JPH07503462A - Azabicyclo compounds as calcium channel antagonists - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Azabinclo Compound as a Calcium Channel Antagonist The present invention provides novel azabinculo compounds Nocro derivatives, their production methods, pharmaceutical compositions containing them and treatments , particularly regarding their use as calcium channel antagonists.

In German OLS No. 4116582, Eq.

[A, B and C are independently -CH,- or type 1 packed; n is 0.1 or 2° X is oxygen or sulfur, R is especially phenylalkyl, nophenylalkyl heterocycle, phenyl, diphenyl or heterocycle, each in its place. Optionally substituted commands The azabicyclo compound represented by is described. These compounds are muscari It is said to be useful as a drug that acts like a drug.

The inventors finally discovered that the aza that is substituted at the apex atom of the bridge Discovered the pinoclo compound. These compounds are calcium channel antagonists. It has activity as

In a first aspect, the present invention provides formula (I) formula (1) %formula% : A is a bond, -CH=CH-1-C=C-1 oxygen, sulfur or NR+.

R1 is hydrogen, CI4 alkyl or phenyl01~. Alkyl: Ar is aryl or heteroaryl, each of which may be optionally substituted] Provided is a compound represented by or a salt thereof.

Preferably p and r are 2 or 3.

Preferably, q is 1 or 2.

The values of m and n are such that the chain (CH2), A(CH2), is at least 2 atoms long. choose as it is. Generally, the length of the chain (CH,), A (CHl) is 2. 6 atoms (for example, 2 to 5 atoms). Preferred values for n and are: Depends on the group A.

Therefore, for example, when A is oxygen, the sum of n and m is preferably 1 to 1. For example, m may be 1.2.3 or 4, and m may be 0 or 1.

Preferably A is oxygen or a bond, most preferably oxygen.

When Ar is aryl, suitable groups include, for example, phenyl, naphthyl, Tetrahydronaphthyl, fluorene, fluorenone, dibenzosuberene and di Unsaturated cyclic and unsaturated or includes partially saturated bicyclic as well as tricyclic systems. Place as desired An optionally substituted phenyl ring is preferred.

For example, C1-2 alkyleneoxy group (e.g. 3,4-methylenedioxy group) (substituted phenyl) or halogen, cl-4 alkoxy, nitro, SC, ~4 alkyl, NR"R" (R""R2"' is independently H or Cl-1 alkyl ), OCF! , CI-s alkyl, trifluoromethyl, C N, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylCl-4 alkyl and and optionally substituted phenyl 01-4 alkokino The aryl group may be substituted with 1 to 3 substituents.

Suitable optionally substituted phenyl 01-, alkyl groups include, for example: Includes benzyl group.

Suitable optionally substituted phenyl C1-4 alkoxy groups include, for example: It includes 7 benzyl oxy groups.

the optionally substituted phenyl, phenoxy, phenylCl-4 alkyl Suitable substituents for phenyl 01-4 alkoxy groups include, for example, rogens, C3-4 alkyls, 01-4 alcoquines, nitro and trifluoromethanes Examples include chill group.

Preferably, the aryl group carries one or two substituents, especially phenyl, phenyl (CI-4) Alkyl (e.g. benyl, phenoxy) or phenyl C1-4 substituted by alkoxy (e.g. benzyloxy group) or in particular a phenyl ring substituted with two chlorines at the 3- and 4-positions of the phenyl ring; be.

When Ar is heteroaryl, suitable groups include, for example, at least one unsaturated or partially saturated bicyclic and tricyclic systems containing heteroatoms of can be mentioned. Preferably, the bicyclic system is quinolinyl, tetrahydroquino Those with 8 to 10 ring members, such as linyl or benzofuranyl. It is. Preferably, the tricyclic system has 11 to 15 ring members; Most preferably, the following formula [In the formula, Yl represents Y(CH2), Y is ○, S or NR3 (R3 is hydrogen or or 01-4 alkyl), Z is (CH,), or -CH=CH-1S is 0,1 or 2, where t means 0 or 1] is a dehydro ring system having or corresponding to the structure represented by to tricyclic Examples of teroaryl groups are dibenzofuranyl, dibenzochenyl, carbazole, Includes N-methylcarbazole, acridine and dibenzoxepine. Applicable Heteroaryl rings include the remainder of formula (1) via any suitable atom of the ring. Vine combined with.

Suitable substituents for the heteroaryl ring include, for example, halogen, triphenyl, fluoromethyl, C6-4 alkyl% Cl-4 alkokyne, phenyl, phenyl c 1 to 3 selected from 1-4 alkyl and phenyl 01-4 alkokyne The following substituents are mentioned.

Alkyl groups present in the compound of formula (I) (whether alone or as part of another group) ) may be straight chain or branched. Therefore, c1-4 alkyl group, e.g. For example, methyl, ethyl, n-propyl, n-butyl or isopropyl or It may be any branched isomer thereof such as t-butyl.

For use in medicine, salts of compounds of formula (1) should be pharmaceutically acceptable. be. Examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, and phosphorus. acid salt, acetate, fumarate, maleate, citrate, lactate, tartrate, Inorganic and organic acid addition salts such as xalates, methanesulfonates, etc. Ru. Non-pharmaceutically acceptable salts may be used for isolation of the final product, e.g. , they are included within the scope of the present invention.

Special compounds of the invention include: 4-[2-(3,4-dichlorophenoquine)ethyl]-1-azabicyclo[2 ゜2.1] Heptane hydrochloride, 4-[2-(4-benzyloxyphenoxy)ethyl-1-azabinclo[ 2゜2.1] heptane hydrochloride, 4-[2-(2-dibenzochenyloxy)ethyl-1-azabicyclo[2 ゜2.1 Cohebutane hydrochloride, (±)5-(4-benzyloxyphenoxymethyl)-1-azabicyclo[32 , 1 co-octane hydrochloride, (±)5-(4-pennorphenoquinemethyl)-1-azabinclo[3,2, 11 octane hydrochloride, (±)5-(2-dibenzofuranyloxy)methyl-1-azabicyclo[3゜ 2.1 co-octane hydrochloride, (±)5-[2-(2-nobenzofuranyloxy)ethyl]-1-azapinoc b [3,2,11 octane hydrochloride, 4-[2-(4-phenoquinphenoxy)ethyl-1-azabinclo[2゜2 ．． 1 cohebutane hydrochloride, 4-[3-(4-benzyloxyphenyl)propyloxymethyl]-1-a Zavinclo [2,2,13hebutane hydrochloride, 4-[5-(4-phenoxyphene)] pentyloxy]-1-azabicyclo[2,2,1]hebutane hydrochloride, 4-(4-benzyloxyphenoxymethyl)-1-azabicyclo[2,2,1 1 hebutane hydrochloride, 4-[4-(4-phenoquinphenyl)butyloxy]-1-azabicyclo[ 2゜2.1] heptane hydrochloride, 4-[3-(4-benzyloxyphenyl)propyloxy]-1-azabine Chlo[2,2,1]hebutane hydrochloride, and 4-[5-(4-penzyloxyphenyl) phenyl)pentyloxy]-1-azapinocro[2,2,1]hebutane hydrochloride can be mentioned.

It is understood that compounds of formula (I) may have one or more asymmetric centers. It will be understood. Such compounds may exist as optically active isomers (enantiomers). Ru. Both the pure enantiomer and the racemic mixture (50% of each enantiomer) Also within the scope of this invention are unequal mixtures of the two enantiomers. moreover , all possible noastereomeric forms (pure enantiomers and their mixtures) ) are also within the scope of the present invention. Furthermore, when A is -CH=CH-, the chemical The compounds exist as geometric isomers and the present invention covers all such isomers and mixtures thereof. all-encompassing.

The compounds of the invention can be synthesized by methods analogous to those known in the art. Wear. The invention therefore provides, in a further aspect, a method for the synthesis of compounds of formula (1) I will provide a. The synthesis method consists of (a) to (f), and then optionally forms a salt. You may let them.

(a) For compounds where A is ○, S or NRI, formula (II): [where pSqlr and n are the same as described for formula (I), and A I means O, S or NRI] and a compound represented by the formula L(CH2), A compound represented by Ar (m and Ar are the same as described for formula (1), L is a leaving group).

(b) For compounds of formula (I) where A is OlS or NRI, [wherein p , q, r and n are the same as described for formula (I), and Ll is the nucleating agent. HA'(CH2)-A The compound represented by r (m and Ar are the same as described for formula (r)) , AI is the same as described for formula (II)), or (c) For compounds of formula (1) where A is N Rl, formula (IV): [In the formula, R4 is a group (CH2)-N(R1)C(OXCH2)-1 or -(C H2)--IC(○)N(R+XCHt)-Ar, p, qSrSn, m Reduction of a compound in which Ar and Ar are the same as described for formula (I): (d) For compounds of formula (1) where A is a bond, formula (V) A compound represented by [wherein L', p, q, r, m and n are the same as defined above] , a compound represented by formula X'A (Ar is the same as described for the compound of formula (1)) (e) A is -CH=CH- For the compound, formula (1'I): [In the formula, n5pSq and r are a compound represented by the same co as in the above definition, and an Ar group (f) from a compound of formula (1) to a compound of formula (1); Interconversion to another compound (for example, in a compound where A is -CH=CH-, 8 is -CH) 2CH2-) In method (a), a compound of formula (II) and The reaction between the compound L(CHz)-Ar was carried out under conditions depending on the nature of the base and the value of m. This can be done on a case-by-case basis. For example, L is a halogen or If m is other than 0, a base may be present if desired. The reaction is carried out under standard conditions in an optionally present solvent. fluorine-substituted aryl When compound F-Ar is used in method (a), (synthesize a compound where m is 0) ), in an inert solvent such as dimethylformamide, and in sodium hydride. When the reaction is carried out in the presence of a strong base. Preferably, the aryl group is CF or N Substitution with an activating group such as Ox. If necessary, azavinchlor nitrogen source can be added during the reaction. For example, it is said that a quaternary derivative such as an N-benzyl derivative is formed on the front side. It may be protected by methods known in the art, such as. Borane (BH,) complex Protection may be provided by forming a body. Does not affect other residues in the molecule It will be appreciated that the N-protecting group should be selected such that it is removed in a manner similar to However, Therefore, the side chain (CHz)-A(CHz)-Ar is also a base such as a benzyloxy group. For example, a benzyl protecting group is not suitable if it contains a benzyl group. Typically provides N-protection when the leaving group is a strong rogogen (e.g. bromine), but when L is a In the case of sulfonic acid residues (eg tonlate), N-protection is not necessary.

Reaction between a compound of formula (III) and a compound of formula HA' (CHJ-A r Process (b)) can be carried out under conditions depending on the nature of Ll and. example For example, when Ll is hydroxy, m is O, and AI is oxygen or sulfur, is carried out in the presence of diethyl azoformate and triphenyl phosphite. Kagaru reaction is known as the Mitsunobu reaction (nonsense (S Synthesis), published in January 1981). Alternatively, the leaving group L1 is , for example, a halogen atom or a sulfonyloxy group (e.g. methane-sulfonyl oxy or p-toluenesulfonyloxy). In this case, the preferred Alternatively, compound (III) is protected as an acid salt, such as the hydrochloride. No 0 The reaction is carried out at a temperature range of 200°C in the presence or absence of a solvent, and Preferably, the reaction is carried out in the presence of a base.

Reduction of the compound of formula (IV) by method (C) can be carried out by methods known in the art, e.g. (using a reducing agent such as lithium aluminum hydride). Wear. Conveniently, the compound of formula (IV) can be synthesized by, for example, as described below. , a “one-pot” reaction (’on e　pot’reaction).

The reaction between the compound of formula (V) and the compound of formula X'Ar in process (d) is carried out on charcoal. can be carried out under standard conditions known to those skilled in the art for the formation of element-carbon bonds. .

Diethylphosphonate represented by Ar(CH2)--+P(OXOAl　k)z Wadsworth-Emmons reagents, such as or represented by the formula A r (CI (2), , P P h, X (where X is an anion) Fittig reagents (these are commercially available or known) Method (e) may be performed using a method (which can be synthesized by a method). Optionally 15-klau may contain crown ethers such as Crown-5 or 18-Crown-6. sodium hydride or potassium tert-butylhydride in a solvent such as tetrahydrofuran. The reaction may be carried out in the presence of a strong base such as Toki/Do.

The interconversion reaction according to method (f) may be carried out by any method known in the art. good. Therefore, for example, in compound (1) where A is -CH=CH-, A is CH2 Conversion to compound (1) which is CH2- may be carried out by reduction using a catalyst. .

A compound of formula (II), where n is 1 to 6 and AI is oxygen, can be converted to a compound of formula (VII ) + [where p, q and r are the same as defined above, and Alk is C1-6 a a group meaning alkyl group (e.g. ethyl) It can be synthesized by reduction of the corresponding ester shown below. The reduction is Lithium alkali hydride in a solvent such as ethyl ether or tetrahydrofuran. It may also be carried out using a reducing agent such as aluminum. E of formula (VII) where n is 1 Stell is, for example, European Patent Application Nos. 287356 and 392803. and Eckhardt et al., Helv, ChiIl, ^cta), 1972, vol. 55, p. 2432 and B. ・Nis Orlek (B, S, 0rlek) et al., Journal of Medicine Synal Chemistry (J, Med, Chea+), 1991, No. 34 Vol., p. 2726 and . The ester where n is 1 is expressed as the corresponding N- For example, hydrolysis of the ester to convert it to methyl-N-methoquinocarboxinamide. , followed by reaction with thionyl chloride and N,O-dimethylhydroxylamine. ), and then reduced to an aldehyde using diisobutylaluminum hydride. Esters where n is greater than 1 may be synthesized by The obtained al Dehyde is further converted into an anomethyl derivative (e.g. described in EPA363085). , followed by acid hydrolysis and esterification to obtain the ester where n is 2. This one Higher homologues may be obtained by repeating the series operation.

Alternatively, the aldehyde of formula (VI) can be substituted with triethylphosphonoacetate or triethylphosphonoacetate. Reaction with ethylphosphonocrotonate followed by catalytic hydrogenation to form ethylphosphonocrotonate. A quinocarbonyl alkyl derivative is obtained, which is further reduced (e.g. by hydrogenated lithium). by obtaining the desired hydroxyalkyl compound (using aluminum) Compounds of formula (II) can also be synthesized. triethylphosphonoacetate The trial resulted in homologation of two atoms, while triethylcrotonate It will be appreciated that homologation of four atoms of carbon occurs.

A compound of formula (II) in which n is O and p and r are both 2 is It can be synthesized from dil-4-piperidone by various methods. for example, Compound (II) in which r is 1 may be synthesized according to the following reaction scheme.

Alternatively, the corresponding cyano and 1-benzyl-4-piperidone can be converted to 4-hydrohydride via a stellate derivative. It may be converted into a roxy-4-hydroxymethyl compound.

A compound of formula (II) in which n is 0 and p, q and r are each 2, is ・A Grob (C1A, Grob) and P Brenneisen (P, B renneisen), Helv Kim Acta (Helv, Chin, Acta, Vol. 41, p. 1184, 1958). Good too. In the method, 1-benzyl-4-piperidone is combined with zinc and bromo By reacting with ethyl acetate, the corresponding 1-hydroxy-1-ethoxycarbonylmethylene 1-Hydroxy-1 - reduction to the hydroxyethyl compound, followed by cyclization and deprotection as described above. I do.

Compounds of formula (II) in which n is O, p is 3, r is 2, and q is 1, according to EPA No. 287 As described in No. 356 (can be synthesized).

A compound of formula (II) in which A1 is S or NR, is combined with a corresponding hydroxy compound from a standard method (e.g., formation of an alkyl halide, followed by a suitable amine or or reaction with thiol).

A compound of formula (III) in which Ll is ○H is described for a compound of formula (II). It can be synthesized using the same method as above. LI is a halogen atom or The compound of formula (III), which is a can be synthesized from the corresponding alcohol.

The formula L(CHz)-Ar and HA'(CH2)mAr The compounds can be synthesized by methods well known in the art. For example, if Ar L (CHz)-A which is substituted phenyl and L is halogen (e.g. bromine) r using a suitable acid chloride and aluminum chloride as a catalyst, then in-situ. the corresponding position by reduction with triethylene in 5 i.tu. Friedel-Craflu of benzene derivatives It can be synthesized by (Friedel-Crachts) unruling.

When Ar is a phenyl group substituted by penzyloxy, compound L(CH z)-Ar can be synthesized according to the following scheme.

Starting materials are commercially available or prepared using standard methods (e.g. 4-benzyloxybenzene). For the synthesis of compound (II), nzaldehyde and triethylphosphonocrotonate were added. It can be synthesized by the same method as described above.

A formula in which R4 is a group -(CH2)-NCR')C(0)(CH2),, -IAr (m compound is combined with a compound of formula (II) in which A1 is NRI and a group -(CH2)m An unlying agent corresponding to Ar (e.g. acid chloride Cl0C(CH2)-IAr) It can be synthesized by reaction.

Formula (IV ) to the corresponding compound where R4 is -(CH2)-+C02H, for example. or activated derivatives thereof such as acid chlorides, esters or anhydrides with the formula HN(R IXCH2), can be synthesized by reacting with an amine. acid When used per se, the reaction with the amine should be carried out in the presence of a coupling agent. That will be understood. The carboxylic acid itself can be used, for example, with the corresponding alcohol (e.g. In other words, it may be synthesized by oxidation of a compound of formula (II) in which AI is oxygen.

Compounds of formula (V) can be synthesized in a similar manner to compounds of formula (In) .

The necessary chain extension may be performed by methods known in the art.

Compounds of formula (vg) can be prepared in a conventional manner, e.g. oxidation of compounds or conversion of the corresponding esters (e.g. hydrolysis and thionyl chloride or and N,O-dimethyl-hydroquinylamine, and then the resulting N-methyl It can be synthesized by (reduction). A compound of formula (VI) where n is 1, It can be synthesized from the corresponding compound where n is O by various methods. example For example, an aldehyde where n is 0 is converted to (methquinmethyl)triphenylphosphonichloride. and potassium t-butoxide, followed by strong acid (e.g. concentrated sulfuric acid). Upon treatment, aldehydes with n=1 can be obtained. Alternatively, EPA No. 3 63085, converting the aldehyde to the corresponding cyanomethyl derivative. , followed by acid hydrolysis and conversion to N-methyl-N-methquine carboxamide. Then, you can also return it. These methods also form higher congeners. It can be used to

When the compound of formula (1) is obtained as an enantiomeric mixture, in the presence of a resolving reagent, crystallization or chromatography (e.g. using a chiral HPLC column) of These may be separated by conventional methods such as.

The compound of the present invention has a high calcium influx blocking activity, for example, in neuron cells. was found to have the following properties. Compounds that bind mammalian (especially human) brain cells related to (e.g. caused or exacerbated by) calcium accumulation in ) is expected to be particularly useful in the treatment of symptoms and diseases. For example, the compound is caused by anoxia, such as ischemia including stroke, migraine, epilepsy, and traumatic brain injury. Neurological problems such as scars, AIDS-related dementia, Alzheimer's disease and age-related memory loss It is expected to be useful in treating degeneration and ethanol addiction withdrawal symptoms.

In a further embodiment of the invention, calcium in mammalian (particularly human) brain cells is provided. symptoms associated with (e.g. caused or exacerbated by) Treatments for and diseases are provided. The treatment method comprises administering to a subject in need of treatment an effective amount of The method comprises administering a compound of formula (+) or a pharmaceutically acceptable salt thereof. Okay For example, the present invention can be used to treat anoxia, ischemia including stroke, and migraine. , dementia, traumatic brain injury, AIDS-related dementia, Alzheimer's disease and age-related symptoms. Provides treatments for neurodegeneration such as memory disorders and ethanol addiction withdrawal symptoms .

In a further embodiment, the compound of the invention is capable of stimulating mammalian (e.g. human) brain cells. symptoms or diseases related to (causing or worsening) calcium accumulation The compound of formula (1) or its pharmaceutically acceptable compound in the manufacture of a medicament used for the treatment of Provide a trial of the salt.

When used in medicine, the compounds of the invention are usually administered in the form of standard pharmaceutical compositions. It will be done. Therefore, in a further aspect, the invention provides compounds of formula (1) or and a pharmaceutically acceptable carrier or excipient. A composition is provided. The compounds of the present invention can be administered in any conventional manner (e.g., orally, parenterally). The pharmaceutical composition may be administered by oral, buccal, rectal or transdermal administration). can be adapted to the method of administration.

Compounds of formula (1) that are active when administered orally and their pharmaceutically acceptable salts, liquid or solid, such as syrups, suspensions or emulsions, tablets, Can be formulated as capsules and troches).

Liquid formulations generally include a suitable liquid carrier such as suspending agents, preservatives, flavoring agents, or ethanol, glycerin, non-aqueous solvents (e.g. polyethylene glycol) with colorants. a suspension of a compound of the invention or a pharmaceutically acceptable salt in oil or water); or consists of a solution.

Tablets can be prepared using any suitable pharmaceutical carrier commonly used to produce solid formulations. Compositions in dosage form can be prepared. An example of such a carrier is stearic acid mag Includes nesium, starch, lactose, sucrose and cellulose.

Compositions in capsule form can be manufactured using commonly used encapsulation methods. can. For example, pellets containing the active ingredient can be prepared using a standard carrier and then can be manufactured by filling hard gelatin capsules. alternatively , dispersion or suspension in any suitable pharmaceutical carrier such as an aqueous gum, cellulose gum, etc. It can also be produced using The dispersion or suspension is filled into soft gelatin capsules.

The compounds of the invention may be administered parenterally, by bolus injection or continuous infusion.

Typical parenteral compositions include a sterile aqueous carrier or a parenterally acceptable oil or fat, such as For example, polyethylene glycol, polyvinylpyrrolidone, lentin, arachis oil or A solution or suspension of the compound of the present invention or a pharmaceutically acceptable salt thereof in sesame oil) Consists of liquid. Alternatively, the solution can be lyophilized and then added with a suitable solvent immediately before administration. It can also be restored.

Both liquid and solid formulations are known in the pharmaceutical field such as cyclodextrins. It may also contain excipients.

Preferably, the composition is in unit dosage form such as tablets, capsules or ampoules. do.

Preferably, each oral dosage form contains a compound of formula (1) or its pharmaceutical 1 to 250 mg of an acceptable salt (calculated as free base) (0 mg for parenteral administration) ．． 1 to 60 mg).

The daily dosing rule for adult patients is for the compound of formula (1) or its pharmaceutically acceptable dosage. For example, 1 mg to 500 mg of the salt (in terms of free base) for oral administration. between 1 mg and 250 mg (for example between 5 and 200 mg). between 0.1 mg and 100 mg for intravenous, subcutaneous, or intramuscular injection. , preferably between 1 mg and 60 mg (eg 1 to 40 mg). Ru. Compounds are administered 1 to 4 times per day. Alternatively, the compound of the invention may be administered as a continuous infusion. (preferably up to 400 mg per day). Therefore, oral administration The total daily dose ranges from 1 to 2000 mg by parenteral administration. The total daily dose ranges from 0.1 to 400 mg. Appropriately, the invention The compounds are administered over consecutive treatment periods (eg, one week or more).

biological data Measurement of Ca” current Cell preparation Sensory neurons derived from the dorsal roots were isolated from 1-day-old rats (fork (F orda) et al., Developmental Plain Research (Developpm) mentalBrain Research), Volume 22 (1985), 55 〜〜65 pages). Place cells on coverslips and use within 3 days to obtain effective Ca 2" voltage clamp of the current was possible.

solution CsC1,130: HEPES, 10: EGTA, 10; MgC1z, 4 : ATP, 2 (values are in mM); buffered with CsOH to pH 7.2 (internal solution) liquid) into a pipette. Cells were subjected to regular Tyrode's lysis prior to whole cell recording. The sample was kept in Tyrode'5 solution. Then, the solution was The solution was changed to a solution that can detect current.

The external solution for current recording of Ca” channel was BaCl2.10; TEA C1,1 30 Nigelcose, 10: HEPES, 10; MgCh, 1; TEA-O It was buffered with H to pH 7.3. Barium helps separate currents and Using barium as a charge carrier avoids the calcium-dependent inactivation of I used it. Compounds were dissolved in DMSO to prepare 20mM stock solutions. for At the same drug concentration, the carrier (0.1%) had an equally significant effect on Ca" I didn't lose it. All experiments were performed at 21-24°C. Li5t EPC- Record and store whole cell ii flow using a 7 amplifier as previously described (Ben Benham and Tsien, Journal of Philosophy Journal of Physiology (1988), Post-analysis using PC-based software (Vol. 404, pp. 767-784) Digitized for.

Ca” current Ca” peak potential up to 10 nA from dorsal root neurons gated at peak potential. Channel currents were recorded using s 10mM Ba'' as potential carrier.

Current is generated every 15 minutes from a holding potential of -80 mV to a test potential of 0 or +10 mV. Made it live. This test potential is at the peak value of the current-potential relationship; Measuring the cutoff at the point reduces any errors due to holding potential variations. let Some cells exhibit a slow current that is normally seen when measuring Ca” current. showed a decrease in The rate of decrease is measured in control conditions and extrapolated over the time of drug application. control values were derived and correlated with the drug that affected the current. with 20μM drug Blockade was measured 3 minutes after drug application.

The compounds of the present invention show 71 to 99% inhibition of Ca2-current Prado values. did.

medical prescription 1. Prescription for intravenous injection Compound of formula (1) 0.1 to 60 mg Sodium hydroxide/hydrochloric acid Add to adjust pH to approximately 7 Polyethylene glycol 0 ~30m1 Propylene glycol 0~30m1 Alcohol 0-10ml Add water to make 100ml 2. Ill-contractable injection preparation Compound of method (1) 0.1 to 60 mg Sodium hydroxide/hydrochloric acid Add polyethylene glycol O to pH approximately 7 ~2.5ml Alcohol O~2.5ml Add water to make 5ml osmotic agents (e.g. sodium chloride, dextrose or mannitol) May be added.

3. Tablets for oral administration mg/tablet Compound of formula (1) 25 Lactose 153 Starch 33 Crospovidone 12 Microcrystalline cellulose 30 The following non-limiting examples illustrate the synthesis of compounds of formula (1).

II Preparation Example 1 4-(methoxycarbonylmethyl)-1-azabinclo[2,2,1]hebutane 4-(Soanomethyl)-1-azabinclo[2,2°] in 5N hydrochloric acid (25 ml) 1] Heptane (EP 363085, description 25) (1°94 g, 14.3 The solution of mmo I) was heated under reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and Then, water was thoroughly removed by evaporation with toluene. Remove the residue Dissolved in ethanol (50ml) and treated with 1M ethereal hydrochloric acid, then for 2 hours. It refluxed. The resulting solution was concentrated under reduced pressure and treated with an aqueous potassium carbonate solution (25 ml). and extracted with chloroform (3x25ml). The combined organic layer was dissolved in sodium sulfate. The title compound was dried as a clear oil by distilling the resulting oil. (2.1 g, 87%). Boiling point: 125°C, 3.4mmHg (ball tube).

'HNmr (CDCl2) δ: 1.28 to 1.42 (2H, m), 1.4 9-1.64 (2H, m), 2.37 (2H, s), 2.52-2.71 (4H, m), 2.87-302 (2H, m), 3.67 (3H, s) key Example 2 4-(2-Hydroxyethyl)-1-azabicyclo[2,2,11butane] 4-(methoxycarbonylmethyl)-1-aza in ethyl ether (10ml) A solution of bicyclo[2,2,Llheptane was dissolved in stirred dry diethyl ether. Lithium aluminum hydride (0.94 g, 24.9 mm) in (70 ml).

1) was added to the suspension. The reaction was stirred at room temperature for 2.5 hours, then a minimum amount of The reaction was stopped by careful addition of water. The reaction mixture was filtered and the precipitate was filtered. Thoroughly washed with 20% methanol in ether. Combined filtrate and washing liquid Concentrate under reduced pressure and distill the residue to obtain the title compound as a white solid (1.49 g, 85%). I got it. Boiling point 155℃, Q, 3mmHg (ball tube).

'HNmr (CDCI3) δ: 1.20-1.35 (2H, m), 1.42-1.57 (2H, m), 1.94 (2H, t, J=7Hz), 2. 29 (2H, m), 2.39~2゜80 (3H, m), 2.84~3.00 (2H, m), 3.72 (2H, t, J=7Hz) Preparation Example 3 (±) 5-Hydroxymethyl-1-azabinclo [3,2,1-cooctane notation The compound is converted into (±)1-azabicyclo[3,2,1]-oct-5-ylcarboxylic acid Ethyl (EP 287356, Example 7) (2g, 10.9mmol) and Preparation Example 2 from lithium aluminum hydride (0.83 g, 21.9 mmol) It was synthesized in a similar manner. The title compound obtained was a transparent rubbery substance (1.24 g).

80%), the boiling point was 150°C, and 0.7 mmHg (ball tube).

Preparation example 4 (±) 5-(2-hydroxyethyl)-1-azabinclo[3,2,1]o (±)5-methoxycarbonylmethyl-1-azabicyclo [3°2.1] Octane (EP No. 363085, description 11) (0.74 g, 4.0mm.

1) and lithium aluminum hydride (0.46 g, 12.1 mmol) , was synthesized in the same manner as in Preparation Example 2. The title compound obtained is a transparent rubbery substance ( 0°54 g, 87%), boiling point 200°C, 0.2 mmHg (ball tube) .

'HNmr (CDCl2) δ, 1.37-1.82 (8, signal overlap), 2 ．． 43-3.05 (6H, m, nobnal overlap), 3.68 (2H, t, J =7Hz) w4 production example 5 4-Hydroxymethyl-1-azapinocro[2,2,1]butane title compound , methyl 1-azapinocro[2,2,1]hept-4-ylcarboxylate (B- Nis Ollek (B, S, 0rlek) et al., Journal of Medicina Le Chemistry (J, Med, Chem, ), 1991, No. 34 Volume, 2726 pages) (313 g, 20.2 mmo I) and lithium hydride From aluminum (1.92 g, 50.6 mmol) in the same manner as Preparation Example 2 Synthesized. The title compound obtained was a colorless solid (1.76 g, 69%) with a boiling point of 250 °C, Q, 3 mmHg (ball tube). Rash HNmr (CDCl2) δ 1. 27 (2H, m), 1.65 (2H, m), 2.32 (2H, s) , 2.62 (2H, m), 2.94 (2H, m), 3.72 (IH, br　s).

3,87 (2H,s) Preparation example 6 1-benzyl-4-hydroxymethyl-4-hydroxypiperidine dry dimethyls Sodium hydride in sulfoxide (476 g of 80% dispersion in mineral oil, 0.159 Trimethylsulfoxonium iodide (34°92 g, 0.0 g) was added to the suspension. 159 mol) was added over 1.5 hours. The resulting mixture was stirred for 1 hour, It was then cooled with water and dissolved in 1-benzyl-4- in dry dimethyl sulfoxide (25 ml). Treated with a solution of piperidone (25g, 0.132mol). Warm the reaction to room temperature. The mixture was stirred for an additional hour. The resulting mixture was diluted with water (500 ml) and Extracted with thyl ether (3x250ml). Combined organic extracts with brine Washed, dried over sodium sulfate, and concentrated under reduced pressure. The residue was extracted with pentane and evaporated. Purification by distillation gave a clear oil (22.48 g). Boiling point 175℃.

0, lmmHg (ball tube). A solution of this epoxide in formic acid (100 ml) was added to the room. Stir overnight at room temperature, then concentrate under reduced pressure. Dissolve the residue in methanol (200ml) Dissolved, treated with water (100 ml) and medium-sized sodium carbonate (30 g), and stirred at room temperature for 21 hours. Stir for a while. Concentrate the reaction mixture to about 1/3 of its original volume and saturate with potassium carbonate. and completely extracted with chloroform. Dry the combined extracts with sodium sulfate. The residue was concentrated under reduced pressure to obtain the title compound (24.5 g).

Preparation example 7 p-Toluenesulfonic acid 1-bentrue 1-azonia pinocloro[2,2,1]he Butan-4-ol 1-benzyl-4-hydroxymethyl-4- in pyridine (150 ml) at 0°C. A solution of hydroxypiperine 7 (16.8 g, 0.076 mo I) was diluted with p-chloride. Add toluenesulfonyl (14.86g, 0.079moI) a little over 10 minutes. The resulting solution was stored at 8° C. overnight. obtained The reaction mixture was vacuum evacuated, the remaining oil was dissolved in chloroform, and potassium carbonate was added. and washed with a saturated aqueous solution. After drying with sodium sulfate, the solution was concentrated under reduced pressure.

The remaining oil was dissolved in cantoluene and heated under reflux for 1.5 hours. Generate The product was separated by filtration and washed with diethyl ether to give the title compound as a solid. (23°3 g, 81%).

Preparation example 8 4-Hydroxy-1-azabicyclo[2,2,1]hebutaneethanol (100 p-toluenesulfonic acid 1-benzyl-1-azabicic O[2,2, 1] Add a solution of heptan-4-ol (5.0 g, 13.3 mmol) to a large Hydrogenation was performed under atmospheric pressure with 10% pd-C (1.0 g) for 18 hours. Kieserg Catalyst The mixture was filtered through a kieselguhr and the filtrate was concentrated under reduced pressure. Potash carbonate the residue The aqueous layer was partitioned between a saturated aqueous solution (20 ml) and chloroform (25 ml). was completely extracted with chloroform. Dry the combined organic extracts with sodium sulfate. and distillation to give the title compound as a colorless solid (1.2 g, 80%). boiling point 17 5℃ (ball tube).

'HNmr (CDCl2) δ: 1.58 (2H, m), 1.78 (2 H, m), 2.37 (2H, s), 2.75 (2H, m), 3.17 (2 H, m), 3.65 (LH, br　s) Preparation Example 9 3-(4-penzyloxyphenyl)-1-probanol potassium carbonate (5, 3-(4) in aceto:z (40ml) containing 9g, 42.75mmol -Hydroxyphenyl)-1-propatol (2.5g, 16.4mmo1) was treated with benzyl bromide (2.54 mL 1.21.35 mmol) and It refluxed for a while. The resulting mixture was concentrated under reduced pressure, and water (50 ml) and chloroform were added. (50 ml) was distributed between. The aqueous layer was further extracted with chloroform (2x50ml) The combined organic extracts were dried over sodium sulfate and then concentrated under reduced pressure. nine Chromatography on a glue gel using loloform 90-8% methanol as eluent Graphical purification gave the title compound as a colorless solid (3.92 g, 99%). (3.92g, 99%).

'HNmr (CDCIdδ: 1.36 (LH, s), 1.85 (2H, m), 2.63 (2H, t, J=7Hz), 3.65 (2H, t, J=7H z), 5.04 (2H, s).

6.91 (2H, d, J=8Hz), 7.11 (2H, d, J=8Hz), 7.27~7°50 (5H, m) Preparation example 10 3-(4-Benzyloxophenyl)propyl p-toluenesulfonate 3-(4-benzyloxyphenyl)-1-propaz in loform (30 ml) A solution of 4.15 g (17.1 mmol) of pyridine (4.15 g, 17.1 mmol) was cooled with water and added with pyridine (3.92 mmol). 1.48.5 mmol), then p-toluenesulfonyl chloride (6.16 g , 32.3 mmol). The mixture was slowly warmed to room temperature and left in the apparatus overnight. did. After dilution with diethyl ether (90 ml), the solution was diluted with 1M orthophosphoric acid ( 50 ml), then a saturated aqueous solution of potassium bicarbonate (50 ml), and water (50 ml). 0 ml). The organic layer was dried with sodium sulfate, then chloroform Chromatography on silica gel using 0-8% methanol as eluent in The title compound was purified as a colorless solid (5.1 g, 75%).

'HNmr (CDCI3) δ, 1.92 (2H, q, J=7Hz), 2.4 5 (3H.

s), 2.57 (2H, t, J = 7Hz), 4.01 (2H, t, J = 7 Hz), 5.02 (2H, s), 6.83 (2H, d, J-8Hz), 6.9 7 (2H, d, J=8Hz).

7.30-7.47 (7H, m), 7.78 (2H, dj=8Hz) Preparation example 11 4-(4-phenoxyphenyl)butyl bromide stirred dry chloromethane ( A suspension of aluminum chloride (13°33 g, 0.1 mol) in 200 ml) , 4-bromobutyryl chloride (11.6 ml.

0.1 mol) was added dropwise over 0.5 hours. The resulting mixture was filtered and then , diphenyl ether (25.5 g, 0.5 g, in dry dichloromethane (150 ml)). A solution of 15m01) was added over 0.5 hours. The mixture was stirred overnight and then , diethylsilane (48ml 1.0.3mol I). After 2 hours, the reaction Stopped with ice water. The organic layer was washed with water (200ml) and then brine (2x100ml). 1), then dried over sodium sulfate, and concentrated under reduced pressure. 40-60 koku on silica gel using 0-15% diethyl ether in oil ether as eluent. The residue was purified by chromatography. Then, distill the title compound to make it transparent. Obtained as an oil (22.12g, 73%). 14 in the boiling point region lmmHg 6-160℃.

'HNmr (CDC13) δ: 1.68-2.00 (4H, m, signal overlap), 2゜60 (2H, t, J=7Hz), 3.42 (2H, t, J=7 Hz), 6.86-7.40 (9H, m) Preparation example 12 5-(4-phenoxyphenyl)pentyl bromide The title compound was converted to 5-bromoba chloride. Leryl (13,39m1.0.1mo+), aluminum chloride (13,33g , Ollmo I), diphenyl ether (25,5 g.

0.15mol) and triethyl runan (48ml1.O13mol). It was synthesized in the same manner as in Production Example 11. The title compound obtained was a transparent oil (175 6 g, 55%), and the boiling point was 165-180°C at 0.2 mmHg.

'HNmr (CDCI3) δ: 1.36-1.75 (4H, m, signal weight double), 1°88 (2H, m), 2.60 (2H, t, J=7Hz), 3.4 0 (2H, t, J = 7H2), 6.86-7.38 (9H, m) Preparation Example 13 5-(4-Hydroxyphenyl)-1-pentanol Dry tetrahydrofuran (5 4-benzyloxybenzaldehyde (5.0 g, 23.56 mm) in ol) and triethyl 4-phosphonocrotonate (7°07g, 28.25mm A solution consisting of 15-crown-5 (0.18 g) Sodium hydride (80% dispersion in mineral oil) in hydrofuran (50ml) ．． 78 g, 26.0 mmol) of the slurry (with stirring). mixture Warmed things up to room temperature. Synthesis was carried out for 1 hour, the reaction was stopped with glacial acetic acid (5 ml), and concentrated under reduced pressure. Ta. The residue was partitioned between water (50ml) and chloroform (100ml). water The layers were further extracted with chloroform (2x50ml) and the combined organic extracts were extracted with sulfuric acid. It was dried over sodium and concentrated under reduced pressure. By recrystallization from ethyl acetate-penkune A pale yellow solid (5.77 g) was obtained, which was dissolved in ethanol (100 ml) and diluted with a large Hydrogenation was performed with 10% Pd-C(Ig) under atmospheric pressure. After 3 hours, lock the reaction mixture. Filtered through Zerguol, then concentrated under reduced pressure to obtain 5-(4-hydroxyphenyl)pene. Ethyl tanthanate was obtained as a transparent curved material (4.08 g). dry diethyl ether A solution of this ester in dry diethyl ether (150 ml) A suspension of lithium aluminum hydride (2.08 g, 54.8 mmol) in (while stirring). After 2.5 hours, wet diethyl ether, then min. The reaction was stopped with a large amount of water. The reaction mixture was filtered and the precipitate was washed with methanol. unity The filtrate and washings were concentrated under reduced pressure. Dissolve the residue 1 in water, acidify with 5M hydrochloric acid, It was saturated with sodium chloride and thoroughly extracted with chloroform. Chloropho united The rum extract was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound as a colorless solid. I got it. The precipitate was dissolved in 5M hydrochloric acid, the solution was saturated with sodium chloride, and the Kiesel Filtered through gur. Further purification was obtained by thorough extraction with chloroform and labeled. The total amount of the compound was 3.04 g (92%).

'HNmr (CDCl 3) δ: 1.25 to 1.80 (7H, m, Sig null overlap), 2゜52 (2H, tj=7Hz), 3.62 (2H, t, J= 7Hz), 4.90 (IH.

br　s), 6.74 (2H, d, J=8Hz), 7.02 (2H, d, J=8 Hz) Preparation example 14 5-(4-benzyloxyphenyl)-1-pentanol potassium carbonate (6,1 g, 44.2 mmol) in ethanol (40 ml) containing 5-(4 -Hydroxyphenyl)-1-pentanol (3.04g, 16.98mmol ) was treated with benzyl bromide (2.63 ml, 22.07 mmol) to give 1 Refluxed for an hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (50 ml) and chloroform. (50 ml). The aqueous layer was further treated with chloroform (2x50ml). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure.

Chroma on silica gel using chloroform 90-8% methanol as eluent Purification by chromatography gave the title compound as a colorless solid (4.31 g, 94%). I got it.

'HNmr (CDCIs) δ: 1.15-1.70 (7H, m, signal weight double), 2゜55 (2H, t, J = 7Hz), 3.62 (2H, t, J = 7H z), 5.01 (2H.

s), 6.87 (2H, d, J=7Hz), 7.23-7.50 (5H, m ) Preparation example 15 The title compound, 5-(4-benzyloxy)pentyl p-toluenesulfonate, -(4-benzyloxyphenyl)-1-pentanol (3°3g, 12.2 mmol), pyridine (3,0ml1.37.2mmol]) and p-chloride Same as Preparation Example 10 from toluenesulfonyl 4.66 g, 24.4 mmol) It was synthesized using the method. After reacting for 4 hours, operate as described above at room temperature. The title compound was obtained as a colorless solid (3.64 g, 70%).

'HNmr (CDCl2) δ: 1.20 to 1.76 (6H, m, nobnal overlap), 2゜33-2.60 (5H, m, signal overlap), 4.0 (2H, t, J=6Hz), 5.0 (2H, s), 6.83 (2H, d, J=8Hz) , 7.02 (2H, d, J=8Hz).

7.23-7.50 (7H, m), 7.77 (2H, d, J=8Hz) Implemented Example 1 4-[2-(3,4-dichlorophenoxy)ethyl]-1-azabicyclo[2 ,2゜1cohebutane hydrochloride (El) 4-(2-hydroxyethyl) in dry tetrahydrofuran (40 ml) under nitrogen atmosphere. Chil)-1-azabicyclo[2,2,11hebutane (0.5g, 3.55mm o]) in dry tetrahydrofuran (2 ml). henol (0.87g, 5.32mmol), then tetrahydrofuran ( treated with triphenylphosphine (1.21 g, 4.61 mmol) in 2 ml) did. Diethyl azodicarboxylate (0.80g, 4.61mmol) was added as a reactant. was added over a period of 5 hours and the resulting mixture was stirred at room temperature overnight. Reduce pressure on reactants Concentrate and treat with saturated aqueous potassium carbonate solution (25 ml), then chloroform (3×25 ml).

The combined organic extracts were dried over sodium sulfate, concentrated under reduced pressure, and the residue Chromatograph on neutral alumina using a gradient of 0-2% methanol in lumen. It was served to Rafi. The resulting gummy material was converted to the HCl salt, which was dissolved in diethyl ethyl ethyl ether. thoroughly washed with ethyl ether and then crystallized (methanol run ethyl ether). The title compound was obtained as a white solid (0.65 g). Melting point 188-190℃ .

'HNmr (DMSO-da) δ 1.70-2.09 (4H, m), 2 ．． 18 (2H, tJ=7Hz), 3.12 (2H, s), 3.23-3.5 6 (4H, m), 4.20 (2H, t, J=7Hz), 7.06 (LH, dd, J=3.10Hz), 7.35 (LH, d, J=3Hz), 7.62 (LH, d, J=10Hz) Example 2 4-[2-(4-benzyloxyphenoxy)ethyl]-1-azabicyclo[ 2゜2.1]Heptane hydrochloride (E2) The title compound was converted into 4-(2-hydroxyethyl)-1-azabicyclo[2,2,1 ] Hebutane (0.5g, 3.55mmol), 4-penzyloxyphenol (1,06g, 5.32mmo I), triphenylphosphine (1,21g, 4.61 mmo]) and diethyl aazodicarboxylate 0.80 g, 4. 61 mmo]) in the same manner as in Example 1. Obtained title compound (from methanol-diethyl ether) is a white solid (0.24 g), melting point 20 The temperature was 9-212°C.

'HNmr (DMSO-ds) δ: 1.70-2.09 (4H, m), 2 ．． 16 (2H.

t, J=6Hz), 3.13 (2H, s), 3.23~3.66 (4 H, m), 4.10 (2H, t, J=6Hz), 5.12 (2H, s) , 6.89-7.08 (4H, m), 7.36-7. :17 (5H, m ) Example 3 4-[2-(2-dibenzofuranyloxy)ethyl]-1-azabicyclo[2 ゜2.1] Heptane hydrochloride (E3) The title compound was converted into 4-(2-hydroxyethyl)-1-azabicyclo[2,2,1 1 Hebutane (0.39 g, 2.77 mmo+), 2-hydroxydibenzofuran (0°76g, 4.15mm0I), triphenylphosphine, azodicarbonate From diethyl acid (0.63 g, 3.60 mmol) in the same manner as in Example 1 Synthesized. The crude product was purified with a gradient of 5-20% methanol in chloroform. Chromatography on silica gel was performed. Contains major components that elute late. The remaining fractions were pooled to obtain an oily substance, which was diluted with ethereal hydrochloric acid. Work-up gave the title compound as a white solid (0.12g) (methanol/acetate). ton/diethyl ether). Melting point: 206-209°C.

'HNmr (DMSO-da) δ 1.75-2.13 (4H, m), 2 ．． 26 (2H, t, J=6Hz), 3.20 (2H, s), 3.26-3. 57 (4H, m), 4.30 (2H, d, J=6Hz), 7.19 (LH , dd, J=2.7Hz), 7.40-7°79 (5H, m), 8.22 ( IH, d, J=7Hz) Example 4 (±) 5-(4-Benzoloxymethyl)-1-azabicyclo[3,2,1 ]Octane hydrochloride (E4) The title compound was converted into (:)5-hydroxymethyl-1-azabicyclo[3,2,1] Octane (0.5g, 3.55mmol), 4-benoloxyphenol (1,065g, 5.32mmo]), triphenylphosphine (1,2 1g, 4.61mmol), diethyl azodicarboxylate (0.80g, 4.61 mmol) in the same manner as in Example 1. Obtained title compound (Metal) (from tanol-acetone-diethyl ether) is a white solid (0.11 g), molten The temperature was 188-191°C.

'HNmr (DMSO-dd) δ: 1.48-1.55 (IH, m), 1.6 0-1.97 (5H, m), 3.02-3.16 (4H, m), 3.25 ~3.37 (2H, m), 3°80 (2H, s), 4.95 (2H, s), 6.74-6.98 (4H, m), 7.18-7.35 (5H , m) Example 5 (±)5-(4-pennorphenoquinemethyl)-1-azabicyclo[3,2, 1] Octane hydrochloride (E5) The title compound was converted into (±)5-hydroxymethyl-1-azabicyclo[3,2,1] Octane (0.5g, 3.55mmo I), 4-hydroxyphenylmethane Tan (0.98g, 5.32mmol1), triphenylphosphine 7 (1.21g , 4.61 mmol) and diethyl azodicarboxylate (0.80 g + 4.6 1 mmo]) in the same manner as in Example 1. The title compound obtained ( methanol-ether) is a white solid (0.15 g), melting point 168 °C (decomposition )Met.

'HNmr (DMSO-da) δ: 1.62 to 1.70 (LH, m), 1.74-2°11 (5H, m), 3.16-3.30 (4H, m), 3. 38-3.51 (2H, m).

3.92 (2H, s), 3.97 (2H, s), 6.88-6.93 (2 H, m), 7.14-7.25 (5H, m), 7.27-3.34 (2 H, m) Example 6 (±) 5-(2-dibenzofuranyloxy)methyl-1-azabicyclo[3 ,21]Octane hydrochloride (E6) The title compound was converted into (±)5-hydroxymethyl-1-azabicyclo[3,2,1] Octane (0.53 g, 3.76 mmol), 2-hydroxydibenzofuran (1 ,04g, 5.64mmo1), triphelphosphine (1.28g, 4.8 9mmo I) and diethyl azodicarboxylate (0.85g + 4.89mm o It was synthesized from I) in the same manner as in Example 1. The crude product was dissolved in toluene at 0.0%. Chromatography on neutral alumina using 5-2% methanol grand end - Served. (Pool the fractions containing the components to be eluted and The gummy material obtained was converted to the hydrochloride salt to give the title compound as a white solid (0.98 g, from methanol-acetone-diethyl ether).

'HNmr (DMSO-d,) δ: 1.62-2.22 (6H, m), 3.15-3°59 (6H, m), 4.10 (2H, s), 7.08-7. 17 (LH, m), 7.33-7, 87 (5H, m), 8.09-8. 18 (LH, m) Example 7 (±)5-[2-(2-dibenzofuranyloxy)ethyl]-1-azabicic b[3,2,11 octane hydrochloride (E7) (±) 5-(2-hydroxyethyl )-1-azabinclo[3,2,1]octane (0.53g, 3.42mmo I), 2-hydroxybenzofuran (0,95 g.

5,13mmo I), triphenylphosphine (1,17g, 4.45mm ol) and diethyl azodicarboxylate (0.54m 1.3.42mmo I ), the title compound was synthesized in the same manner as in Example 17, with a reaction time of 2 hours. did. The crude product was purified by neutral aqueous solution using 0.5-2'% methanol in toluene as eluent. Purified by chromatography on Lumina, then converted to hydrochloride and labeled The compound was obtained as a colorless solid (0.7 g) (methanol-acetone-diethyl ether). from Tel). Melting point: 137-138°C.

'HNmr (DMSOds) δ: 1.60-2.08 (8H, m), 3.1 0~3゜50 (6H, m), 4.14 (2H, t, J=5Hz), 7.12 (LH, dd, J=8Hz and 2Hz), 7.40 (LH, t, J=8H z), 7.52 (IH, t, J=8Hz), 7.63 (LH, d, J=8H z), 7.67 (LH, d, J=8Hz), 7.77 (IH, d, J=2H z), 8.14 (IH, d, J=8Hz), 10.93 (LH.

br　s) Example 8 4-[2-(4-phenoquinphenoquine)ethyl]-1-azabicyclo[2,2 ゜1] Heptane hydrochloride (E8) The title compound was converted into 4-(2-hydroxyethyl)-1-azabicyclo[2,2,1 ] Hebutane (0.62 g, 4.4 mmol), 4-phenoxyphenol ( 1.23g.

6.61 mmol), phosphine (1.5 g, 5.72 mmol), l) and diethyl azodicarboxylate (0.9m 1.5.72mmo I) was converted into Example 1 and the salt. Disperse the salt in ether and saturated water with potassium carbonate solution (20ml) and extracted with chloroform (3x25ml). united The extracted extract was dried over sodium sulfate, concentrated under reduced pressure, and then diluted with chloroform at 90~ Purified by chromatography on neutral alumina using 2% methanol as eluent. The title compound was obtained as a colorless solid (0.85 g) (methanol-acetate). (from ethyl ether). Melting point: 209-211°C.

'HNmr (DMSO-di) δ: 1.73 (2H, m), 1.93 ( 2H, m), 2°12 (2H, t, J=6Hz), 3.07 (2H, s ), 3.25 (4H, m), 4.12 (2H, t, J=6Hz), 6.8 8-7.13 (7H, m), 7.38 (2H, t, J=7Hz) Example 9 4-[3-(4-benzyloxyphenyl)propyloxymethyl]-1-a Zabicyclo[2,2,11butane hydrochloride (E9) dry N,N-dimethylforma to 4-hydroxymethyl-1-azabicyclo[2,2,1] in Mido (5 ml) A solution of butane (0.2 g, 1.57 mmol) was dissolved in sodium hydride (mineral oil). 80% dispersion was treated with 50 mg, 1.66 mmol) and placed under nitrogen atmosphere. The mixture was then stirred at 50° C. until hydrogen gas evolution ceased. p-Toluenesulfone Acid 3-(4-benzyloxyphenyl)propyl (0.58g, 1.57mm o l) was added little by little over 1 hour, and the resulting mixture was stirred for another 1 hour. did. The reaction was concentrated in vacuo and the residue was evaporated with toluene. Toluene was added little by little each time). The residue was dissolved in a saturated aqueous solution of potassium carbonate (1 0ml) and extracted with chloroform (3x15ml). combined extract was dried over sodium sulfate and then concentrated under reduced pressure. The crude product was dissolved in chloroform. Chromatograph on neutral alumina using medium 0-15% methanol as eluent It was purified by Pooled fractanol containing fast eluting components from diethyl ether). Melting point: 166-168°C.

'HNmr (DMSOds) δ: 1.72 (2H, m), 1.87 (2H , m), 2°03 (2H, m), 2.65 (2H, t, J=8Hz), 3. 12 (2H, s), 3.28-3.55 (6H, m, nobnal overlap), 3 ．． 68 (2H, s), 5.16 (2H, s).

7.01 (2H, dj=9Hz), 7.20 (2H, d, J=9Hz), 7 ．． 37~7゜63 (5H, m) Example 10 4-[5-(4-phenoquinophenyl)pentyloxy]-1-azabinclo[ 2゜2.1] Heptane hydrochloride (Elo) p-Toluenesulfonic acid 1-beta in dry N,N-dimethylformamide (7 ml) True 1-azoniavinclo[2,2,1]butan-4-ol (0,5g .

1.33 mmol) of sodium hydride (80% dispersion in mineral oil) 80 mg, 2.66 mmo I), then treated with 1 hour under nitrogen atmosphere. Stirred. 5-(4-Fe bromide) in dry N,N-dimethylformamide (2 ml) Add noxyphenyl)pentyl (0.85 g, 2.66 mmo I) and mix The mixture was stirred for 3 hours. The reaction was stopped with glacial acetic acid (0.5ml) and then concentrated under reduced pressure. did. The residue was evaporated successively with toluene and ethanol (10 ml) and hydrogenated with 10% Pd-C (0.1 g) under atmospheric pressure for 2 hours.

The reaction mixture was filtered through a pad of Kieselguhr, and the filtrate was concentrated under reduced pressure. charcoal the residue saturated aqueous potassium acid solution (20 ml) and chloroform (3x20 ml). Extracted. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. crudely purified product 0 to 15% in chloroform on neutral alumina with ethanol as eluent. Purified by rush chromatography. pooled pure fractions The title compound (0.14 g) was then treated with ethereal hydrochloric acid (acetone). (from ethyl ether). Melting point: 129-131°C.

'HNmr (DMSOda) δ: 1.33 (2H, m), 1.55 (4H , m), 180-2.10 (4H, m), 2.53 (2H, t, J=7Hz) , 3.18 (2H, s).

3.30-3.58 (6H, m, nobnal overlap), 6.93 (4H,, m ), 7.11 (IH, t, J=8Hz), 7.22 (LH, d, J=8H z), 7.38 (2H, t, J=8Hz) Example 11 4-(4-benzyloxyphenoxymethyl)-1-azabicyclo[2,2,1 1 Hebutane hydrochloride (Ell) The title compound was converted to 4-hydroxymethyl-1-azabicyclo[,2,2,1] Tan (0.5g, 3.94mmo+), 4-benzyloxyphenol ( 1.18g.

5.91 mmol), triphenylphosphine (1.55 g, 5.91 mmol ) and diethyl azodicarboxylate (0.93m1, 5.91mmo1) , was synthesized in the same manner as in Example 1. After reacting for 5 hours, as described with respect to Example 1 I performed the operation as shown. Chloroform 95% ethanol is used as eluent. Purification over neutral alumina gives a pale yellow oil, which is purified with ethereal hydrochloric acid. The title compound was obtained as a colorless solid (0.09 g) (methanol-acetate). ton-diethyl ether). Melting point: 206-208°C.

'HNmr (DMSO-d6) δ: 1.73 (2H, m), 2.02 (2H, m), 3°12 (2H, s), 3.20~3.50 (4H, m , nobnal duplication), 4.17 (2H.

S), 5.03 (2H, s), 6.93 (4H, m), 7.26-7.48 (5H, m) Example 12 4-[4-(4-phenoquinphenyl)butyloxy]-1-azabicyclo[ 2゜2.1] Heptane hydrochloride (E12) The title compound was converted into p-toluenesulfonic acid 1-benzyl-1-azoniabicyclo[ 2,2,1 cohebutan-4-ol (0.5 g, 1.33 mmol), sodium hydride Thorium (80 mg of 80% dispersion in mineral oil, 2.66 mm1) and 4-bromide From (4-phenoquinphenyl)butyl (0.89g, 2.91mmo I) , was synthesized in the same manner as in Example 10. The crude product was dissolved in chloroform 95-10% Purified by chromatography on Nori gel using ethanol as eluent The title compound was obtained as a colorless solid (from acetone-diethyl ether). Melt Point 115-117.5°C.

'HNmr (DMSOdi) δ: 1.46 to 1.67 (4H, m), 1 ．． 85-2゜06 (4H, m), 2.57 (2H, tj=7Hz), 3.1 7 (2H, s), 3.30-3.60 (6H, m, signal overlap), 6. 93 (4H, m, signal overlap), 7.11 (LH, t, J=7Hz), 7 ．． 21 (2H, d, J=8Hz), 7.38 (2H, t.

J=8Hz) Example 13 4-[3-(4-benzyloxyphenyl)brobyloxy]-1-azabine Chlo[2,2,1 cohebutane hydrochloride (E13) dry N,N-tumethylformamide (15 ml) of 4-hydroxy-1-azabinclo[2,2,1]hebutane ( A solution of 0.38 g, 3.36 mmol) was added to sodium hydride under a nitrogen atmosphere. (120 mg of 80% dispersion in mineral oil, 4.0 mmol). Mixed The mixture was warmed to 40-50°C and stirred for 2 hours. Raise the temperature to 60℃, dry N, N- 3-(4-benzyloxyphenyl)prop in dimethylformamide (8 ml) Pyrtosylate (0.90 g, 2.69 mmol) was added over 2 hours.

After a further 1 hour at 60°C, the reaction was cooled and reacted with glacial acetic acid (0.23ml). stopped responding. The reaction mixture was concentrated under reduced pressure and then added with chloroform (20 ml) and and saturated aqueous potassium carbonate solution (20ml). Remove the aqueous layer from chloroform (2 The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Black Purification over neutral alumina using Roform 91-2% ethanol as eluent A colorless crystalline solid was obtained, which was treated with ethereal hydrochloric acid to give the title compound as a colorless crystalline solid. Obtained as a solid (0.30 g) (from methanol-acetone-diethyl ether) ). Melting point: 180-181°C.

'HNmr (DMSO-da) δ 1.78 (2H, m), 1.92 ( 2H, m), 2°02 (2H, m), 2.56 (2H, t, J=7Hz) , 3.18 (2H, s), 3.25-3.60 (6H, m), 5.07 ( 2H, s), 6.92 (2H, d, J=8Hz), 7°12 (2H, d, J =8Hz), 7.28-7.50 (5H, m) Example 14 4-[5-(4-benzyloxyphenyl)pentylokitaco-1-azabisi Chlo[2,2,1]hebutane hydrochloride (E14) dry N,N-dimethylformamide (15 ml) of 4-hydroxy-1-azabicyclo[2,2,1]hebutane ( A solution of 0.38 g + 3.36 mmo I) was added to sodium hydride under a nitrogen atmosphere. (120 mg of 80% dispersion in mineral oil, 4.0 mmol).

The mixture was warmed to 50°C and stirred for 2 hours. Raise the temperature to 60℃ and add dry N, N-jime 5-(4-benzyl 1)-toluenesulfonic acid in chloroformamide (9 ml) A solution of (oxyphenyl)pentyl (1.07 g, 2.52 mmo I) was added for 3 hours. It dripped over time. The mixture was further cooled at 60 °C for 45 min, and glacial acetic acid (0, The reaction was stopped at 23 ml). The reaction mixture was concentrated under reduced pressure, and then chloroform (7 5 ml) and a saturated aqueous potassium carbonate solution (75 ml).

The aqueous layer was completely extracted with chloroform, and the combined organic layers were dried over sodium sulfate. , concentrated under reduced pressure. Neutral alkali using chloroform 91% ethanol as eluent Purification with Mina and then treatment with ethereal hydrochloric acid yielded the title compound as a colorless solid (0, (from acetone-diethyl ether). Melting point 150-151 ．． 5℃.

'HNmr (DMSO-da) δ: 1.32 (2H, m), 1.53 (4H, m), 1°82~2.08 (4H, m), 2.50 (2H, t, J=7Hz), 3.17 (2H, s).

3.25-3.60 (6H, m), 5.06 (2H, s), 6.92 (2 H, d, J=8Hz), 7.10 (2H, d, J=8Hz), 7.28-7. 50 (5H, m) International search report , , = + PCT/GB 93100174 Continued from front page (51) Int, C1,' Identification code Office B1 number A61K 31/43 5　ADY 31155 AAM 9454-4C C07D 487108 7019-4C (81) Designated country EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD.

TG), AU, BB, BG, BR, CA, CZ, FI.

HU, JP, KP, KR, LK, MG, MN, MW, NO, NZ, PL, RO, RU, SD, SK, USI (72) Inventor: Brown, Thomas Henry, Essex, England M19.5Aday, Barlow, The Pinnacles, Coldharbour Road (No street address displayed) SmithKline Beecham Pharmaceuticals (72) Inventor Cooper, Dipid Brine Essex Sea, UK M19.5Aday, Barlow, The Pinnacles, Coldharbour Row (No address displayed) SmithKline Beecham Pharmaceuticals Z

Claims (1)

[Claims] Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula (I) [where p, q and r are each independently a number from 1 to 4; n is 0 to 6; m is 0 to 6; A is a bond, -CH=CH-, -C≡C-, oxygen, sulfur or NR1; R1 is water C1-8 alkyl or phenylC1-4 alkyl; Ar is aryl or heteroaryl, each of which may be optionally substituted] A compound represented by or a salt thereof. 2. 2. A compound according to claim 1, wherein p and r are independently 2 or 3. 3. 3. The compound according to claim 1 or 2, wherein q is 1 or 2. 4. 4. A compound according to any one of claims 1 to 3, wherein A is oxygen or a bond. 5. Claim 1, wherein the chain -(CH2)nA(CH2)m has a length of 2 to 6 atoms. The compound according to any one of item 4. 6. The compound according to any one of claims 1 to 5, wherein m is 0 to 3. 7. 4-[2-(3,4-dichlorophenoxy)ethyl]-1-azabicyclo[2, 2,1] heptane, 4-[2-(4-benzyloxyphenoxy)ethyl]-1-azabicyclo[2 ,2,1]heptane, 4-[2-(2-dibenzofuranyloxy)ethyl]-1-azabicyclo[2, 2,1] heptane, (±)5-(4-benzyloxyphenoxymethyl)-1-azabicyclo[3, 2,1] octane, (±)5-(4-Benzylphenoxymethyl)-1-azabicyclo[3,2,1 ] Octane, (±)5-(2-dibenzofuranyloxy)methyl-1-azabicyclo[3,2 ,1] Octane, (±)5-[2-(2-dibenzofuranyloxy)ethyl]-1-azabicyclo [3,2,1]octane, 4-[2-(4-phenoxyphenoxy)ethyl]-1-azabicyclo[2,2 ,1] heptane, 4-[3-(4-benzyloxyphenyl)propyloxymethyl]-1-aza Bicyclo[2,2,1]heptane, 4-[5-(4-phenoxyphenyl)pentyloxy]-1-azabicyclo[ 2,2,1]heptane, 4-(4-benzyloxyphenoxymethyl)-1-azabicyclo[2,2,1 ]Heptane, 4-[4-(4-phenoxyphenyl)butyloxy]-1-azabicyclo[2 ,2,1]heptane, 4-[3-(4-benzyloxyphenyl)propyloxy]-1-azabicic b[2,2,1]heptane, and 4-[5-(4-benzyloxyphenyl)pentyloxy]-1-azabicic B[2,2,1]heptane or a pharmaceutically acceptable compound thereof. 8. (a) For compounds where A is O, S or NR1, formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula (II) [where p, q, r and n are the formula As described for (I), Al means O, S or NR1 ] and a compound represented by the formula L(CH2)mAr (m and A r is the same as described for formula (I), L is a leaving group); (b) A is O , S or NR1, formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula (III) [where p, q, r and n are As described for formula (I), L1 can be substituted by a nucleophile A compound represented by the formula HA1(CH2)mAr compound (m and Ar are the same as described for formula (I), A1 is formula (I) the same as described for I); or (c) For compounds of formula (I) where A is NR1, formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula (IV) [wherein, R4 is the group (CH2)n N(R1)C(O)(CH2)m-1 or -(CH2)m-1C(O)N(R 1) (CH2)mAr, where p, q, r, n, m and Ar are related to formula (I). Reduction of the compound shown in [same as described above]; (d) For compounds of formula (I) where A is a bond, formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula (V) [In the formula, L1, p, q, r, m and and n is the same as defined above], and a compound represented by formula X1A (Ar is the same as described for the compound of formula (I), and X1 is an alkali metal) (e) For compounds where A is -CH=CH-, reaction with formula (VI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula (VI) [where n, p, q and r are Reaction of a compound represented by [same as the above definition] with a reagent useful for introducing an Ar group (f) interconversion of one compound of formula (I) to another compound of formula (I), e.g. Reduction of a compound in which A is -CH=CH- to a compound in which A is -CH2CH2- ) The preparation of a compound of formula (I) as defined in any one of claims 1 to 7 consisting of Construction method. 9. A compound of formula (I) as defined in any of claims 1 to 7 or its Pharmaceutical composition consisting of a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient thing. 10. of formula (I) as defined in any of claims 1 to 7 for use in treatment. A compound or a pharmaceutically acceptable salt thereof. 11. an effective amount of a compound of formula (I) or a pharmaceutically acceptable thereof to a subject in need of treatment; To reduce calcium accumulation in mammalian vagina cells, Treatment of associated symptoms or diseases.