The reaction with the amine should be carried out in the presence of For example, the corresponding alcohol, Chi, A¹Wherein the carboxylic acid itself is produced by oxidation of a compound of formula (II) wherein Is also good.   The compound of formula (V) may be prepared in an analogous manner to the compound of formula (III). necessary In such cases, the chain length may be increased using methods well known in the art. .   The compound of (VI) is synthesized using the general method described in the above processes (a) to (d). Things may be manufactured.   Conventional methods, such as A¹By oxidation of a compound of formula (II) wherein is oxygen Or thionyl chloride and N, O-dimethylhydroxylamine hydrochloride The corresponding ester is converted to N-methyl-N-methoxycarboxamide by reaction. (Which can be reduced to aldehyde using diisobutylaluminum hydride) By obtaining, a compound of formula (VII) may be prepared. Formula (VII) wherein n is 1 May be prepared by various methods from the corresponding compound wherein n is zero. For example, an aldehyde where n is zero is converted to (methoxymethyl) triphenylphosphonium. Treatment with muchloride and potassium t-butoxide, followed by a strong acid such as concentrated sulfuric acid Treatment with an acid may give an aldehyde wherein n is 1. Alternatively, EPA 36 The aldehyde is converted to the corresponding cyanomethyl derivative as described in 3085, and then , Acid hydrolysis to convert to N-methyl-N-methoxycarboxamide, No, it may be reduced. Higher homologs may be formed using these procedures. No.   When the compound of formula (I) is obtained as an enantiomeric mixture, Crystallization at, or chromatography, for example using a chiral HPLC column These may be separated by a conventional method. A suitable resolving reagent is R- Includes optically active acids such as (-)-or S-(+)-mendelic acid. Alternative As a mixture of an enantiomeric mixture of formula (I) with a reactive derivative such as an acid chloride Reacts with optically active reagents such as S (+)-α-methoxyphenylacetic acid in form May produce a diastereomeric amide mixture. Amide The mixture is separated by conventional methods and then converted to the resolving amine by hydrolysis. You may.   Ischemic diseases, such as seizures, disrupt the blood supply to the brain and deprive the brain of essential oxygen. U. After all, the so-called Voltage Operated Calcium Channels ( Voltage Operated Calcium Channels (VOCCs) mediated brain cells Biolon, which allows calcium ions to enter the cell and causes cell death. A cascade of reactions follows. Drugs that block such calcium influx can cause cell death It is believed that minimization would thereby increase resilience.   The compounds of formula (I) have, for example, a high calcium influx blocking activity in neurons. It was found to show. Such compounds can be found in mammalian, particularly human, brain cells. Useful in therapies to treat symptoms and diseases associated with calcium accumulation in Is expected. For example, the compounds may be used, for example, in stroke, hypoxia, and external It is expected to be useful in the treatment of ischemia, including traumatic head injury. They are migraines For visceral pain, epilepsy, AIDS-related dementia, Alzheimer's disease and aging Treatment of neurodegenerative diseases and mood disorders such as memory impairment and ethanol addiction It may also be useful for escape from drug addiction, such as the escape of a drug.   Therefore, in a further embodiment of the present invention, calcium in mammalian brain cells is Associated with (or caused or exacerbated by) A method of treating a condition or disease, comprising administering to a subject in need of treatment an effective amount of a formula ( Providing a method comprising administering a compound of I) or a pharmaceutically acceptable salt thereof. Is done. Thus, for example, the invention relates to a method for treating seizures, hypoxia or traumatic heads, for example. A method for treating ischemia, including injury, comprising administering to a subject in need of treatment an effective amount of a formula ( Providing a method comprising administering a compound of I) or a pharmaceutically acceptable salt thereof. I do. The present invention also relates to migraine, visceral pain, epilepsy, AIDS-related dementia, Rutuja Treatment of neurodegenerative diseases and mood diseases such as Immer's disease and memory impairment due to aging. And escape from drug indulgence such as escape from ethanol indulgence. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a subject in need of treatment A method comprising administering   The present invention also relates to conditions associated with calcium accumulation in mammalian brain cells. Or a compound of formula (I) or a medicament thereof in the manufacture of a medicament for the treatment of a disease. Provide use of acceptable salts.   Preferably, the compounds of the invention will be useful in treating ischemic stroke.   For use in medicine, the compounds of the present invention will usually be used as standard pharmaceutical compositions. Administration. Therefore, the present invention relates in a further aspect to compounds of the formula (I) Or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. Pharmaceutical compositions are provided.   The compounds of the present invention can be prepared by any conventional method, for example, orally, parenterally, May be administered rectally or transdermally, and the pharmaceutical composition may be adapted accordingly. You. Compounds of formula (I) active when administered orally and their pharmaceutically acceptable The salt to be incorporated can be a liquid or solid, such as a syrup, suspension or emulsion. , Tablets, capsules and sweetened tablets.   Generally, the liquid formulation will be a suitable liquid carrier such as ethanol, glycerin , Non-aqueous solvents (eg, polyethylene glycol, oils and fats), or suspending agents, preservatives, Of a compound of the present invention or a pharmaceutically acceptable salt in water containing coloring or coloring agents. Consists of a suspension or solution.   Any suitable pharmaceutical carrier routinely used for preparing solid formulations may be used. Thus, a composition in the form of a tablet can be prepared. An example of such a carrier is stearin Includes magnesium acid, starch, lactose, sucrose and cellulose.   Preparation of compositions in capsule form using conventional encapsulation methods be able to. For example, a pellet containing the active ingredient is produced using a standard carrier. Can be made and then filled into hard gelatin capsules. Alternatively, Any suitable pharmaceutically acceptable carrier, such as aqueous rubber, cellulose, silica A dispersion or suspension is made with the aid of a dispersion or suspension and then dispersed or suspended. The suspension can be filled into soft gelatin capsules.   The compounds of the invention may be administered parenterally by bolus injection or continuous infusion. . A typical parenteral composition is a sterile aqueous carrier or parenterally acceptable fat or oil. For example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanuts Solution or suspension of a compound of the present invention or a pharmaceutically acceptable salt in oil or sesame oil Consists of Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent just prior to administration. Can be ex.   Both liquid and solid compositions contain other excipients known in the pharmaceutical arts, For example, solubles such as cyclodextrin or Cremophor An agent may be contained.   Preferably, the composition is in unit dosage form, such as a tablet, capsule or ampoule. It is.   Each dose for oral administration is preferably 1 to 250 mg (parenteral administration). Preferably from 0.1 to 60 mg) of a compound of formula (I) or a medicament thereof Contains the above acceptable salts (calculated on a free base basis).   The daily dosage regimen for adult patients is that of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, 1 mg to 500 mg, preferably Preferably an oral dose between 1 mg and 250 mg, for example between 5 and 200 mg, Alternatively, 0.1 mg to 100 mg, preferably 0.1 to 60 mg, for example, It may be an intravenous, subcutaneous or intramuscular dose of between 1 and 40 mg, wherein the compound is Administer 1 to 4 times a day. Alternatively, the compounds of the present invention can be administered by continuous intravenous infusion. It may be administered, preferably in dosages up to 400 mg daily. Thus, the sutra The total daily dose by oral administration may range from 1 to 2000 mg, parenteral The total daily dose due to administration will be in the range of 0.1 to 400 mg. Appropriately Administering the compound for a continuous treatment period, for example for a week or more It shall be.   If desired, one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof can be used. If more therapeutic agents are present, such as anistreplase, streptokinase Thrombolytic agents such as tissue plasminogen activator; NMDA antagonis Stimulant amino acid antagonists such as It may be administered in combination or simultaneously with a pine inhibitor. Biological data   Dorsal nerves as described in WO 92/02501 and WO 92/02502 Nodal root-derived sensory neurons or cranial nerves as described in WO 95/04027 Ca preparation using sensory neuron cell preparation from cervical ganglion²⁺Flow in vivo Can be measured. result   Certain compounds of the present invention can be used to test compounds in SCG (head cervical ganglia) preparations. When the concentration is 5 μM, the plateau Ca is in the range of 40 to 90%.²⁺Flow inhibition was indicated. Pharmaceutical prescription   Typical pharmaceutical formulations of the present invention that can be manufactured using standard methods are shown below. Intravenous infusion Compound of formula (I) 1-40 mg Buffer almost pH7 Solvent / complexing agent Make up to 100ml Concentrated lump injection Compound of formula (I) 1-40 mg Buffer almost pH7 Make cosolvent 5ml Buffer: Suitable buffers are citric acid, phosphoric acid, sodium hydroxide / hydrochloric acid Is included. Solvent: typically water, but cyclodextrin (1-100 mg) and Propylene glycol, polyethylene glycol and alcohol It may contain a solvent. tablet Compound 1 to 40 mg Diluent / filler * 50-250mg Binder 5-25mg Disintegrant * 5-50mg Lubricant 1-5mg Cyclodextrin 1-100mg   * May contain cyclodextrin. Diluents: eg microcrystalline cellulose, lactose, starch Binder: for example, polyvinylpyrrolidone, hydroxypropyl methylcellulose Disintegrants: for example, sodium starch glycolate, crospovidone Lubricants: for example, magnesium stearate, sodium stearyl fumarate Oral suspension or solution Compound 1 to 40 mg Suspension or solubilizer 0.1 to 10 mg Diluent 20-60mg Preservative 0.01-1.0mg Buffer almost pH 5-8 Cosolvent 0-40mg Perfume 0.01-1.0mg Colorant 0.001-0.1mg Suspensions: for example, xanthan gum, microcrystalline cellulose Solubilizing agent: for example, hydroxypropyl β-cyclodextrin Diluent: for example, sorbitol solution, typically water Preservatives: for example, sodium benzoate Buffer: for example, citrate Cosolvent: for example, alcohol, propylene glycol, polyethylene glycol   The invention is further illustrated by the following non-limiting examples: Preparation Example 1 (±) 2- [2- (4- {1-methyl-1- (4-fluorophenyl) ethyl} Phenoxy) ethyl] piperidine-1-carboxylic acid tert-butyl ester   Diethyl azadicarboxylic acid (2.47 mM, 0.4 ml) in dichloromethane (5 ml). 43 g) at 0 ° C. in trichloromethane (20 ml) under argon. Phenylphosphine (2.47 mM, 0.647 g), 4- [1- (4-fluoro Phenyl) -1-methylethyl] phenol (2.47 mM, 0.57 g) and Tert-butyl 2- (2-hydroxyethyl) piperidine-1-carboxylate It was added dropwise to steal (2.47 mM, 0.566 g). The reaction mixture under these conditions Was stirred for 1 hour, then allowed to come to room temperature and stirring continued for 2 days. Dissolution The solvent was removed under reduced pressure to give a yellow oil, which was eluted with dichloromethane. Subjected to chromatography to give the title compound as a clear oil (yield = 0.537). g, 50%).¹ HNMR (250 MHz, CDCl_Three) Δ 1.39 (9H, s), 1.59 (6H, m), 1.63 (6H, m), 1.85 (1H, m), 2.21 (1H, m), 2.8 0 (1H, m), 3.95 (3H, m), 4.47 (1H, m), 6.76 (2H, m) ), 6.92 (2H, m), 7.12 (4H, m). Preparation Example 2 (±) 2- [2- (4- {1-methyl-1-phenylethyl} phenoxy) ethyl Ru] piperidine-1-carboxylic acid tert-butyl ester   Using the conditions described in Preparation Example 1, 4- [1- (4-fluorophenyl) -1 -Methylethyl] phenol is converted to 4- [1-methyl-1-phenylethyl] pheno (10 mM, 2.12 g) and use other reagents of the corresponding molar fraction. After column chromatography, the title product was obtained as a colorless transparent oil ( 4.13 g).¹ HNMR (250 MHz, CDCl_Three) Δ 1.38 (9H, s), 1.60-1.7 0 (12H, m), 1.85 (1H, m), 2.20 (1H, m), 2.80 (1H, m) m), 3.90 (3H, m), 4.47 (1H, m), 6.75 (2H, m), 7.0 5-7.30 (7H, m). Example 1 (±) 2- [2- {4- (4-fluorophenylsulfone) phenoxy} ethyl ] Piperidine hydrochloride   A solution of 2-piperidineethanol in dry DMSO (20 ml) was added at room temperature Sodium hydride (0.36 g of an 80% dispersion in oil) , 12 mM) for 2 hours. Bis- (4-fur) in dry DMSO (20 ml) Orophenyl) sulfone (3.05 g, 12 mM) solution was added dropwise, and foaming was observed. Was guessed. After the addition, the mixture was stirred for 30 minutes. Glacial acetic acid (0.69 ml, 12 mM ) To inactivate the mixture and to evaporate the resulting brown solution using xylene as azeotrope. It was allowed to dry. K residue_TwoCO_ThreePartition between aqueous solution and ether, The solution is extracted again with ether (3 times) and the combined organic extracts are washed (H_TwoO, bu Line) and dry (Na_TwoSO_Four) And evaporated to dryness. Light brown organic extract remaining The product (3.18 g) was first added to CH_TwoCl_TwoIs used as eluent, then CH 2_TwoC l_Two/ 2% MeOH, CH_TwoCl_Two/ 5% MeOH, and finally CH_TwoCl_Two/ 1 0% MeOH (MeOH is 10% NH_FourSilica gel using OH) An oily substance (1.5, which crystallizes on standing, is evaporated and subjected to 2g) I got This was dissolved in hot ethyl acetate and excess ethereal HCl was added. cold Upon filtration, the title compound separated as white crystals, which were collected and washed with ether. And dried (0.67 g). Melting point = 179-181 ° C C₁₉H_{twenty two}FNO_ThreeS · HCl Calculated C, 57.1, H, 5.8, N, 3.5                            Found C, 56.9, H, 5.7, N, 3.5% Example 2 (±) 2- [2- (4- {1-methyl-1- (4-fluorophenyl} ethyl) Phenoxy) ethyl] piperidine hydrochloride   (±) 2- [2- (4- {1-methyl-1- () in dichloromethane (6 ml) 4-fluorophenyl) ethyl {phenoxy) ethyl] piperidine-1-carbo Acid tert-butyl ester (1.13 mM, 0.5 g) Under gon, add excess trifluoroacetic acid in dichloromethane (2ml) did. Stirring was continued for 2 hours. Sodium hydroxide (10%, 10ml) in solution It was added dropwise and then extracted with dichloromethane (3 × 15 ml). Combined organic layers Was washed with water (20 ml), brine (20 ml) and dried over sodium sulfate . The solvent was removed in vacuo to give a yellow oil which was converted to the hydrochloride salt with ethereal HCl. Conversion yielded the title compound as a white crystalline solid. Melting point = 160 ° C., yield = 0.3 7 g (82%) (recrystallized from methanol / ethyl acetate).¹ HNMR (270 MHz, DMSO) δ: 1.45 (2H, m, J = 14), 1.6 0 (6H, s), 1.72 (2H, m, J = 14), 1.92 (2H, m), 2.12 (1H, m), 2.86 (1H, m), 3.20 (2H, m, J = 14), 4.06 ( 2H, t, J = 7), 6.85 (2H, d, J = 7), 7.02 to 7.27 (8H, m) , 8.98 (2H, s). MS EI⁺Data was also obtained. Example 3 (±) 2- [2- (4- {1-methyl-1-phenylethyl} phenoxy) ethyl R] piperidine hydrochloride   Using the conditions described in Example 2, the product of Preparation 1 was prepared using the product of Preparation 2 (9.4 5 mM, 4.0 g) and use other reagents and solvents with corresponding mole fractions. To give the title compound as a white crystalline solid (2.3 g, mp = 151-153 ° C.). ), And recrystallized from methanol / ethyl acetate. C_{twenty two}H₂₉NO · HCl Calculated value C, 73.4, H, 8.4, N, 3.9                       Found C, 73.4, H, 8.6, N, 4.1%

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI A61K 31/445 AAM A61K 31/445 AAM ABN ABN ABR ABR ABS ABS ADD 9454-4C ADD ADR ADR 31/535 9454- 4C 31/535 C07D 211/22 8014-4C C07D 211/22 265/30 9639-4C 265/30 279/12 9737-4C 279/12 (72) Inventor Cooper, David Guin CM, 19.5 AD, UK , Esex, Harlow, The Pinnacles, Cold Harbor Road (No address shown) SmithKline Beecham Pharmaceuticals

Claims (1)

[Claims]   1. Formula (I): Wherein W is-(CH_Two)_Four,-(CH_Two)_Five,-(CH_Two)_TwoO (CH_Two)_TwoOr-(CH_Two)_Two S (CH_Two)_Two;   n is 0 to 6;   m is 0 to 3;   A is a bond, -CH = CH-, -C≡C-, oxygen, sulfur or NR¹;   R¹Is hydrogen, C_{1 ~ 8}Alkyl or phenyl C_{1 ~Four}Alkyl;   Ar is a group: (Where X is -SO_Two-Or -C (CH_Three)_TwoAnd Y and Z are each water Element, fluorine, chlorine, bromine, C_{1 ~Four}Alkyl, C_{1 ~Four}Alkoxy or trifluoro Lomethyl) Means Or a salt thereof.   2. W is (CH_Two)_FourOr (CH_Two)_FiveThe compound according to claim 1, which is   3. Group-(CH_Two)_nA (CH_Two)_mAr is in α-position to the ring nitrogen atom. Or the compound of 2.   4. Chain- (CH_Two)_nA (CH_Two)_m4. The method according to claim 1, wherein the length is 2 to 6 atoms. The compound according to any one of the above.   5. The compound according to any one of claims 1 to 4, wherein A is oxygen or a bond. Stuff.   6. Formula (IA): Wherein X, Y and Z are as defined above for formula (I), and n is 1 or Is 2. The compound or a salt thereof according to any one of claims 1 to 5, having the following formula:   7. Base Is-(CH_Two)_nA (CH_Two)_m-Or-(CH_Two)_n2. The compound of claim 1, which is in the 4-position to the O-group. 7. The compound according to any one of claims 6 to 6.   8. 8. A method according to claim 1, wherein Y is fluoro or chloro and Z is H. A compound according to any one of the preceding claims.   9. 9. The compound according to claim 1, wherein Y is at the 4-position to the X group. Compound.   10. 10. The method according to claim 1, wherein both Y and Z are hydrogen. Compound.   11. (±) 2- [2- ｛4- (4-fluorophenylsulfone) phenoxy [Ethyl] piperidine,   (±) 2- [2- (4- {1-methyl-1- (4-fluorophenyl) ethyl] {Phenoxy) ethyl] piperidine,   (±) 2- [2- {4- (3-fluorophenylsulfone) phenoxy} ethyl Le] piperidine,   (±) 2- [2- (4- {1-methyl-1- (3-fluorophenyl) ethyl] {Phenoxy) ethyl] piperidine,   (±) 2- [2- {4- (4-chlorophenylsulfone) phenoxy} ethyl ] Piperidine,   (±) 2- [2- (4- {1-methyl-1- (4-chlorophenyl) ethyl} Phenoxy) ethyl] piperidine,   (±) 2- [2- {4- (phenylsulfone) phenoxy} ethyl] piperidi ,   (±) 2- [2- (4- {1-methyl-1-phenylethyl} phenoxy) e Chill] piperidine Or a compound of claim 1 selected from salts thereof.   12. A therapeutic agent for the compound according to any one of claims 1 to 10 or a salt thereof. Use.   13. For the treatment of diseases requiring calcium channel antagonists The use of the compound of any one of claims 1 to 10 or a salt thereof in the manufacture of a medicament. use.   14． The disease may include symptoms related to the accumulation of calcium in mammalian brain cells. The use according to claim 11, which is a disease or a disease.   15. A compound according to any one of claims 1 to 10, or a salt thereof, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.   16. A process for the preparation of a novel compound of formula (I), (A) A is O, S or NR¹For compounds of formula (I) that are: Wherein W and n are the same as described for formula (I);¹Is O, S or NR¹, R^FourRepresents an N-protecting group] And a compound of formula L (CH_Two)_mAr [wherein, m and Ar represent formula (I) The same as described above, and L represents a leaving group]. (B) A is O, S or NR¹For compounds of formula (I) that are: Wherein W, n and R^FourIs the same as described above, and L¹Is replaced by a nucleophilic group Means a group that can be replaced] And a compound represented by the formula HA¹(CH_Two)_mAr [where m and Ar represent the formula (I) Is the same as described for¹Is the same as described for equation (II).] Reaction with the indicated compound; (C) A is NR¹For compounds of formula (I) that are: [Wherein, R^FiveIs a group-(CH_Two)_mN (R¹) C (O) (CH_Two)_m-1Ar or-(CH_Two)_n-1C (O) N (R¹) (CH_Two)_mAr and R^4aIs hydrogen or an N-protecting group; W, n , M and Ar are the same as described above] Reduction of the compound represented by (D) For compounds of formula (I) wherein A is a bond, formula (V): [Where W, R^Four, L¹, M and n are the same as defined above] And a compound of formula X¹Ar [Ar is the same as described with respect to formula (I) Yes, X¹Represents an alkali metal] with a compound represented by the formula: (E) W is (CH_Two)_FiveAnd A is O, S, NR¹Or for compounds that are And the formula (VI): Wherein A, Ar, m and n are the same as defined above;^4aIs hydrogen or N-protecting group And X- means a counter ion. Reduction of the compound represented by (F) For compounds where A is -CH = CH-, formula (VII): [Where W, R^FourAnd n are the same as defined above. And a group (CH_Two) reaction with a reagent that serves to introduce the mAr; (G) interconversion of one compound of formula (I) into another compound of formula (I), for example -(CH) of the compound in which A is -CH = CH-_Two)_nA (CH_Two)_m− Is part -CH_Two-CH_TwoReduction to a compound comprising- Then, if necessary, the N-protecting group R^FourRemoval, followed by salt formation if desired. When Method consisting of.