JPH06508353A - Compound - 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] Compound The present invention describes the use of known and novel 3-1f substituted pyrrolidine derivatives in therapy, novel Regarding the compounds themselves, their preparation methods, and pharmaceutical compositions containing them. Ru.

USP 3,360.526 provides the formula: [wherein Y is nitrogen, inter alia, lower alkyl or phenyl lower alkyl] pyrrolidino group which may be substituted on an elementary atom] is disclosed. has been done. These compounds have antihistamine activity, antitussive activity, antiemetic activity and It is said to have antifungal activity.

EP338331 describes the 3-position substituent -XA [where X is -OC] as an intermediate. H2, CH. O or 0, and A is aryl or heteroaryl] N-protected (e.g., benzyl)pyrrolidine derivatives having the following are disclosed.

tJsP4918073 has the formula: R'-0 (CH2), A(CHI), CH (R''XR3) [wherein R1 is, inter alia, an optionally substituted group] phenyl or certain bicyclic aryl or heteroaryl groups, m is 2 -4, 80 is 1-4, and R2 and R3 are each phenyl or phenylalkyl] is disclosed. USP4933 346 has the formula: RIS(CH2), A(CHI), CH(R''XR3) [in the formula , R1 is, inter alia, optionally substituted phenyl. The compounds L'I are disclosed. Both of these USP compounds are calcium antagonists. I was told that it was a medicine.

The inventors have disclosed in USP 4918073 and 4933346) Substituted pyrochemicals that are different from compounds and exhibit activity as calcium channel antagonists discovered a class of lysine derivatives. Therefore, they block calcium channels for the treatment of disorders in which calcium accumulates in mammalian brain cells It is useful for

Therefore, in a first aspect, the present invention provides calcium channel antagonists. Formula (I): Structural Formula (I) for the manufacture of pharmaceuticals for treating disorders [In the formula, R is C1, □8 alkyl, C, -, alkyl (phenyl), C24 alkenyl ( phenyl), C2-8 flukynyl (phenyl), C3-87 chloroalkyl or or C1-8 alkyl/chloroalkyl: p is 0 to 2, n is 0 to 6; A is a bond, -CH=CH-, -c=c-, oxygen, sulfur or NR'; R 1 is hydrogen, C,-8 alkyl or phenylC1-4 alkyl; m is Available from 0 to 3.

Ar is aryl or heteroaryl, each optionally substituted with one ] The present invention provides the use of a compound represented by or a pharmaceutically acceptable salt thereof. .

The compound represented by formula (I) exhibits high calcium influx blocking activity. There was found. Such compounds are useful for therapy, especially for the treatment of molecules in brain cells of mammals, especially humans. It may be useful in treating conditions and diseases associated with lucium accumulation. example For example, the compound may be used to treat anoxia, ischemia, including stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases like Alzheimer's disease and age-related memory and drug addiction withdrawal symptoms, such as ethanol addiction withdrawal symptoms. It appears to be.

Accordingly, in a further aspect of the invention, a subject in need of treatment is provided with the structural formula (I ) or a pharmaceutically acceptable salt thereof. caused by calcium accumulation in mammalian brain cells, or Provide methods for treating recurring symptoms or diseases. Thus, for example, the invention provides: administering a compound of structural formula (I) or its pharmaceutically acceptable form to a subject in need of treatment; Anoxia, ischemia, including stroke, unilateral, consisting of administering an effective amount of salt to be administered Pain, dementia, traumatic head injury, AIDS-related dementia, neurological conditions such as Alzheimer's disease Degenerative diseases and age-related memory disorders, as well as drugs such as ethanol addiction withdrawal symptoms The present invention provides a method for treating addiction withdrawal symptoms.

In the compound represented by the structural formula (I), an alkyl chloroalkyl group, an alkyl phenylene Nyl group, alkenylphenyl group and alkynylphenyl group each represent alkyl When bonded to the pyrrolidine nitrogen atom through groups, alkenyl groups and alkynyl groups be understood.

In compounds of structural formula (I), R is preferably C1-8 alkyl. In particular, n-pentyl or 02-8 alkenyl (phenyl), [wherein p is 1], for example nannamil.

Preferably A is oxygen or sulfur, most preferably A is oxygen .

The preferred definitions of n and m depend on the group A. Generally, the chain -(CH2). A The length of (CH2)- is 2 to 5 atoms. Thus, for example, if A is an acid When it is prime, n is preferably 1 or 2, and m is preferably O. stomach.

In general, it is preferred that n is from O to 3, such as 1 or 2; m is , 0 or 1 is preferred.

When Ar represents aryl, suitable groups include, for example, groups having up to 12 carbon atoms. Unsaturated monocyclic ring systems and unsaturated or partially saturated bicyclic ring systems, or up to 15 carbon atoms bicyclic systems, such as phenyl, naphthyl, tetrahydronaphthyl, fluorene, Examples include fluorenone, dibenzosuberene and dibenzosuberenone.

Preferred is a phenyl ring which may be optionally substituted.

The aryl group is substituted with, for example, a C1-2 alkylenedioxy group. (e.g., phenate substituted by 3,4-methylenedioxy group) ), or halogen, CI-4 alkokene, nitro, SCI-4 alkyl NR2R2' [wherein R2 and R2'' are independently H or C1-4 represents alkyl], OCF3, C,-6 alkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenyl enoquine, optionally substituted phenyl Ci4 alkyl, optionally substituted phenyl Ci4 alkyl optionally substituted phenylC2-, alkenyl and optionally substituted with 1 to 3 substituents selected from phenyl C1-4 alcoquine which may be may be replaced. Preferably, the aryl group has 1 or 2 substituents In particular, one 710ge〉, trifluoromethyl, unsubstituted phenyl or by an unsubstituted phenyl C1-4 alkokyne group or by a phenyl ring, especially 3 It is a phenyl ring substituted by two chlorine atoms at the and 4-positions.

Suitable optionally substituted phenylCio4alkyl groups include: Examples include benol or phenethyl. With suitable optional substitutions Phenyl C1. □． As the alkokino group, for example, benzyloxy Examples include groups. Suitable optionally substituted phenyl C2-4 alkyl Examples of the kenyl group include phenetenyl.

Optionally substituted phenyl group, phenoxy group, phenyl CI-4 Alkyl group, phenyl C2-4 alkenyl group, and phenyl C1-4 alco Suitable substituents for the xy group include, for example, halogen, CI-4 alkyl group , CI-4 alkoxy/group, nitro group and trifluoromethyl group.

When Ar represents heteroaryl, suitable groups include, for example, at least one unsaturated or partially saturated bicyclic systems of up to 12 carbon atoms containing heteroatoms of can be lost. Bicyclic systems include 8-10 such as quinolinyl and tetrahydroquinolinyl. It is preferable that the ring-constituting atoms are contained. Bicyclic systems have 11 to 14 ring atoms It is preferable to contain the structural formula: [wherein Yl is Y(CH 2 R, and Y is O, S or NR3 (where R3 is hydrogen or C 1-4 alkyl), Z is (CH2), or 1CH=CH-, and q is 0 , 1 or 2 and r is 0 or 1], or the corresponding This is a dehydroscience field. Examples of bicyclic heteroaryl groups include nobenzofuranyl , nbenzochenyl, carbazole, N-methylcarbazole, acriline and and cibenzoxepine. A heteroaryl ring can be any suitable ring atom. may be bonded to the remainder of Structural Formula (I) through a child.

Suitable substituents for the heteroaryl ring include, for example, halogen, C1-4 1 to 3 substituents selected from alkyl and C1-4 alkoxy; Ru.

Alone or as part of another group in a compound of structural formula (I) The alkyl group may be linear or branched.

Examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, phosphate. , Acetate, Fumarate, Maleate, Citrate, Lactate, Tartrate, Noyu Inorganic and organic acid addition salts such as acid salts, or similar pharmaceutically acceptable inorganic salts. Examples include organic acid addition salts. Other non-pharmaceutically acceptable salts may be used, e.g. It is within the scope of the present invention.

The present invention provides structural formula (IA) + Structural formula (IA) In formula c, Ro is C5-1 alkyl, C61 alkyl (phenyl), C2-5 alkenyl (phenyl)-1Cz-s alkynyl (phenyl)-1Cs-a nocroalkyl or Cl-8 alkyl-C3-8 cycloalkyl; p is 0-2.

n is 0 to 6 and 1 A is a bond, -CH=CH-1-C=C-1 oxygen, sulfur or NR'.

R1 is hydrogen, C1□alkyl or phenylC1-4alkyl; m is It is 0-3.

Ar is aryl or heteroaryl, each optionally substituted. ] The present invention also provides novel compounds and pharmaceutically acceptable salts thereof. .

In compounds of structural formula (IA), R1 is preferably C6-, alkyl. Preferably, especially n-pentyl or C2-S alkenyl (phenyl), [wherein , p is 1, for example cinnamyl. Preference for m, nSA and Ar The definitions are the same as the above definitions for Structural Formula (I).

Particular compounds of the invention include: 3-(4-fluoro fenoquine methyl)-1-pentylpyrrolidine hydrochloride, 3-(3,4-methylene dioxyphenoxymethyl)-1-pentylpyrrolidine hydrochloride, 3-(4-Benzylphenoxymethyl)-1-pentylpyrrolidine hydrochloride, 3 -(4-fluorobenzyloxymethyl)-1-pentylpyrrolidine oxalic acid salt, 3-[2-(4-fluorobenzyloxy)ethyl]-1-(n-pentyl)- pyrrolidine oxalate, 3-(3,4-dichlorophenoxymethyl)-1-pentylpyrrolidine shu acid salt, 3-(2-Phenylphenoxymethyl)-1-pentylpyrrolidine oxalate , 3-(4-isopropylphenoxy)methyl-1-pentylpyrrolidine Urate, 3-(3-phenylfeliximethyl)-1-pentylpyrrolidine oxalate , 3-(4-chlorophenoxymethyl)-1-pentylpyrrolidine oxalate , 1-pentyl-3-[4-(2-p-chlorophenylethynyl)phenoxyco Methylpyrrolidine oxalate, 1-pentyl-3-[4-(2-phenylethynyl)phenoxycomethyl-pyro lysine oxalate, 1-pentyl-3-[4-(2-phenylethyl)phenoxycomethyl-pyrroli Gin oxalate, 1-pentyl-3-(3,4-dichlorobenzylamino)methyl-pyrrolidine. nin sulfate, and 3-[N-(3,4-dichlorobenzyl)-N-methylaminomethyl]-1-pe pyrrolidine dioxalate.

It is understood that compounds of structural formula (I) contain one or more asymmetric centers. Kaga Compounds exist as optical isomers (enantiomers). pure enantiomers, Racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are Included within the scope of. In addition, all possible diastereoisomeric forms (pure enantiomers and mixtures thereof) are within the scope of this invention. Furthermore, eight- When CH=CH-, the compounds exist as geometric isomers and the present invention It includes all such isomers and mixtures thereof.

The compounds of the invention can be prepared by methods similar to those known in the art. can be done. Accordingly, the invention provides in a further aspect that (a) A is OSS or Regarding the compound represented by Structural Formula (I) which is NRI, Structural Formula (■) 8 Structural formula (II) [wherein R and n are the same as defined for structural formula (1), A1 is 0, S or NR’] A compound represented by the structural formula L(CH2), Ar [where m and Ar are The same definition as for structural formula (I), L is a leaving group] Do you want it to react with things?

(b) For a compound represented by structural formula (I) where A is O, S or NRI, Structural formula (III) Day Structural formula (I[[) [wherein n and R are as defined for Structural Formula (I), and Ll is the claim nucleus. It is a group that can be substituted with a substance] A compound represented by the structural formula: HA'(CHz)-Ar [where m and Ar are , is the same as the definition regarding structural formula (I), and A1 is the definition regarding structural formula (ff). or (c) A is NRI; For a compound represented by a certain structural formula (1), structural formula (■): structural formula (rV) [In the formula, R4 is a group -(CH2), N(R')C(OXGHz), -+Ar or represents (CH2), -1c(0)N(Rs(CHz),,Ar), where n, mSR and and Ar are the same as defined for structural formula (1)] React the compound shown by; (d) For compounds represented by structural formula (I) where A is a bond, structural formula (V): Structural formula (v) A compound represented by [wherein R, Ll, n and m are the same as defined above] Structural formula: X'Ar [wherein, Ar is the same as defined for structural formula (I), l is an alkali metal]; (e) Compound R By reaction with L2 [where R2 is a leaving group], the structural formula ■ H Structural formula (VI) (f) Structural formula (■)・ Structural formula (■) [In the formula, R5 is C1-7 alkyl (phenyl), C2-7 alkenyl (phenyl) Nyl), C2-7 fulkynyl (phenyl), or Cl-7 alkyl cycloalkyl]; (g) For compounds represented by structural formula (I) where A is NR', structural formula (■) : Structural formula (■) [wherein R and R4 are the same as defined for structural formula (IV)] Does it reduce the compound that is present?

(h) Structural formula (IX) Structural formula (IX) [where n, m, A, R and Ar are the same as defined for structural formula (I) ] to reduce the compound represented by; (i) For compounds where A is -CH=CH-, structural formula (X): structural formula (X) [wherein R and n are the same as defined above] Whether to react with the reagent to be introduced: (D For example, a compound where A is -CH=CH- is reduced to a compound in which A is -CH2CH,- or Ar is optionally Compounds substituted by phenyl C2-4 alkyl which may be substituted For example, by reducing the corresponding phenyl C2-4 alkenyl compound, , one compound represented by structural formula (I) is added to another compound represented by structural formula (I). Convert.

Then, optionally, a compound of structural formula (I) is formed by forming a salt. Provides a manufacturing method.

In method (a), a compound represented by structural formula (n) and a compound L (CH2)- The reaction between Ar can occur under conditions depending on the nature of the L group and the value of m.

For example, L is a halogen or a sulfonic acid residue such as Tonrad or Mesorad. group, the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base. It will be done.

In case P, (a) (to produce compounds where m is 0) fluoro-substituted aryl When using compound F-Ar, the reaction is performed in the presence of a strong base such as sodium hydride. in an inert organic solvent such as dimethylformamide. Compound F-A The aryl ring in r is substituted with an activating group such as CF3 or NO2. is preferred.

Compounds represented by the structural formula (I[[) and structural formula: HA' (represented by CHJ-Ar) The reaction between the compounds (method (b)) is carried out under conditions that depend on the nature of Ll and A. It can happen.

For example, Ll is hydroxy, m is 0, and AI is oxygen or sulfur. In this case, the reaction is performed in the presence of diethyl azodicarboxylate and triphenylphosphine. It will be carried out in the country's presence. Such a reaction is known as the Mitsunobu reaction. [Disclosed in Noncens (Synthesis) 1981.1] ]. Alternatively, the leaving group L1 is, for example, a halogen atom or a methanesulfur atom. Sulfonyloxy such as fonyloxy or p-toluenesulfenyloxy It may be a base. In this case, the reaction is carried out at 0-200°C in the presence or absence of a solvent. and optionally in the presence of a base.

Reduction of compounds of structural formula (rV) by method (c) is known in the art. For example, using a reducing agent such as lithium aluminum hydride, It can be done using Conveniently, the compound of structural formula (IV) is The compound (rV) can be produced in a one-pot J reaction without isolating itself. (eg, as described below) and then reduced.

Compounds represented by structural formula (V) and structural formula X'Ar in method (d) The reaction between the compounds involved is based on the standards known to those skilled in the art for the formation of carbon-carbon bonds. can occur under standard conditions.

The reaction of the compound of structural formula (Vl) with RL2 according to method (e) can be carried out using the conventional method For example, in an organic solvent such as dimethylformamide. Leaving group L 2 is, for example, a halide such as bromide or chloride, acetoxy or Anoloxy group such as chloroacetoquino, or methanesulfonyloxo or is a sulfonyloxy group such as p-toluenesulfonyloxy. R2 is halo In the case of a genide, the reaction is carried out in the presence of a weak base such as potassium carbonate. and when R2 is sulfonyloxy, sodium hydride or A strong base such as t-butoxide is used.

Reduction of the compound represented by the structural formula (■) by method (f) involves the reduction of aluminum hydride. This is done using standard reducing agents such as lithium.

Reduction of compounds of structural formula (■) or (IX) can be carried out using methods known in the art. For example, the method for the compound represented by the structural formula (TV) can be carried out using a reducing agent such as lithium aluminum hydride in a similar manner to the Ru.

Method (i) can be used to obtain compounds with the formula: Ar(CHz), 4+P(OX Wadsworth-Emmons reagent, denoted by OAlk)z, or the formula: Ar(CHz ) -++PPhJ- [wherein X- is an anion] Witsch test It is done using drugs.

These compounds are commercially available or can be produced by known methods.

The reaction is optionally carried out using clusters such as 15-crown-5 or 18-crown-6. hydrogenated sodium in a solvent such as tetrahydrofuran, which may contain an ether. It is carried out in the presence of a strong base such as thorium or potassium t-butoxide.

The conversion reaction according to method (D) is carried out by methods well known in the art. It will be done. Thus, for example, in compound (I) where A is -CH=CH-, A is -CH Conversion to compound (I) which is 2-CH2- or Ar is optionally substituted. of structural formula (I), which is optionally substituted with phenyl C2-4 alkyl; Preparation of the indicated compound from the corresponding phenyl C2-4 alkenyl compound is This is done by using a catalytic hydrogenation method.

The compound represented by structural formula (II) in which A1 is oxygen and n is 1 is Y-HWu [Journal on Organic Chemistry (J According to the method of Org, Chem, ), 1961.26.1519-24 , dimethyl itaconate (H2C=CCO2CHs)", structural formula RNH2 [In the formula, R is the structural formula ■ CH2-CO2CH5 Reaction with a compound represented by , which is the same as the definition for (1), followed by hydrogenation. It can be produced by reduction with aluminum lithium or the like. Cyclization process at temperatures ranging from +50 to +150°C in a solvent such as an alcohol such as methanol. The reduction is conveniently carried out at 30°C, preferably at the reflux temperature of the solvent; It is carried out in any solvent, conveniently at the reflux temperature of the solvent. A1 is sulfur or NRI Compounds of a given structural formula (n) can be prepared using methods well known in the art. Therefore, via the corresponding halide, hydroxyl of structural formula (II) It can be produced from compounds.

Alternatively, compounds of structural formula (II) can be prepared under standard conditions by can be prepared from the corresponding compounds in which R is hydrogen by hydrogenation. example For example, a compound of structural formula (II) in which R is n-pentyl may be prepared in a suitable solvent, For example, in the presence of a base such as potassium carbonate, a C1-4 alkanol (e.g. in dimethylforma (tanol) or in the presence of a base such as sodium hydride By reaction with n-pentyl halides such as n-pentyl bromide in can be prepared from the corresponding precursor where is hydrogen.

A compound represented by the structural formula (I[[) in which Ll is OH is represented by the structural formula (II) can be prepared in a similar manner to that described for the compound in which Ll is Structural formula (I[ Compounds shown in [) can be produced from the corresponding alcohol by conventional methods. can.

Structural formula ( The compound represented by TV) is a compound represented by the structural formula (II) in which AI represents NRI. Acylating agents corresponding to -(CH2), Ar, such as the acid chloride CICl It can be produced by reacting with OC(CH2)+Ar.

Structural formula in which R4 is a group -(CHz), -+C(0)N(R'XCHz)-Ar In the compound represented by (IV), for example, R4 is -(CH,), ICO! It is H the corresponding compound or its active derivatives such as its acid chloride, ester or anhydride. Produced by the reaction of a conductor with an amine represented by the formula: HN (R'XCHz), Ar. can be built.

If the acid itself is used, the reaction with the amine should be carried out in the presence of a binding agent. It is understood that The carboxylic acid itself can be, for example, the corresponding alcohol, i.e. A It can be produced by oxidation of a compound of structural formula (II) where I is oxygen. can.

The compound represented by Structural Formula (V) is similar to the compound represented by Structural Formula (III). manufactured by the method. If desired, the length of the burlap is well known in the art. may be increased using a method.

The compound represented by the structural formula (Vl) is, for example, one in which R is substituted with an N-protecting group. Using intermediates similar to structural formulas (I[) to (TV), (d) and then converting the N-protecting group to Remove by known methods. Suitable protecting groups include benzyl, diphenyl, Aralkyl groups such as nylmethyl or triphenylmethyl, and acetyl, triphenylmethyl, Lifluoroacetyl, benzoyl, methoxycarbonyl, etquincarbonyl, or an acyl group such as penzyloxycarponyl. such as benzyl Aralkyl groups are eliminated by hydrogenolysis, and acyl groups such as benzoyl are removed by hydrolysis. Desorbed by water splitting. When the N-protecting group is aralkyl, the compound has the structure It is a compound of formula (I), and thus this reaction sequence is How to convert a certain compound represented by (I) into another compound represented by structural formula (1) It is understood to provide law.

The compound represented by the structural formula (■) is a compound represented by the structural formula (Vl), for example , an acid chloride or an anhydride.

A structure in which R4 is a group -(CH2), , NCR')C(○)(CH2)e-, Ar The compound represented by the formula (■) has the structural formula (X[): Structural formula (X[) [where n and R are the same as defined for Structural Formula (II), and AI is N RI] The compound represented by is related to the production of the corresponding compound represented by structural formula (IV). It can be produced by reacting with the same acylating agent.

Structural formula (■ ), for example, with respect to the corresponding compound represented by structural formula (IV). Then, in the same way, the corresponding conversion where R4 is −(CHz)R−+C○2H the formula of the compound or its active derivatives such as its acid chlorides, esters or anhydrides; :HN (Produced by reaction with an amine represented by R'XCHJ-Ar.

Compounds of structural formula (IX) are prepared in which a suitable starting material is substituted for the pyrrolidino ring. The compound represented by structural formula (I) except that it has a 5-oxopyrrolidino ring It can be manufactured in a similar manner. For example, a compound represented by structural formula (IX) is the structural formula (X[[) In formula 1, n, R and 2 are the same as defined for structural formula (I[r)] of the compound with the structural formula HA'(CH2), 'Ar I, where m, A' and and Ar are the same as the definitions for the structural formula (■)] It can be manufactured by

When Ll is hydroxy, the reaction with the compound represented by structural formula (III) is The Mitsunobu reaction can be used as described above.

The compound represented by the structural formula (X) can be prepared by a conventional method, for example, a structure in which 81 is oxygen. Oxidation of a compound of formula (IT) or, for example, thionyl chloride and N, React with 0-nomethylhydroxylamine hydrochloride to produce N-methyl N-methoxy The carboxamide was obtained and alkalized using diisobutyl aluminum hydride. Produced by conversion of the corresponding ester as can be reduced to dehyde Ru.

The compound represented by the structural formula (X) where n is 1 can be prepared by various methods when n is 0. produced from certain corresponding compounds. For example, an aldehyde where n is 0 is (toxymethyl)triphenylphosphonium chloride and potassium t-buto is then treated with a strong acid such as concentrated sulfuric acid to obtain an aldehyde with n=1. It will be done. Alternatively, the aldehyde can be prepared as described in EPA 363085. converted to the corresponding cyanomethyl derivative and then acid-hydrolyzed to give N-methyl -N-methoxycarboxinamide and then reduced. These people The method is also used to form higher congeners.

When the compound of formula (1) is obtained as a mixture of enantiomers, these are , crystallization in the presence of a resolving agent, or e.g. using a chiral HPLC column. separated by conventional methods such as chromatography.

For use in medicine, the compounds of the invention are typically administered in standard pharmaceutical compositions. given. Accordingly, in a further aspect, the present invention provides or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or provides a pharmaceutical composition comprising excipients.

The compounds of the present invention can be administered orally, parenterally, bucally, rectally or transdermally. The pharmaceutical composition may be administered by any conventional method such as administration, and the pharmaceutical composition may be administered accordingly. Things are adapted.

Compounds of structural formula (I) that are active when administered orally and their pharmaceutical Acceptable salts are suitable for use in solutions such as syrups, suspensions or emulsions, tablets, caps. It can be formulated as cells and lozenges.

Liquid formulations generally include ethanolic formulations of the compound or a pharmaceutically acceptable salt thereof. glycerin, non-aqueous solvents such as polyethylene glycol, oil or water. Suspensions or solutions in any suitable liquid carrier, as well as suspending agents, preservatives, and flavors. It consists of a coloring agent or a coloring agent.

Compositions in tablet form can be prepared using any suitable pharmaceutical agent conventionally used for the manufacture of solid dosage forms. It can also be produced using a carrier. Examples of such carriers include stearic acid Magnesium, starch, lactose, sucrose and cellulose are among the Compositions in capsule form can be manufactured using conventional encapsulation methods.

For example, pellets containing the active ingredient can be manufactured using standard carriers and then can be filled into hard gelatin capsules; alternatively, the dispersion or The suspension may be carried in any suitable pharmaceutical carrier, such as aqueous gums, cellulose, silicone, etc. The dispersion or suspension is then softened with gelatin. Can be filled into capsules.

The compounds of the invention are administered parenterally, by porous injection or continuous infusion. You can also do that. Typical parenteral compositions include the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, such as polyethylene glycol. Kohl, polyvinylpyrrolidone, lecithin, solution in peanut oil or sesame oil or Consists of a suspension. Alternatively, the solution can be lyophilized and then It can be reconstituted in a suitable solvent.

Both liquid and solid compositions are commonly used in the pharmaceutical field, such as cyclodextrins. It may also contain other excipients known in the art.

Preferably, the composition is in unit dosage form, such as a tablet, capsule or ampoule. Delicious.

Each dosage unit for oral administration is represented by structural formula (I), calculated as the free base. Preferably contains a compound or a pharmaceutically acceptable salt thereof 1-25019 , each dosage unit for parenteral administration is represented by structural formula (1), calculated as the free base. The composition preferably contains 11 to 251 g of the compound or pharmaceutically acceptable salt thereof. Yes.

A daily dosage regimen for adult patients is, for example, calculated as the free base, with structural formula (I): IIIg to 500 grams of the indicated compound or a pharmaceutically acceptable salt thereof, preferably or 119 to 250 m, for example 5 to 200 m, or 0.1 *q~100mg9, preferably 0.1mg~60u, e.g. 1~40mw static Intravenous, subcutaneous, or intramuscular doses, the compound is administered 1 to 4 times per day. Ru. Alternatively, the compounds of the invention preferably provide up to 40 Chy per day. Administered by continuous intravenous infusion in doses. Thus, the total daily use by oral administration The amount ranges from 1 to 2000+p, with a total daily dose by parenteral administration of 0.1 It is in the range of ~400119.

Suitably, the compound is administered for a continuous treatment period, e.g. one week or more. Dew.

Example Production of intermediates 1) 1-pentyl-3-hydroxymethylpyrrolidine a) YH -HWu) method [Journal on Organic Chemistry (J, Org, Chem, ), 1961.26.1519-241. Dimethyl taconate (15,89) was dissolved in n-pentyl chloride in methanol (20 ml). Reacted with amine (8.72g). Reflux for 2 hours, cool, then methanol After removing the 1-pentyl-5-oxopyrrolidine, the residue was vacuum distilled to give 1-pentyl-5-oxopyrrolidine. -3-carboxylic acid J thyl 18.99 (0,02+++mHgT boiling point 1oo~ 105°C) was obtained.

Measured values: C, 61,83; H, 8,96+N, 6.31%.

Theoretical values of C1, Hl, NO3: C, 61,95; H, 8,98; N, 6.57% .

b) Lithium aluminum hydride (4 , 699) and then 1-pentyl- Methyl 5-oxopyrrolidine-3-carboxylate (18,43w) was slowly added to It was added dropwise at such a rate that reflux occurred. The mixture was refluxed for an additional hour and cooled to 0°C. Cool and water (7 ml) was carefully added. Add more ether and remove the solid salt. Filtered off and then evaporated the ether (8.989-oil). Inorganic matter Extracted with ethanol in a Cousclet overnight (6.09-bundle). combined oily The product was vacuum distilled to yield 11.26 g of the title compound (boiling point 85-90°C at 0.1 mmHg). ) was obtained.

Measured values: C, 69,78; N, 12.54; H, 7,82%.

Theoretical value of C + eHy + NO: C, 70, 12; H, 12, 36; N, 8.18 .

if) 1-pentyl-3-(2-hydroxyethyl)pyrrolidine a) YE Y-HWu's method [Journal on Organic Chemistry] - (J Org Chew), 1961.26.1519-241, 1-pentyl-3-hydroxymethylpyrrolidine in chloroform (10 mA') (6,54r) was dissolved and the mixture was saturated with dry hydrogen chloride gas. The mixture is reduced Thionyl chloride ( 5°6 IN). The mixture was refluxed for an additional hour.

Excess thionyl chloride was removed by co-distillation with ethanol. Evaporation and salt The product was obtained by extraction of the basic residue with ether. For evaporation of ether solutions An oil is thus obtained which is subjected to Kugelrohr distillation. I refined it. 1-Pentyl-3-chloromethylpyrrolidine was obtained as an oil. (5°79g).

Measured value: C, 62,99; H, 10,78: N, 6.99; C1! , 18.7 2%.

Theoretical value of C+oHxoCIN: C, 63,31; H, 10,63; N, 7.38 (J, 1868%.

b) 1-pentyl-3-chloromethylpyrrolidine (5°4 2g), sodium cyanide (7,259), aliquot 336 (375 inches), and water (12,5++/) were vigorously stirred together.

Extraction of the cooled reaction mixture with ethyl acetate followed by evaporation gave an oil (5° 03g) was distilled to give 1-pentyl-3-cyanomethyl-pyrrolidine. (2,989) was obtained.

Measured values: C, 60,32; H, 9,72; N, 12.31%.

Theoretical value of C++HzoNt・HC/: C, 60, 67; H, 10, 18: N, 1 2.23%.

C) A. E. Fadia's method [Journal on ・Medicinal Chemistry (J Med Chew), 1985.28.6 Methanol (60 ml) saturated with dry hydrogen chloride gas using 53-601 1-pentyl-3-cyanomethyl-pyrrolidine (2,982e) was added to.

The mixture was left at room temperature for 16 hours.

The solvent was evaporated in vacuo and the residue was partitioned between sodium hydroxide solution and ether.

(HzO) and then evaporate the dried (NazSo<) ether phase. , an oil was obtained which was distilled by Kugelrohr distillation to give 3-(1-pentyl-pyrrolidium). iii) Methyl acetate (2,139) (boiling point 100°C at 0.2m Hg) was obtained.

d) Lithium aluminum hydride (0,79) in diethyl ether for 30 minutes. Methyl 3-(1-pentylpyrrolidino)acetate (1, 967g) was added. The mixture was refluxed for 4 hours, then cooled to room temperature.

Water (5d) was added and the inorganics were filtered off. The filtrate was evaporated to an oil (1,918 g), which was subjected to Kugelrohr distillation to give 1-pentyl-3-[2-hydroxy ethyl]-pyrrolidi” (1,489) (1, OamHg boiling point 150°C) I got it.

Precise mass spectrometry M” 185.17800++HuOH0iii) 3-[N- (3,4-dichlorophenyl)methylaminocarboxy]-5-oxo-1-pe pyrrolidine 1-pentyl-5-oxopyrrolidine-3-carbo at 150°C for 1 hour under nitrogen. Methyl phosphate (2,13 g) and 3,4-dichlorobenzylamine (1,76 g) ) were melted together.

The reaction mixture was dissolved in ethyl acetate, and the silica was dissolved in a mixture of ethyl acetate and methanol. It eluted below the ram. The resulting oil was crystallized with diethyl ether. The title compound (1.84 g) (melting point = 69-73°C) was obtained.

Measured values: C, 56,82; H, 6,14; N, 7.54; (J', 20.26% .

C+tHz2C/1Ntot theory [: C, 57, 15; H, 6, 21; N, 7.84; C4°19, 85%.

rv) 3-chloromethyl-1-pentyl-5-pyrrolidinone a) P.A.Z. P A Zoretic method [Journal on Organic ・Chemistry (J Org Chew), 45.810, (1980): l 1-pentyl-5-oxo in ethanol (600d) under dry nitrogen using Methyl pyrrolidine-3-carboxylate (21.30 g) and sodium borohydride ( 37.83 g) was added in small portions over 6 hours. The mixture was heated at room temperature for 16 hours. Stir for a while.

The solvent was removed in vacuo and the residue was partitioned between aqueous sodium hydroxide and ether. . The ether phase was washed with brine), dried with NazSO4) and then evaporated. An oil was obtained which was distilled to give 3-hydroxymethyl-1-pentyl-5 -pyrrolidinone (7,469) (boiling point 150-160 °C at 0,8 mBar) was obtained Ta.

Measured values: C, 64,31; H, 10,98; N, 7.56.

B + o H + e N Theoretical value of O2: C, 64, 83: H, 10, 34; N, 7.56%.

b) 3-hydroxymethyl-1-pentyl-5-pyrrolidinone (1,85 g) Dissolved in ether (5M). Thionyl chloride (1,611) was added and the mixture was stirred at room temperature for 24 hours.

Solid anhydrous potassium carbonate was added and the mixture was stirred for 10 minutes. Filter the mixture and the solvent was removed from the filtrate in vacuo. Coevaporation of excess thionyl chloride with toluene removed by.

Purify the residue by chromatography on silica using ethyl acetate as eluent. The title compound (1,674 g) was obtained as an oil.

Measured values: C, 58,77; H, 8,87; N, 6.75%.

Theoretical value of C+oH1, ClN0: C, 58,96; H, 8,91: N, 6.88 %.

V) 3-[N-(3,4-dichlorophenyl)methyl-N-methylaminocarbo Xico-5-oxo-1-pentylpyrrolidine 1-pentyl-5-oxopyrroli Methyl di-3-carboxylate (4,26 g) and N-methyl-3,4-dichloro Lobenzylamine (3.80g) was melted together at 150°C for 4 hours. cool to room temperature After cooling, the product was chromatographed using an ethyl acetate, methanol mixture. Purified by graphite. The title compound (oil) thus obtained (1, 49g) was used as is.

Example 1 3-(4-fluorophenoxymethyl)-pentylpyrrolidine hydrochloride under nitrogen, Dry THF (3-hydroxymethyl-1-pentylpyrrolidine (3-hydroxymethyl-1-pentylpyrrolidine) 0,8539), 4-fluorophenol (0,56 g) and triphenylpho Sphine (1,319) was stirred together. The mixture was cooled in a water bath and azodi Diethyl carboxylate (0.79 mA') was injected. Leave the mixture at room temperature overnight The THF was removed by evaporation and the residue was purified on silica using ethyl acetate as eluent. Flash chromatography on gel was performed. The obtained oil is dissolved in ether. and extracted with 10% hydrochloric acid. The aqueous phase was basified with 2N NaOH and Extracted with tel. The ether was washed with N20, dried and evaporated to give an oil; This was liberated from triphenylphosphine oxyto. This oily substance is mixed with Et, O Treatment with IMHCl in 559) (melting point = 92-94°C).

Measured value: C, 63,34; H, 8,39; N, 4.56; C1, 11,77 %.

Theoretical value of Cl6H14FNo-HCl: C, 63,67; H, 8,35; N, 4 ．． 64: C1, 11, 70%.

Example 2 3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpyrrolidine ・Hydrochloride In Example 1, 4-fluorophenol was replaced with 3,4-methylenedioquinephenol ( 0,695 g) and the other reagents were used in corresponding molar ratios as described above. Initial acid/base extraction followed by flash chromatography (silica gel-vinegar (ethyl acid) to give an oily substance. Dissolve this oil in ether and Treated with IMHcI. The resulting solid was crystallized twice from ethyl acetate and labeled Compound (0,6539) (melting point = 133-134°C) was obtained.

Measured value: C, 62,15; H, 8,13; N, 4.24; C1, 10, 61% .

CI? Theoretical value of H2s N O2・HCI: C, 62,28; H, 7,99 ;N, 4.27;CJ', 10.81%.

Example 3 3-(4-benzyloxyphenoxymethyl)-1-pentylpyrrolidine/hydrochloric acid salt In Example 1, 4-fluorophenol was replaced with 4-benzyloxyphenol (1°0 0g), other reagents were used in corresponding molar ratios to obtain an oil, which was converted into acid- Base extraction followed by flash chromatography (silica gel-ethyl acetate) It was attached to. The residue was dissolved in ether with a slight excess of H in ether (J’ Work-up gave a solid which was washed with ether and then dried. Next, this The solid was crystallized from ethyl acetate to give the title compound (0,481 9) (melting point = 155-156°C) was obtained.

Measured value C, 70, 85; H, 8, 43; N, 3.59; Cj! ,9.18% .

C21H3+N O2・HCI theoretical value・C,70,84;H,8,31;N 3.73; CA'.

On 9.09.

Example 4 3-(4-fluorobenzyloxymethyl)-1-pentylpyrrolidine shu acid salt Sodium hydride (60% oil) in anhydrous dimethylformamide (20 ml) under nitrogen Dispersion, 0.449) was suspended. 3-hydroxymethane in DMF (2011) Tyl-1-pentylpyrrolidine (1,729) was added and the mixture was stirred for 10 minutes. Stirred.

4-Fluoropencyl chloride (1,2ml) was added and the mixture was stirred at room temperature for 48 hours. Stir. The reaction mixture was partitioned between water and ether. washing the ether phase; Drying and evaporation gave an oil (2,459). Vacuum distillation (150°C1Q, 2 mmHg), but no pure product was obtained. The distillate (1,989) flash chromatography on silica gel (CHzC7!z/MeOH ) to give an oil (1,479). This is converted into noyulic acid (0,679). After addition to the solution in hot ethyl acetate and cooling, a solid was obtained which was collected and washed with ether. Cleaned and then dried.

The obtained solid was recrystallized from ethyl acetate to give the title compound (1,31 g) (melting point: 110-114°C) was obtained.

Measured values: C, 61,66; H, 7,64; N, 3.99%.

Theoretical value of C+5H28FNO-CtHtO<: C, 61,77; H, 7,64; N, 3.79%.

Example 5 3-[2-(4-fluorobenzyloxy)ethyl]-1-(n-pentyl)- Pyrrolidine oxalate Under dry nitrogen, sodium hydride (8 0% oil dispersion, 0.32 g) was suspended. 3-[2-hydroxyethyl)-1- Pentylpyrrolidine (1.83g) was added and the mixture was stirred for 10 minutes.

4-fluorobenzyl chloride (1,22,/) was added and the mixture was heated at room temperature for 1 hour. The mixture was then stirred at 60° C. for 6 hours. The mixture was allowed to come to room temperature over 16 hours.

The solvent was evaporated in vacuo and the residue was treated with water. Product by extraction into ether I got it. The ether phase was extracted with hydrochloric acid. The acidic solution was dissolved in sodium hydroxide water for 5 minutes. It was made basic with a 0% (W/W) solution. The resulting oil was extracted into ether.

The ether phase was washed with H, O), dried with NazS (O), and then evaporated. An oil (1,763 g) was obtained.

The product was column coated on silica using a dichloromethane/methanol mixture. It was purified as its hydrochloride salt by chromatography. the product as its free salt and then converted to its oxalate salt using oxalic acid in THF. did. The product was purified by treatment with ethyl acetate to give a white microcrystalline solid (0 , 7469) (melting point = 80-82°C).

Measured values: C, 62,39; H, 7,82; N, 3.83%.

Theoretical value of C+5H28FNO・(CO2H)2 C, 62, 65: H, 7, 8 9;N, 3.6 Example 6 3-(3,4-dichlorophenoxymethyl)-1-pentylpyrrolidine shu acid salt In Example 1, 4-fluorophenol was replaced with 3,4-dichlorophenol (1,22 Instead of g), other reagents were used in corresponding molar ratios to obtain oils. this oily substance was treated with an equimolar amount of oxalic acid dihydrate in warm ethyl acetate to give a solid, which was recrystallized from ethyl acetate to obtain the title compound (0,746w) (melting point = 116-11 7°C).

Measured values: C, 52,94; H, 6,09; N, 3.54%.

Theoretical value of C+5H1sC4NO・(COzH)t: C, 53,21; H, 6,2 0; N, 3°45%.

Example 7 3-(2-Phenylphenoquinemethyl)-1-pentylpyrrolidine oxalate The 4-fluorophenol of Example 1 was replaced with 2-phenylphenol (1.28 g) Instead, other reagents were used in corresponding molar ratios to obtain an oil, which was combined with the eluent. Chromatograph on silica using a mixture of ethyl acetate, methanol, and ammonia. It was purified by lithography. The purified product was dissolved in 10% excess in warm ethyl acetate. was converted to its oxalate salt by treatment with oxalic acid dihydrate. profit The resulting solid was recrystallized from ethyl acetate and then treated with charcoal in methanol. .

Filtration and treatment of the filtrate with diethyl ether gave the title compound (0,278 9) (melting point = 119-121°C) was obtained.

Measured values: C, 68,42: H, 7,44; N, 3.77%.

Theoretical value of CzzHuNO・(CO2H)2・0.5H20・C,68,22;H , 7,63; N, 3.31%.

Example 8 3-(4-isopropylphenoquine)methyl-1-pentylpyrrolidine shu acid salt In Example 1, 4-fluorophenol was replaced with 4-isopropylphenol (1,02 9), other reagents were used in corresponding molar ratios to obtain an oil, which was used for elution. Silica chromatography using a mixture of ethyl acetate, methanol, and ammonia as liquids. It was purified by roughy. The purified oil was dissolved in 10% excess silica in warm ethyl acetate. Treated with oxalate dihydrate. The obtained solid was recrystallized from ethyl acetate and given the title A compound (0,342 g) (melting point = 103-105°C) was obtained.

Measured values: C, 66,37; H, 8,73; N, 3.95%.

Theoretical value of CnHs+NO・(COzH)2: C, 66,46; H, 8,76; N , 3.69%.

Example 9 3-(3-Phenylphenoxymethyl)-1-pentylpyrrolidine oxalate In Example 1, 4-fluorophenol was replaced with 3-phenylphenol (1,28v) Instead, other reagents were used in corresponding molar ratios to obtain an oil, which was combined with the eluent. chromatograph on silica using a mixture of ethyl acetate, methanol, and ammonia. It was purified by subjecting it to a fee. The purified product was dissolved in a 10% excess of sulfate in warm ethyl acetate. It was converted to its oxalate salt by treatment with uric acid dihydrate. The obtained solid Recrystallization from ethyl acetate gave the title compound (0,5159) (melting point = 100-10 3°C).

Measured values: C, 69,64; H, 7,55; N, 3.64%.

Theoretical value of CuHuNO・(COzH)z: C, 69,71; H, 7,56; N, 3.39%.

Example 10 3-(4-chlorophenoxymethyl)-1-pentylpyrrolidine oxalate fruit In Example 1, 4-fluorophenol was replaced with 4-chlorophenol (0.96 g). In addition, other reagents were used in corresponding molar ratios to obtain an oil. Add this oily substance to warm vinegar. Treatment with 10% excess oxalic acid dihydrate in ethyl acetate gave a solid, which was dissolved in ethyl acetate. Recrystallization from chill and water (charcoal) gave the title compound (0,308 g) (melting point = 1 32°C) was obtained.

Measured values: C, 58,13; H, 7, OO; N, 3.89%.

Theoretical value of C+5HuC/No・(CO2H)2: C, 58,14; H, 7,0 5; N, 3°77%.

Example 11 1-pentyl-3-[4-(2-p-chlorophenylethynyl)phenoxy]- Methylpyrrolidine oxalate In Example 1, 4-fluorophenol was converted into 4-chloro-4'-hydroxystilbene. (4,609), other reagents are used in corresponding molar ratios and salts are added at appropriate stages. Washing with dilute sulfuric acid rather than acid gave an oil. Add a portion of this oil to warm acetic acid. The oxalic acid was dehydrated by treatment with a 10% excess of oxalic acid dihydrate in ethyl Converted to acid salt. The salt was recrystallized from ethanol/water to give the title compound (0,233 9) (melting point = 201-202°C (dec)) was obtained.

Measured value: C, 65,66+H, 6,68; N, 3.06; CI, 7.21%.

Theoretical value of C44H3゜ClN0・(Co,H)2: C,65,88; H,6, 80; N, 2°96: CA', 7.48%.

Example 12 1-pentyl-3-[4-(2-phenylethynyl)phenoxy]methyl-pyro Nonone oxalate In Example 1, 4-fluorophenol was converted into 4-hydroxy-trans-stilbene. (3,9259), other reagents were used in corresponding molar ratios to obtain an oil. .

A portion of this oil was dissolved in a 10% excess of oxalic acid dihydrate in warm ethyl acetate. Converted to oxalate. The salt was first extracted from ethanol, then acetonitrile, The title compound (0,1269) was recrystallized from a water mixture (melting point 198-199°C). ) was obtained.

Measured values: C, 70,98; H, 7,53; N, 3.23%.

Theoretical value of C24831NO・(C02H)2: C,71,05:H,7,57; N, 3.19%.

Example 13 1-pentyl-3-[4-(2-phenylethyl)phenoxycomethyl-pyrroli Gin oxalate 1-Pentyl-3-[4-(2-phenylethynyl) prepared according to Example 12 ) phenoxy]-methyl-pyrrolidine (2,009) in ethanol (100 ml ) and a slight excess of hydrochloric acid was added. 5% palladium on carbon (0,19 ) was added and the mixture was hydrogenated at 4 Qpsi and room temperature for 16 hours.

The catalyst was filtered off and the volume of the filtrate was reduced under vacuum. Dissolve the residue in sodium hydroxide solution Partitioned between solution and ether. Wash the ether phase with H2O and dry with N. a2S○4), then evaporated to give an oil. The oil was dissolved in warm ethyl acetate. It was converted to its oxalate salt with a 10% excess of oxalic acid dihydrate. The salt is converted into acetonate. The title compound (1,41 g) was recrystallized from tolyl (melting point = 143-144°C) I got it.

Measured values: C, 70.34; H, 7.92; N, 3.56%.

Theoretical value of Cx5H33NO・(C02H)2・C,70,72:H,7,99; N, 3.17%.

Example 14 1-pentyl-3-(3,4-dichlorobenzylamino)methyl-pyrrolidine. nin sulfate Lithium aluminum hydride (0,1 4g) was suspended. 3-[N dissolved in dry tetrahydrofuran (30m/) -(3,4-dichlorophenyl)methyl-amino-carboxy]-5-oxo 1-pentylpyrrolidine (0.50v) was added over 15 minutes at ice temperature.

The reaction mixture was refluxed for 1 hour and left at room temperature for 16 hours. The reaction is complete until the reaction is complete. Water was carefully added to the reaction mixture. The mixture was extracted with ether. ether phase was washed with H2O), dried with Na25OJ, and then evaporated to give an oil. .

The oil was treated with 2 equivalents of oxalic acid dihydrate in warm ethyl acetate to remove the oxalate. Converted to acid salt. Stirring the resulting solid with dimethylformamide The title compound (0,214 g) (melting point = 217-218°C) was purified by Obtained.

Measured value: C, 49,79: H, 6,05; N, 5.80; C1', 13.17% .

Theoretical value of Cl7HHCA'lNm 2 (COzH)z: C, 49, 52; H, 5,94; N, 5°50: CA', 13.92%.

Example 15 3-[N-(3,4-dichlorobenzyl)-N-methylaminomethyl]-1-pe pyrrolidine salt Tetrahydrofuran (IC) +7' of lithium aluminum hydride (0,49) ) 3-[N-3,4-dichlorophenyl)methyl-N-methylamine was added to the Nakano suspension. Tet of nocarboxyco-5-oxo-1-pentyl-pyrrolidine (1,499) The solution in lahydrofuran (30 mA') was added over 30 minutes. Place the mixture in the chamber Stir at room temperature for 1 hour, then reflux for 1 hour.

The mixture was cooled in a water bath and enough water was added to break up the composite. Aete (100,1) was added and the mixture was dried over anhydrous sodium sulfate. the mixture The material was filtered and the filtrate was evaporated to give an oil. The oil was dissolved in 2 equivalents of warm ethyl acetate. It was converted to its salt by treatment with oxalic acid dihydrate.

The obtained solid was recrystallized from ethanol to obtain the title compound (1,2659) (melting point = 163-165°C).

Measured value C, 50,63; H, 6,06; N, 5.35; (J', 13.99 %.

C+ m H2llC12N 2.2 (theoretical value of CO2Hh C, 50, 48; H, 6,16; N, 5°35; Cf, 13.55%.

Example 16 3-[4-(2-p-chlorophenylethyl)phenoxycomethyl-1-pentyl L-pyrrolidine nosulfate In Example 1, 4-fluorophenol was converted to 1-(p-chlorophenyl)-2-(p -Hydroxyphenyl)ethane (2,00g) and other reagents with corresponding molar A solid was obtained using an ethyl acetate/methanol mixture as eluent. was purified on a silica gel column using

The product (white solid) was soluted with 10% excess oxalic acid dihydrate in warm ethyl acetate. was converted to oxalate. The salt was recrystallized from ethanol to give the title compound (0°7 39) (melting point = 121-123°C) was obtained.

biological data Ca2′″ current measurement cell preparation Sensory neurons in the dorsal root ganglion were removed from 1-day-old rat pups [Fo rda) et al., Developmental Plain Research (Developme ntalBrBinResearch), 22 (1985), 55-651° It is possible to effectively fix the potential difference of Ca” current by placing cells on a cover glass. Used within 3 days.

solution Pipette (internal solution): CsC 1130mM; HEPES 10mM: EGT AlomM; MgCl24wM; Contains 2mM of ATP and p Buffered to H7.2.

Once the soaking solution has changed to dissociate the Ca'' current, place the cells at the specified temperature. Recordings were made on whole cells after immersion in the loading solution.

The external solution for Ca” channel current recording was BaCl210mM; TEA-C I2130mM Nigel: l-su 10mM; HEPES 10mM: MgCIh It contained 1mM and was buffered to TEA-OHT pH 7.3. Barium is This is useful because it helps separate currents and avoids calcium-dependent current inactivation. It was used as a charge carrier.

Compounds were dissolved in DMSO to prepare 20mM stock solutions. At the drug concentration used, Excipient (0.1%) showed no significant effect on Ca'' current.

All experiments were performed at 21-24°C. Whole-cell current is Li5tEPC-7 amplified record and store using instruments previously disclosed [Benz 1m & Cheno (Benham & Tsien), Journal on Physiology (J of Physiology) (1988), 404.767- Digitized for later analysis using PC software similar to [784]. did.

result Ca2“ current originating from dorsal root ganglion neurons using lQmM Ba'' as a charge carrier. The resulting Ca2+ channel current up to 1QnA gated at the peak voltage is Recorded. 15 seconds from holding potential of -8QmV to test potential of O or +101V A current was generated each time. This test potential is at the peak of the current-voltage relationship, Evaluating the cutoff at this point reduces errors due to holding potential drift. I set it.

In some cells, as is commonly seen when recording Ca2+iJ fluxes, The current will gradually attenuate. This rate of decay was measured under controlled conditions and over the course of drug application. By extrapolation, control values were derived to relate the drug-influenced currents. 20μM drug (Second block was assessed 3 minutes after drug application.

The compounds of Examples 1 to 16 had plateau Ca"Li flow inhibition rates (%) of 36 to 99. It was within the range of %.

PCT/GB 9210101111 h-Akebono---＾--1--Tk Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number C07D405/12 207 7602-4C (72) Inventor Cooper, Dipid Breinigi Rhys Country Essex CM 19.5 A.D., Barlow, The Binnacles, Coldharbour Road (no address displayed) SmithKline Beecham ・Pharmaceuticals I (72) Inventor King, Ronald Joseph Essex CM, UK 19.5 A.D., Barlow, The Pinnacles, Coldharbour Road (No street address displayed) SmithKline Beecham Pharmaceuticals

Claims (11)

[Claims] 1. Structural formula ( I): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼Structural formula (I) [in the formula, R is C1-8 alkyl, C1-8 alkyl (phenyl), C2-8 alkenyl ( phenyl) p, C2-8 alkynyl (phenyl) p, C3-8 cycloalkyl or or C1-8 alkylC3-8 cycloalkyl; p is 0 to 2; n is 0 to 6; A is a bond, -CH=CH-, -C≡C-, oxygen, sulfur or NR1; R 1 is hydrogen, C1-8 alkyl or phenylC1-4 alkyl; m is 0-3; Ar is aryl or heteroaryl, each optionally substituted. ] Use of a compound represented by or a pharmaceutically acceptable salt thereof. 2. The disorder is a condition or disease related to the accumulation of calcium in mammalian brain cells. The use according to claim 1. 3. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to administration of calcium in mammalian brain cells to a subject in need of treatment. Methods for treating symptoms or diseases caused or flared by mucosal accumulation . 4. Structural formula (IA): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Structural formula (IA) [wherein, Ra is C5-8 alkyl, C5-8 alkyl (phenyl), C2-8 alkenyl (phenyl) p, C1-8 alkynyl (phenyl) p, C3-8 cycloalkyl or C1-8 alkylC3-8 cycloalkyl; p is 0 to 2; n is 0 to 6; A is a bond, oxygen, sulfur or NR1; R1 is hydrogen, C1-8 alkyl or phenylC1-4 alkyl; m is 0 to 3; Ar is aryl or heteroaryl, each optionally substituted. ] A compound represented by or a salt thereof. 5. Ra is C5-8 alkyl or C2-8 alkenyl (phenyl) p, 5. The compound according to claim 4, wherein p is 1. 6. 6. A compound according to claim 4 or 5, wherein A is oxygen. 7. Claims 4 to 6, wherein the chain -(CH2)nA(CH2)m has a length of 2 to 5 atoms. A compound according to any one of the items. 8. Any of claims 4 to 7, wherein Ar is optionally substituted phenyl. The compound according to item 1. 9.3-(4-fluorophenoxymethyl)-1-pentylpyrrolidine; 3-( 3,4-methylenedioxyphenoxymethyl)-1-pentylpyrrolidine; 3- (4-Benzylphenoxymethyl)-1-pentylpyrrolidine; 3-(4-fluor (obenzyloxymethyl)-1-pentylpyrrolidine; 3-(3,4-dichloro lophenoxymethyl)-1-pentylpyrrolidine; 3-(2-phenylphenoxymethyl)-1-pentylpyrrolidine; dimethyl)-1-pentylpyrrolidine; 3-(4-isopropylphenoxy)methyl Tyl-1-pentylpyrrolidine; 3-(3-phenylphenoxymethyl)-1- Pentylpyrrolidine; 3-(4-chlorophenoxymethyl)-1-pentylpyro Lysine; 1-pentyl-3-[4-(2-p-chlorophenylethenyl)phenol [xy]methyl-pyrrolidine; 1-pentyl-3-[4-(2-phenylethenyl)phenoxy]methyl-pyro lysine; 1-pentyl-3-[4-(2-phenylethyl)phenoxy]methyl-pyrroli Di1-pentyl-3-(3,4-dichlorobenzylamino)methyl-pyrrolidine ;or 3-[N-(3,4-dichlorobenzyl)-N-methylaminomethyl]-1-pe pyrrolidine; 5. The compound according to claim 4, which is a pharmaceutically acceptable salt thereof. 10. (a) For compounds represented by structural formula (I) where A is O, S or NR1 and structural formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼Structural formula (II) [wherein R and n are Same definition as for formula (I), A1 is O, S or NR1] A compound represented by the structural formula: L(CH2)mAr [where m and Ar are The same definition as for formula (I), L is a leaving group] Should it react? (b) For a compound represented by structural formula (I) where A is O, S or NR1, Structural formula (III): ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ Structural formula (III) [where n and R are Same definition as for formula (I), L1 is a group displaceable by a nucleophile ] A compound represented by the structural formula: HA1(CH2)mAr [where m and Ar are The definition is the same as for structural formula (I), and A1 is the definition for structural formula (II). or (c) A is NR1. Regarding the compound represented by structural formula (I), structural formula (IV): ▲ mathematical formula, chemical formula, There are tables etc. ▼Structural formula (IV) [In the formula, R4 is the group -(CH2)nN(R1) C(O)(CH2)m-1Ar or -(CH2)n-1C(O)N(R1)( CH2)mAr, where n, m, R and Ar have the same definitions with respect to structural formula (I). are the same] React the compound shown by; (d) For compounds represented by structural formula (I) where A is a bond, structural formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼The compound represented by the structural formula (V) is represented by the structural formula: 1Ar [wherein Ar is the same as defined for structural formula (I), and X1 is (e) Compound RL2 [in the formula , L2 is a leaving group] to form structural formula (VI): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼Introducing the group R to the compound represented by the structural formula (VI) (f) Structural formula (VII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Structural formula (VII) [wherein, R5 is C1-7 Alkyl (phenyl) p, C2-7 alkenyl (phenyl) p, C2-7 alkyl p or C1-7 alkyl C3-8 cycloalkyl] reacting the indicated compounds, optionally then forming a salt; (g) A For a compound represented by structural formula (I) where is NR1, structural formula (VIII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Structural formula (VIII) [In the formula, R and R4 are , which is the same as the definition for structural formula (IV)] ; (h) Structural formula (IX): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼Structural formula (IX) [In the formula, n, m, A, R and and Ar are the same as defined for structural formula (I). Ruka; (i) For compounds where A is -CH=CH-, structural formula (X): ▲ mathematical formula, chemical There are formulas, tables, etc. ▼ Structural formula (X) [wherein R and n are the same as the above definitions] (j) For example, , reduce a compound where A is -CH=CH- to a compound where A is -CH2CH2- or Ar is optionally substituted phenyl C2-4 a For compounds substituted by alkyl, the corresponding phenylC2-4alkyl Certain compounds of structural formula (I) can be prepared by into another compound of formula (I); then, if desired, forming a salt. A method for producing a compound represented by structural formula (I). 11. A compound according to claim 1 or claims 4 to 9 and a pharmaceutically acceptable carrier. Pharmaceutical composition consisting of the body.