JP2003502404A - 4-Aminopiperidine derivatives of tetrahydronaphthalene, chroman and thiochroman - Google Patents

Abstract

(57) [Summary] The following formula (I): Of 1,2,3,4-tetrahydronaphthalene, chroman and thiochroman, pharmaceutical compositions comprising the same, and their use for the treatment of neurological diseases. In the above formula, r, s and X are as defined in the description, and R ¹ , R ² , R ³ and R ⁴ are various substituents and are as defined in the description.

Description

Detailed Description of the Invention

The present invention relates to compounds, in particular 1,2,3,4-tetrahydronaphthalene, chromans and thiochromans, processes for their preparation and chemical intermediates useful in said processes. The invention further relates to 1,2,3,4-tetrahydronaphthalene, chromans and thiochromans, pharmaceutical compositions containing them, and their use in methods for treating animals, including humans, in particular for treating neurological disorders. .

Neurological disorders for which the compound is useful include stroke, head trauma, transient ischemic stroke,
And chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia. The compounds useful in the present invention are believed to act by binding via the [ ³ H] -emopamil binding site.

[0003]

[Prior art]

Emopamiru is long, its efficacy, have probably been considered for a long time and neuroprotective agents derived from the action of voltage-sensitive calcium channels (VSCC) or 5-HT ₂ receptors. An obvious paradox to this logic is that verapamil, which is chemically and pharmacologically very similar to emopamil, has no neuroprotective effect. The lack of neuroprotective effects by verapamil was initially explained by its inability to enter the CNS, but recent studies have suggested the involvement of other factors (Keith et al., Br. J. Pharmacol. 113: 379-384 (1994)).

[ ³ H] -Emopamil binding has revealed a site with a high affinity that is abundant in the brain but highly abundant in the liver, unrelated to VSCC (Moebius et al., Mo
l. Pharmacol. 43: 139-148 (1993)). Moebius et al. Named it the "anti-ischemic agent" binding site because it is displaced by strong affinity by several chemically different neuroprotective agents. In the liver, the [ ³ H] -emopamil binding site is localized to the endoplasmic reticulum.

Neuroprotective compounds such as emopamil and ifenprodil are known to show a strong affinity for the [ ³ H] -emopamil binding site. However, these are not selective suppressors, but rather neuronal VSCC, NMDA receptors (N-
Methyl-D-aspartate) exhibits activity at either the polyamine site and / or the sigma-1 binding site.

[0006]

[Problems to be Solved by the Invention]

One of the features of the present invention is that it exhibits a selective action at the [ ³ H] -emopamil binding site and further a neuroprotective action without directly acting on either the VSCC or NMDA receptors, and related side effects such as Includes compounds with low blood pressure seen with emopamil or less behavioral expression seen with ifenprodil.

Accordingly, the present invention provides a compound of formula (I): embedded image or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester, amide or carbamate thereof:

[Chemical 11] Wherein R ¹ and R ² are each independently selected from hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 alkenyl, optionally substituted C _3-6 alkynyl Wherein the optionally substituted substituents are halo, nitro, hydroxy, C _1-6 alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulfamoyl, mesyl, N -C _1-6 alkylamino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkoxycarbonyl, N-C _1-6 alkylcarbamoyl or N, N-
Selected from one or more groups selected from (C _1-6 alkyl) ₂ carbamoyl;

Alternatively, R ¹ or R ² is a group of formula (IA) consisting of B- (CH ₂ ) _q- , wherein B is aryl, carbon-linked heteroaryl, carbon-linked heterocycle, C _3-12 cycloalkyl. Or a C _3-12 cycloalkyl fused to a benzene ring; q is 0, 1, 2, 3, 4, 5 or 6; and further wherein said aryl, heteroaryl or heterocycle is optionally halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N- (C _1-6 alkyl) amino, N, N-
(C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, N- (C _1-6 alkyl)
Carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkyl S (O) _a (a is 0, 1 or 2), C _1-6 alkoxycarbonyl, N- (C _1-6 Alkyl)
Sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulphamoyl, and phenyl C _1-6 with one or more groups selected from alkyl may be optionally substituted on ring carbon; and -NH- heterocycle or heteroaryl containing groups is optionally C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, by C _1-6 alkanoyl, C _1-6 alkylsulfonyl or phenyl C _1-6 alkyl Optionally substituted on said nitrogen;

[0009]   Or R¹And R²Is a heterocycle together with the nitrogen atom to which they are attached
Or forming a heteroaryl ring, in which case said heterocycle or heteroaryl ring
Is optionally halo, nitro, cyano, hydroxy, trifluoromethyl,
Lifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulf
Amoy, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Arcoki
Shi, C_1-6Alkanoyl, C_1-6Alkanoyloxy, N- (C_1-6Alkyl)
Mino, N, N- (C_1-6Alkyl)₂Amino, C_1-6Alkanoylamino, N- (C_{1 -6} Alkyl) carbamoyl, N, N- (C_1-6Alkyl)₂Carbamoyl, C_1-6A
Rukiru S (O)_a(A is 0, 1 or 2), C_1-6Alkoxycarbonyl, N- (C _1-6 Alkyl) sulfamoyl, N, N- (C_1-6Alkyl)₂Sulfamoyl
Is phenyl C_1-6On one or more groups selected from alkyl on a ring carbon
Optionally substituted; heterocycle or heteroaryl ring further containing -NH- group
May be C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6A
Lucanoyl, C_1-6Optionally substituted on said nitrogen with alkylsulfonyl.
;   R³Is halo, hydroxy, C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Archi
Le, cyano, nitro, or C_2-6Alkenyl;   R^FourIs C_1-6Alkyl;   X is -CH₂-, -O-, or -S-;   r is 0, 1, 2, 3 or 4 and in this case R³The groups of may be the same or different
Well;   s is 0, 1, 2 or 3 and in this case R^FourThe groups of may be the same or different
.

In another aspect, the invention features a neurological disease (eg, stroke, head trauma, transient ischemic stroke and chronic neurodegenerative disease (eg, Alzheimer's disease, Parkinson's disease, diabetic neuropathy, muscle). Atrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia
)) For the treatment of compounds of formula (I). In yet another aspect, the invention includes a method of making a compound of formula (I). In yet another aspect, the invention includes pharmaceutical compositions containing a compound of formula (I) with excipients, diluents or stabilizers as further disclosed herein.

[0011]

[Means for solving the problem]

As used herein, the term "alkyl" includes straight chain and branched chain alkyl groups, but is limited to the straight chain version only for individual alkyl groups such as "propyl". Similar conventions apply to "alkenyl", "alkynyl" and other radicals. For example, "phenyl C _1-6 alkyl" includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl. The term "halo" refers to fluoro, chloro, bromo and iodo. The term aryl refers to an unsaturated carbocycle. Preferably aryl is phenyl,
It is naphthyl or biphenyl. More preferably aryl is phenyl.

The term “heteroaryl” or “heteroaryl ring”, unless otherwise limited, is an unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic 5-1
A 4-membered ring having up to 5 heteroatoms in the ring selected from nitrogen, oxygen and sulfur,
In this case -CH ₂ - -C sometimes groups (O) - substituted by, endocyclic nitrogen atom to form a oxidized to N- oxides sometimes. Examples of said heteroaryl are thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl. , Benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl.

The term “heterocyclyl” or “heterocycle”, unless otherwise limited, is a fully saturated mono- or bicyclic 5-14 membered ring up to five selected from nitrogen, oxygen and sulfur. It has endocyclic heteroatoms, in this case -CH ₂ - -C sometimes groups (O) - is replaced by. Examples of said heterocyclyl include monofolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.

When the substituents of the optional substitutions are selected from “one or more” groups, this definition includes all substituents selected from one of the specified groups. It will be understood that this includes the case where a substituent is selected, or the substituent is selected from two or more than three of the specified groups.

In the present invention, examples of C _1-6 alkyl include methyl, ethyl, isopropyl and t-butyl; examples of phenyl C _1-6 alkyl include benzyl, phenylethyl and phenylpropyl. Examples of C _1-6 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl; examples of C _1-6 alkoxy include methoxy, ethoxy and propoxy; Examples of _1-6 alkanoylamino include formamide, acetamide and propionylamino; examples of C _1-6 alkyl S (O) _a (where a is 0, 1 or 2) include methylthio, ethylthio, methylsulfinyl. , ethylsulfinyl, include mesyl and ethylsulfonyl; examples of C _1-6 alkylsulfonyl is mesylate And it contains ethylsulfonyl; examples of C _1-6 alkanoyl, include propionyl and acetyl; Examples of C _1-6 alkanoyloxy, include propionyloxy and acetyloxy; N-C _1-6 Examples of alkylamino include N-methylamino and N-ethylamino; examples of N, N- (C _1-6 alkyl) ₂ amino include N, N-dimethylamino, N, N-
Include diethylamino and N-ethyl-N-methylamino; examples of _C3-12 cycloalkyl include cyclopropyl and cyclohexyl;

Examples of C _3-12 cycloalkyl fused to the benzene ring include 1,2,3,4-tetrahydronaphthyl and 2,3-dihydroindenyl; examples of C _3-6 alkenyl are , Allyl and 1-propenyl; examples of C _2-6 alkenyl include vinyl, allyl and 1-propenyl; examples of C _3-6 alkynyl include 1-propynyl and 2-propynyl Examples of C _2-6 alkynyl include ethynyl, 1-propynyl and 2-propynyl; Examples of haloC _1-6 alkyl include 2-chloroethyl, trifluoromethyl and 2-bromopropyl. Re; N- examples of (C _1-6 alkyl) sulphamoyl, include N- methylsulfamoyl and N- ethylsulfamoyl; N, N- examples of (C _1-6 alkyl) ₂ sulphamoyl Is , N, N-dimethylsulfamoyl and N-methyl-N-ethylsulfamoyl; examples of N- (C _1-6 alkyl) carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl. Re; and N, examples of N- (C _1-6 alkyl) ₂ carbamoyl, N, include N- dimethylcarbamoyl and N- methyl -N- ethylcarbamoyl.

Preferably R ¹ and R ² are each independently selected from hydrogen and optionally substituted C _1-6 alkyl, or R ¹ or R ² is of the formula (defined above)
IA), wherein B is aryl and q is 1; or R ¹ and R ² together with the nitrogen atom to which they are attached form a heterocycle.

More preferably R ¹ and R ² are each independently selected from hydrogen, optionally substituted C _1-5 alkyl and benzyl; or R ¹ and R ² are attached to them. Together with the nitrogen atom, it forms a heterocycle.

In particular R ¹ and R ² are each independently selected from hydrogen, methyl, n-propyl, isopropyl, isoamyl and benzyl; or R ¹ and R ² are the nitrogen atom to which they are attached. Together they form the piperidine ring.

Preferably r is 0. Preferably s is 0. In one of the features of the invention, preferably X is CH ₂ . In another aspect of the invention, preferably X is S. In yet another aspect of the invention, preferably X is O.

Therefore in a preferred aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an ester, amide or carbamate, which is hydrolyzed in vivo as follows: R ¹ and R ² are each independently selected from hydrogen and optionally substituted C _1-6 alkyl, or R ¹ or R ² is a group of formula (IA) as defined above, where B is aryl Or q is 1; or R ¹ and R ² together with the nitrogen atom to which they are attached form a heterocycle; r is 0; s is 0; and X is CH ₂ , S or O.

In a more preferred aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an ester, amide or carbamate, which is hydrolyzed in vivo as follows: R ¹ and R ² are each independently selected from hydrogen, optionally substituted C _1-5 alkyl and benzyl; or R ¹ and R ² are taken together with the nitrogen atom to which they are attached a heterocycle R is 0; s is 0; and X is CH ₂ , S or O.

In a particularly preferred aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an ester, amide or carbamate, which is hydrolyzed in vivo as follows: R ¹ and R ² are each independently hydrogen, methyl, n-propyl, isopropyl,
Is selected from isoamyl and benzyl; or R ¹ and R ² together with the nitrogen atom to which they are attached form a piperidine ring; r is 0; s is 0; and X is CH ₂ , S or O.

Preferred compounds according to the invention are those mentioned in the examples. Preferred features of the invention relate to any of those listed in the examples. A preferred feature of the present invention relates to a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and phosphoric acid and sulfuric acid. The salt produced is included. In another aspect, suitable salts are base salts such as alkali metal salts (eg sodium salts), alkaline earth metal salts (eg calcium or magnesium salts), organic amine salts (eg triethylamine, morpholine,
N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N, N-dibenzylethylamine) or amino acids (eg lysine).
There will be more than one cation or anion depending on the number of charged functional groups and the valence of the cation or anion. A preferred pharmaceutically acceptable salt is the sodium salt.

The compounds of formula (I) have a chiral center at the 1-position of the 1,2,3,4-tetrahydronaphthalene ring and at the 4-position of the chroman and thiochroman rings. Some of the compounds of formula (I) will also have other chiral centers. For example, some of the R ² , R ³ , R ⁴ , R ⁵ groups, and optional substitutions, will have chiral centers. The present invention provides a formula () that suppresses the [ ³ H] -emopamil binding site.
It should be understood to include all such optical isomers and diastereomers of the compounds of I).

The invention further relates to all tautomeric isomers of the compounds of formula (I). It will also be appreciated that some of the compounds of formula (I) may exist as unsolvates as well as solvates (eg hydrates). It will be appreciated that the present invention includes all such solvates and unsolvates.

Esters, amides and carbamates that are hydrolyzed in vivo are compounds that are hydrolyzed in the human body to give the parent compound. Such esters, amides and carbamates can be identified, for example, by administering the test compound intravenously to the test animal and subsequently examining the body fluid of the test animal. Suitable amides and carbamates that are hydrolyzed in vivo include N-carbomethoxy and N-acetyl.

In vivo hydrolysable esters of compounds of formula (I) containing a carboxy or hydroxy group are, for example, pharmaceutically acceptable esters which are hydrolyzed in the human or animal body to give the original acid or alcohol. is there.

Suitable pharmaceutically acceptable esters for carboxy include C _1-6 alkoxymethyl esters (eg methoxymethyl), C _1-6 alkanoyloxymethyl esters (eg pivaloyloxymethyl), phthalidyl Ester, C _3-8 cycloalkoxy-carbonyloxy C _1-6 alkyl ester (eg 1-cyclohexylcarbonyloxyethyl), 1,3-dioxolen-2-onylmethyl ester (eg 5-methyl-1,3-dioxolene 2-onylmethyl), and C _1-6 alkoxycarbonyloxyethyl esters (eg, 1-methoxycarbonyloxyethyl) and can be formed at any carboxy group within the compounds of the invention.

In vivo hydrolysable esters of compounds of formula (I) containing a hydroxy group include inorganic esters (eg phosphates) as well as α-acyloxyalkyl ethers and related compounds, which are in vivo hydrolysates of the esters. The decomposition results in the original hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Selected as in vivo hydrolyzable esters that form the group for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (resulting in an alkyl carbonate ester), dialkylcarbamoyl and Included are N- (dialkylaminoethyl) -N-alkylcarbamoyls (which yield carbamates), dialkylaminoacetyls and carboxyacetyls.

In another aspect of the invention, there is provided a method of making a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester, amide or carbamate. The method comprises the following steps (wherein R ¹ , R ² , R ³
, R ⁴ , X, r and s are as defined in formula (I) unless otherwise specified):

[0033]   a) a compound of the following formula (II) (wherein L is a leaving group):

[Chemical 12] Reacting with a compound of formula (III) below, wherein R ^a and R ^b are R ¹ and R ² excluding hydrogen, or R ^a and R ^b are amino protecting groups;

[Chemical 13]

[0034]   b) a compound of the following formula (IV) (wherein L is a leaving group):

[Chemical 14] Reacting with a compound of formula (V) R ^a —NH—R ^b , where R ^a and R ^b are as defined above;

C) In the case of compounds of formula (I) wherein R ¹ and R ² are not both hydrogen, then
Or reacting the compound of VI) with the formula (VII) of R ^d -L,

[Chemical 15] Where L is a leaving group and i) R ^c is R ¹ excluding hydrogen, or R ^c is an amino protecting group, and R ^d is R ² excluding hydrogen; or ii ) R ^c is R ² excluding hydrogen, or R ^c is an amino protecting group, and R ^d is R ¹ excluding hydrogen);

[0036]   d) a compound of formula (VIII)

[Chemical 16] Reacting with a compound of formula (III);

[0037]   e) a compound of formula (IX)

[Chemical 17] Reacting with a compound of formula (V);

F) a formula (wherein q> 0) in which one of R ¹ and R ² is optionally substituted C _1-6 alkyl or a group of formula (IA) as defined above, and in which the other is not hydrogen ( I)
In the case of the compound of formula (VI), a compound of formula (VI) is reacted with a compound of formula (X):

[Chemical 18] (Wherein i) R ^c is R ¹ excluding hydrogen, and R ^c is optionally substituted C _1-5 alkyl or a group of formula (IA) as defined above, wherein q is 0-5. Or ii) R ^c is R ² excluding hydrogen, and R ^c is optionally substituted C _1-5 alkyl or a group of formula (IA) as defined above, wherein q is 0-5. )); Or

G) In the case of compounds of formula (I) wherein R ¹ and R ² are optionally substituted C _1-6 alkyl or a group of formula (IA) as defined above (q is> 0): The following formula (XI)
Reduce the compound of

[Chemical 19] (Wherein i) R ^f is R ¹ and further R ^g is optionally substituted C _1-5 alkyl or a group of formula (IA) as defined above, wherein q is 0-5. , Or ii) R ^f
Is R ² and R ^g is optionally substituted C _1-5 alkyl or a group of formula (IA) as defined above, wherein q is 0-5.

In addition, if necessary thereafter: i) converting a compound of formula (I) into another compound of formula (I); ii) removing any protecting groups; or iii) a pharmaceutical It produces pharmaceutically acceptable salts or in vivo hydrolysable esters, amides or carbamates. L is a leaving group, suitable groups for L are, for example, halogeno or sulphonyloxy groups, such as chloro, bromo, methanesulphonyloxy, or toluene-4-.
It is a sulfonyloxy group. Specific reaction conditions for the above reactions a), b) and c) are as follows.

The amine and the compound with the appropriate leaving group are reacted together under standard alkylation conditions. For example, the presence of an inert solvent (eg tetrahydrofuran, dimethylacetamide or toluene) in the presence of a base, eg an inorganic base (eg sodium carbonate or sodium hydroxide) or an organic base (eg Hunig's base) or an excess of amine. It is carried out at a temperature in the range 50 to 120 ° C., preferably near or at reflux temperature.

[0042]   Compounds of formula (IV) can be prepared according to the following scheme:

[Chemical 20] Examples of suitable functional group interconversions include, for example, the reaction of (IVb) with thionyl chloride to convert L = chloro, or the reaction of (IVb) with tosyl chloride to L
= -O-tosyl.

[0043]   Compounds of formula (VI) can be prepared according to the following process scheme:

[Chemical 21] In the formula, Pg is an amino protecting group, suitable groups are described below.

Formulas (II), (III), (IVa), (V), (VIa) and (VII) are commercially available compounds or are described in the literature or are known in the art. Manufactured by standard methods. The specific reaction conditions for reactions d), e) and f) above are as follows.

The ketone or aldehyde can be reacted with the amine under standard reductive amination conditions. For example, a reducing agent (eg hydrogen) and a hydrogenation catalyst (eg palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and It is carried out in the presence of potassium hydroxide alcohol solution, or borane and pyridine or formic acid. The reaction is preferably carried out in the presence of a suitable solvent such as an alcohol (eg methanol or ethanol) at 0.
It is carried out in a temperature range of -50 ° C, preferably at or near room temperature.

[0046]   The compound of formula (IX) can be prepared according to the following scheme:

[Chemical formula 22]

Compounds of formula (VIII), (IXa), (IXb) and (X) are commercially available compounds or are described in the literature or by standard methods known in the art. Manufactured.

Specific reaction conditions for the above reaction g) are as follows: The compound of formula (XI) is reduced under standard reducing conditions to reduce the amide to the amine. For example, in the presence of a reducing agent (eg borane, sodium borohydride or lithium aluminum hydride) in an inert solvent (eg toluene or tetrahydrofuran) in the temperature range of 50 to 120 ° C. (preferably at reflux temperature or reflux). Carry out near temperature).

[0049]   The compound of formula (XI) can be prepared according to the following process scheme:

[Chemical formula 23]

Some of the various ring substituents of the compounds of this invention can be introduced by standard aromatic substitution reactions or can be generated by conventional functional group modification either before or immediately after the above steps. However, it will be understood that such is also included in the method of the present invention. Such reactions and modifications include, for example, introduction of substituents by aromatic substitution reactions, reduction of substituents, alkylation of substituents and oxidation of substituents.
Reagents and reaction conditions for such methods are well known in the chemical arts.
Specific examples of aromatic substitution reactions include the introduction of nitro groups using concentrated nitric acid; eg, acyl halides and Lewis acids (eg, aluminum trichloride) under Friedel-Crafts conditions; Introducing alkyl groups using alkyl and Lewis acids (eg aluminum trichloride) under Friedel-Crafts conditions; and introducing halogeno groups. Specific examples of modifications include reduction of the nitro group to an amino group with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl. .

Furthermore, it will be appreciated that in some of the reactions described herein it may be necessary or desirable to protect any reactive groups in the compounds. Those skilled in the art are familiar with cases in which protection is necessary or desirable and suitable methods of protection. Conventional protecting groups can be used according to standard techniques (see below for a description: TW Greene, Protective Groups in
Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect those groups in some of the reactions described herein.

Suitable protecting groups for amino or alkylamino groups are eg acyl groups, eg alkanoyl groups (eg acetyl), alkoxycarbonyl groups (eg methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups), arylmethoxycarbonyl. A group (eg benzyloxycarbonyl) or an aroyl group (eg benzoyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, an acyl group such as, for example, an alkanoyl or alkoxycarbonyl group or an aroyl group is, for example, a suitable base (
It can be removed by hydrolysis using, for example, an alkali metal hydroxide (eg lithium hydroxide or sodium hydroxide). Alternatively, an acyl group such as a t-butoxycarbonyl group may be removed, for example by treatment with a suitable acid (eg hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid) to give an arylmethoxycarbonyl group such as a benzyloxycarbonyl group. The group can be removed, for example, by hydrogenation over a catalyst (eg palladium on carbon) or by treatment with a Lewis acid (eg boron tris (trifluoroacetate)). Another suitable protecting group for primary amino groups is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine (eg dimethylaminopropylamine) or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group (eg acetyl), an aroyl group (eg benzoyl) or an arylmethyl group (eg benzyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, an acyl group such as, for example, an alkanoyl or aroyl group is, for example, a suitable base (eg an alkali metal hydroxide (
It can be removed by hydrolysis with, for example, lithium hydroxide or sodium hydroxide). Alternatively, an arylmethyl group such as a benzyl group may, for example, be a catalyst (
It can be removed by hydrogenation over (for example palladium on carbon).

Suitable protecting groups for the carboxy group are eg esterifying groups, eg methyl or ethyl groups (eg removed by hydrolysis with a base such as sodium hydroxide) or eg t-butyl groups (eg , An acid (eg, an organic acid such as trifluoroacetic acid), or a benzyl group (eg, can be removed by hydrogenation over a catalyst such as palladium on carbon).
Is. Protecting groups can be removed at any convenient reaction stage using conventional techniques well known in the chemical arts.

To use a compound of formula (I), a pharmaceutically acceptable salt thereof, or an ester, amide or carbamate which is hydrolyzed in vivo for therapeutic treatment (including prophylactic treatment) of mammals including humans. In general, it is formulated as a pharmaceutical composition according to standard pharmaceutical practice.

The pharmaceutical compositions of the compounds of the invention may be administered in standard manner for the condition for which treatment is desired, eg by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration, or by inhalation. Administered by. For such purposes, the compounds of the present invention may be administered by means known in the art, such as tablets, capsules, aqueous or oily solutions, dispersions, emulsions, creams, ointments, gels, nasal sprays, suppositories, It can be formulated as a finely divided powder or aerosol for inhalation, and as a sterile aqueous or oily solution (including intravenous, intramuscular use or infusion) or sterile emulsion for parenteral use. The preferred route of administration is intravenous administration of sterile isotonic solution.

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also include one or more agents useful in the treatment of one or more of the conditions cited above. Or in combination (simultaneously or sequentially).

The pharmaceutical composition of the present invention is usually administered to a human so that, for example, 0.05 to 75 mg / kg body weight (preferably 0.1 to 30 mg / kg body weight) is obtained as a daily dose. . This daily dosage may be divided and administered in parts if necessary and the precise dose of the compound and the route of administration will depend on the weight, age and age of the patient to be treated according to principles known in the art. And sex and the particular condition being treated. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.

In yet another aspect of the invention, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester, amide or carbamate is pharmaceutically acceptable form. There is provided a pharmaceutical composition comprising the agent or carrier together.

According to yet another aspect of the present invention, a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof for use in a method of treating the human or animal body. An ester, amide or carbamate is provided which is decomposed.

Yet another feature of the invention is that a compound of formula (I) or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester, amide or carbamate for use as a medicament treats humans or animals. Provided for use in the method. Conveniently, this is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof in vivo for use as a medicament for inhibiting the [ ³ H] -emopamil binding site in warm-blooded animals (eg humans). Esters, amides or carbamates that are decomposed.

Thus, according to yet another aspect of the invention, a warm-blooded animal (eg, human).
(I) in the manufacture of a medicament for use in inhibiting the [ ³ H] -emopamil binding site of
There is provided the use of a compound of claim 1 or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester, amide or carbamate.

According to yet another aspect of the invention, there is provided a method of inhibiting the [ ³ H] -emopamil binding site in a warm-blooded animal (eg, human) in need of such treatment. To be done. Said method comprises administering to said animal a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester, amide or carbamate. . The following bioassay methods, data and examples are provided to illustrate the present invention.

Biological Test Methods [ ³ H] -Emopamil Binding to Guinea Pig Liver Membranes (−)- ³ H-Emopamil binding methods were described in the literature (C. Zech, R. S.
taudinger, J. Muehlbacher & H. Glossmann, Novel sites for phenylalkylami
nes: characterisation of a sodium-sensitive drug receptor with (-)- ³ H-em
opamil. Eur. J. Pharm. 208: 119-130 (1991)).

The reaction mixture contained the following: Assay buffer: 10 mM Tris-HCl, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4 ° C. . Radioligand: 0.96nM (-) - ³ H- Emopamiru (Amersham). Guinea pig liver membrane: 40 mg / mL as initial wet weight Compound: 1-300 nM Total volume: 500 μL This mixture was incubated at 37 ° C. for 60 minutes. Incubation was stopped by filtration with a Brandel-Celle-Harvester placed on a Whatman GF / C filter. The filters were soaked in 0.3% polyethylenimine (PEI) for at least 120 minutes and 5 mL of wash buffer (10 mM Tris-HCl, 10 mM MgCl ₂ , 0.2%).
It was washed 3 times with BSA (containing pH 7.4 at 25 ° C.). Specific binding was identified using 10 μM emopamil. In general, compounds with an IC ₅₀ of 300 nM or less in this test are important.

Guinea Pig Liver Membrane Preparation: Male guinea pigs were sacrificed by CO ₂ asphyxiation with dry ice. The liver was rapidly removed, weighed, and the membrane preparation buffer (10 mM Hepes, 1 mM Tris base-EDTA,
It was washed in 250 mM sucrose (containing pH 7.4). Then the liver was minced by a motor driven Teflon ^(R) - were homogenized by 3 strokes on ice in 10 volumes of in using a glass homogenizer. S. this homogenate at 1000 xg
It was centrifuged at 4 ° C. for 5 minutes in an S34 rotor. The supernatant was filtered through 4 layers of gauze, followed by centrifugation at 8000 xg for 10 minutes at 4 ° C. The supernatant obtained is 1 at 40,000 xg
It was centrifuged at 4 ° C. for 5 minutes. Resuspend the resulting pellet in assay buffer,
Centrifuge again at 000 xg for 15 minutes at 4 ° C. The pellet assay buffer (2.5 times the initial wet weight) was suspended again, Teflon ^(R) - were homogenized with one stroke of a glass homogenizer. Aliquots of 1 mL were stored at -70 ° C.

³ H-D-888 Binding to Rat Brain Cortical Membranes The method of ³ H-D-888 binding is described in the literature (IJ Reynolds, AM Snowman & SH.
Synder, (-)-[3H] Desmethoxyverapamil labels multiple calcium channel modu
lar receptors in brain and skeletal muscle membranes: differentiation by
temperature and dihydropyridines. J. Pharmacol. Exp. Ther. 237 (3): 731-
738 (1986)).

Assay tubes contained the following: Assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4 Radioligand: 1 η M ³ H-D888 (Amersham) Rat cortical membranes: as initial wet weight 6 mg / mL Compound: 0.3-100 μM Total volume: 1000 μL The above mixture was incubated at 25 ° C. for 60 minutes. The assay was stopped by filtration with a Brandel-Cel-Harvester placed on a Whatman GF / C filter. The filter should be at least 120 minutes with 0.3% polyethylenimine (PE
I) and 5 mL of wash buffer (20 mM Hepes, 20 mM MgCl ₂ (pH 7.4)
It was washed three times with (including). Specific binding was measured using 10 μM methoxyverapamil (D-600). This assay was used to measure the in vivo selectivity of compounds for L-type voltage sensitive calcium channels. Ie ³ H
High affinity for the -D888 binding site would indicate a lack of selectivity.

Preparation of rat brain cortical membranes Male Sprague-Dawley rats were sacrificed by decapitation and the brains were rapidly removed.
The cerebellum and brain stem were removed and discarded, and the rest of the brain was washed with 320 mM sucrose. Then the brain motorized Teflon ^(R) - was homogenized by 10 strokes with 320mM sucrose on ice 10 times the volume using a glass homogenizer. The homogenate was spun in an SS34 rotor at 1000 xg for 10 minutes at 4 ° C. Further, the supernatant was centrifuged at 29,000 × g for 20 minutes. 60 mg (initial wet weight) of the resulting pellet in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4).
Redispersed at a final concentration of / mL.

Cerebral ischemic whole model of gerbils Male Mongolian gerbils (Charles River) (weight 60-70 grams) were used for these experiments. The above mice were housed in cages one by one, and the bait (Purina Rod
ent Chow) and water were always given. Keep the temperature in the breeding room at 23 ± 2 ℃ and use automatic lighting 1
It was cycled for 2 hours.

The test agent or vehicle is administered intraperitoneally to the rat in the operating room 45 minutes prior to surgery. The drug is administered (intraperitoneally) in a volume of 5 mL / kg. The excipient is generally saline, with sodium phosphate added if necessary for pH adjustment. 45 minutes after administration,
Anesthetize the mouse by sending halothane (3.3%) with oxygen (1.5 L / M) from an oxygen mask. Once the rat is anesthetized, maintain a maintenance level of halothane in addition to oxygen of 1
Persist at 0.5-2%. Shave the ventral side of the neck and clean with alcohol. Surgery is performed on a thermostatically controlled heating pad set at 37 ° C. The neck was dissected and the carotid artery was dissected free of surrounding tissue and isolated using a 5 cm long silastic tube. When both arteries were isolated, they were microaneurysm clips (Roboz Instruments)
Use to fix. Whether blood flow is stopped is determined by visual inspection of the artery. 5
After a minute, gently remove the clip from the artery and resume blood flow. The sham control group is treated similarly, but without carotid artery occlusion. The incision is closed with sutures and the rat is removed from the anesthesia mask and placed on another heating pad to recover from anesthesia. When the mouse regains its righting reflex and begins to walk around, it is given the test compound again and returned to its original cage. Such a condition occurs about 5 minutes after the surgical operation is completed.

24 hours after the ischemia, the photo beam = activity = system (San
Diego Instruments) are used to test for spontaneous motor activity in mice. 1 mouse
Each animal is placed in a Plexiglas chamber (27.5 cm x 27.5 cm x 15 cm depth). The chamber is surrounded by a photocell and one count is recorded each time the beam is interrupted. Inspect each rat for 2 hours and total count 3
Record at 0, 60, 90 and 120 minutes. Mean counts were recorded for each group, drug and control groups were ANOVA and Bonferroni (Bonferro).
ni) Compare using post test. After testing each rat, return them to their original cage. At this time, also observe the mouse for any changes that differ from normal behavior.

No special tests are performed during the next two days, but a few days a day for any abnormal behavior or obvious neurological signs (ie, ataxia, convulsions, stereotyped behavior).
Observe the rat once. Four days after ischemia, the mice are killed by decapitation, the brains are removed and stored in 10% buffered formalin. The brain is removed, fixed, and further stained with hematoxylin and eosin. The hippocampal area is observed under a light microscope and graded 0-4 for damage to the CA1 subfield: 0 indicates no damage and 4 indicates severe damage.

Rat Transient Local Ischemia This method is described in the literature (TN. Lin, YY He, G. Wu, M. Khan & CY Hsu, Effect of
brain edema on infarct volume in a focal model cerebral ischaemia model
in rats. Stroke 24: 117-121 (1993)). The ischemia model in this document is considered to correlate with clinical findings. Male Long-Evan Slut (25
0-350 g) was used. The surgery resulting in local ischemia was performed under anesthesia with 100 mg / kg ketamine and 5 mg / kg intramuscular xylazine. Monitor rectal temperature,
The temperature was maintained at 37.0 ± 0.5 ° C. The right central cerebral artery (MCA) was exposed by microsurgery. The MCA trunk was ligated with 10-0 suture just above the olfactory sulci. Complete blockage of blood flow was confirmed under a surgical microscope. Both common carotid arteries were subsequently occluded with non-traumatic aneurysm clips. When a predetermined ischemic time (45 minutes) has elapsed, blood flow is restarted in all three arteries. 24 hours after occlusion, 0.9% N under ketamine anesthesia
Rats were sacrificed by infusing 200 mL of aCl into the heart. The brain was removed and treated with 2% triphenyltetrazolium chloride to identify and quantify the infarct region of the brain. Compounds were administered by intravenous infusion for 4 hours.

Data ³ H-emopamil binding assay on guinea pig liver membranes gave the following results. Example IC ₅₀ (nM) 6 39 8 32 13 17

[0076]

【Example】

The present invention will now be illustrated and described, but the present invention is not limited to the following examples. This example was carried out as follows unless otherwise specified: (i) Concentration was carried out in vivo by rotary evaporation; (ii) Operation was at ambient temperature (ie 18-26 ° C) unless specified otherwise. ) And under a nitrogen atmosphere; (iii) column chromatography (flash chromatography) was performed on Merck Kieselgel silica (Art.9385), unless otherwise specified; (iv) Yield provided for illustration only. (V) The structure of the final product of formula I is generally confirmed by NMR and mass spectroscopy methods, and the proton magnetic resonance spectrum is DMSO-δ ₆ unless otherwise specified.
And a Varian Gemini 2000 spectrometer was used with an intensity in the 300 MHz region. Chemical shifts are recorded in ppm downfield from tetramethylsilane as internal standard (δ scale) and the multiplicity of peaks is therefore indicated as follows: s, singlet; bs, broad singlet; d, doublet. AB or dd, doublet doublet; t, triplet; dt, triplet doublet; m
, Multiplet; bm, broad multiplet. ¹ H NMR is quoted unless otherwise specified;

(Vi) TLC was monitored on silica gel plates: silica gel GHLF (
Analtech), 250 micron, plate (2.5 x 10 cm). The detection methods used were UV light, iodine, chloroplatinate. (vii) For Kugelrohr distillation, Aldrich Chemical Company (Akd
A device supplied by rich Chemical Co.) was used. This device is a distillation device with a short valve passage. The temperature of the air bath in which the material is distilled is shown as boiling point; (viii) the nature of the intermediate was not usually completely determined, but the purity was usually determined by mass spectroscopy or NMR analysis; (ix) Solvents were dried over magnesium sulphate unless otherwise specified; (x) The following abbreviations are used: DMSO is dimethylsulfoxide; CDCl ₃ is deuterium chloroform; THF is tetrahydrofuran; DCM is dichloromethane; MeOH is methanol; TLC Is thin layer chromatography; EA is elemental analysis; DMAC is dimethylacetamide.

Example 1 4-piperidino-N- (1,2,3,4-tetrahydro-1-naphthalenyl) pipet
The flask was charged with 4-piperidinopiperidine (4.25 g; 24 mmol) under a lysine nitrogen atmosphere.
And DMAC (20 mL). Potassium iodide (300 mg) was added, followed by a solution of 1-chloro-1,2,3,4-tetrahydronaphthalene (Method G) (2.0 g, 12 mmol) in DMAC (6 mL). The solution was subsequently heated in an oil bath at 60 ° C. for 20 hours. The reaction mixture was partitioned between water and ethyl acetate, washed with brine and dried. Filtration and evaporation of solvent gave a yellow liquid (3.6g). This was allowed to solidify upon standing and purified by Kugelrohr distillation to give the title compound as a viscous yellow oil (2.4g): bp (air bath temperature) 160 ° C (100 mtorr). TLC (CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH, 89: 10: 1) R _f 0.6
0; EA: Calculated for C ₂₀ H ₃₀ N ₂ : C, 80.48; H, 10.13; N, 9.39; Found: C, 80.45;
H, 9.96; N, 9.06.

Example 2 4- (N-benzyl-N-methyl) amino-1- (1,2,3,4-tetrahydro
1-naphthalenyl) a flask under piperidine nitrogen atmosphere methanol (10 mL) solution of N-(1,2,3,4-tetrahydro-1-naphthalenyl) -4-piperidone (Method A) (0.39 g; 1.
7 mmol) and N-methylbenzylamine (0.31 mL, 2.4 mmol) successively. This solution was treated with ethanolic hydrochloric acid (4.5 M, 0.53 mL). Sodium cyanoborohydride (0.17 g, 2.7 mmol) was added to this stirred solution as a solid and the solution was stirred for 22 hours. The contents of the flask were subsequently concentrated, the residue was treated with aqueous potassium carbonate solution and extracted several times with ethyl acetate, which was subsequently dried. Filtration and evaporation of solvent gave a yellow oil (0.61 g). This was subjected to Kugelrohr distillation to obtain the title compound (0.40 g): bp (
Air bath temperature) 175-182 ° C (100 mtorr). TLC R _f 0.25 (1: 2, ether:
Hexane); NMR (CDCl ₃ ) 2.22 (s, 3H), 3.65 (s, 2H), 3.82-3.85 (m, 1H), 7.03-
7.44 (m, 8H), 7.70-7.72 (d, 1H); m / z 335 (M + H) ⁺ ; EA: C ₂₃ H ₃₀ N ₂ calculated: C,
82.58; H, 9.04; N, 8.37; Found: C, 81.76; H, 9.01; N, 8.42.

Following the procedures of Examples 3-10 Example 2 using the appropriate starting materials, the following compounds were prepared. All Kugelrohr boiling points for distillation are estimated at air bath temperatures.

[0081]

[Table 1]

[0082]

[Table 2]

Example 11 (S) -4-N-isoamylamino-1- (1,2,3,4-tetrahydro-1-)
Naphthalenyl) amino] piperidine dry flask was charged with (S) -1- (1,2,3,4-tetrahydro-1-naphthalenyl) -4-piperidone (Method D) (1.0 g, 4.36 mmol), isoamylamine ( Charged with 5.0 mL, 43.2 mmol), THF (20 mL) and methanol (10 mL) under nitrogen atmosphere. Sodium cyanoborohydride (0.41g, 6.5
8 mmol) was added followed by acetic acid (0.3 mL) and the solution was stirred overnight at ambient temperature. After concentration, the residue was treated with sodium carbonate solution and extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine and dried. After filtration and removal of the solvent, the residue (1.7 g) was heated on Kugelrohr to 70 ° C. (100 mtorr) to remove volatiles. The residue was Kugelrohr distilled to give a yellow oil (1.
05 g) was obtained: bp (air bath temperature) (70 mtorr) 155 ° C. [α] _D ²³ + 52 ° (c,
0.443, MeOH); NMR (CDCl ₃ ) 0.88-0.91 (d, 6H), 3.81-3.84 (m, 1H), 7.01-7.16 (
m, 3H), 7.69-7.71 (d, 1H); EA: Calculated for C ₂₀ H ₃₂ N ₂ : C, 79.94; H, 10.73; N, 9
.33; Found: C, 79.79; H, 10.64; N, 9.29.

[0084] Example 12 4-N, N- dimethylamino-1- (3,4-dihydro -2-H- Benzochiopira down-4-yl) piperidine dry flask 1- (3,4-dihydro-2 H-benzothiopyran-4-yl) -4-piperidone (Method F) (0.6 g, 2.4 mmol), dimethylamine hydrochloride (0.24 g, 2.94 mmol) and methanol (20 mL) were charged under nitrogen. .. Sodium cyanoborohydride (0.23 g, 3.6 mmol) was added and the solution was stirred overnight at ambient temperature. It was partitioned with saturated sodium carbonate solution and ethyl acetate and the aqueous phase was extracted again with ethyl acetate. The combined organic extracts were washed with brine and dried. After filtration and removal of the solvent, the residue (0.7
Ku) was subjected to Kugelrohr distillation to give a yellow oil (0.53 g): bp (air bath temperature
) 140-150 ° C (70 mtorr). NMR (CDCl ₃ ) 2.28 (s, 6H), 3.62-3.66 (m, 1H),
7.01-7.16 (m, 3H), 7.49-7.53 (d, 1H).

Example 13 4-Nn-propylamino-1- (3,4-dihydro-2-H-benzothiopyi)
Lan-4-yl) piperidine dry flask was charged with 1- (3,4-dihydro-2-H-benzothiopyran-4-yl) -4-piperidone (Method F) (0.75 g, 3.0 mmol), THF (16 mL). )
And charged with methanol (8 mL) under nitrogen. Continuously n-propylamine (2.6 mL, 31.6 mmol), sodium cyanoborohydride (0.30 g, 4.
8 mmol) and acetic acid (0.3 mL) were added and the solution was stirred overnight at ambient temperature. The contents were concentrated and the residue was partitioned with saturated sodium bicarbonate solution and ethyl acetate. The organic extract was washed with brine and dried. After filtering and removing the solvent, this (
Kugelrohr distillation of 0.90 g) gave a yellow oil (0.49 g): bp (air bath temperature) 150-160 ° C. (100 mtorr). _{NMR (CDCl 3): 0.89-0.94 (} t, 3H), 3
.63-3.66 (m, 1H), 6.97-7.08 (m, 3H), 7.50-7.53 (d, 1H).

Example 14 4-N-isoamylamino-1- (3,4-dihydro-2-H-benzothiopyra
N-4-yl) piperidine According to the method of Example 13, dry flask was charged with 1- (3,4-dihydro-2-
H-benzothiopyran-4-yl) -4-piperidone (Method F) (1.0 g, 4.
0 mmol), THF (20 mL) and methanol (10 mL) under nitrogen. Isoamylamine (4.7 mL, 40.5 mmol), sodium cyanoborohydride (0.40 g, 6.42 mmol) and acetic acid (0.5 mL) were added successively and the solution was stirred overnight at ambient temperature. . An oil (1.65 g) was obtained according to routine procedure and Kugelrohr distilled to yield a yellow oil (0.92 g): bp (air bath temperature) 170-180 ° C (100 mtorr). _{NMR (CDCl 3): 0.88-0.90 (} d, 6H), 3.
63-3.67 (m, 1H), 6.96-7.12 (m, 3H), 7.50-7.53 (d, 1H); EA: C ₁₉ H ₃₀ N ₂ S calculated: C, 71.65; H, 9.49; N, 8.79; Found: C, 71.09; H, 9.46; N, 8.87.

Example 15 4- (N-benzyl-N-methyl) amino-1- (1,2,3,4-tetrahydro
-1-Naphthalenyl) piperidine bismaleate 4- (N-benzyl-N-methyl) amino-1- (1 in ethanol (5 mL)
A portion of 2,2,3,4-tetrahydro-1-naphthalenyl) piperidine (0.3 g) was treated with a saturated solution of maleic acid in ether (12 mL) and further ether (5 mL).
) Was added and diluted. After stirring for 20 hours at ambient temperature, the resulting white solid was collected by filtration, washed with ether and dried in vacuo to give 0.42 g: Mp 195.5.
〜196.1 ℃; EA: Calculated for C ₂₃ H ₃₀ N ₂ O ・ 2C ₄ H ₄ O ₄ : C, 65.71; H, 6.76; N, 4.94; measured value: C, 65.31; H, 6.81; N, 4.96 .

Examples 16-27 Using the procedure of Example 15, the salts of the above example were prepared. The following bismaleates are provided as examples.

[0089]

[Table 3]

[0090]

[Table 4]

[0091] Example 28 (S) -4-N, N- dimethylamino-1- (3,4-dihydro -2-H- benzo thiopyran-4-yl) dried flask under piperidine nitrogen (S) - (-)-1- (3,4-dihydro-2-H-
Benzothiopyran-4-yl) -4-piperidone (Method G) (1.05 g, 4.2)
4 mmol), 16 mL THF and 9 mL methanol. TH
2.55 mL (5.1 mmol) of a 2M solution of dimethylamine in F was added, followed by sodium cyanoborohydride (0.40 g, 6.4 mmol). 0.34 mL of acetic acid (
6.4 mmol) was added and the solution was stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue was partitioned with sodium bicarbonate solution and ethyl acetate. The aqueous portion was extracted again with ethyl acetate and the combined organic extracts were washed with brine and dried.
After filtration and removal of solvent, the residue (1.08 g) was purified by column chromatography on silica gel eluting with methanol: chloroform (1:10) to give 0.29 g of a yellow oil. TLC (silica _{gel, 1: 10, CH 3 OH} : CHCl 3) R f 0.
21; m / z 277 (M + H) ⁺ ; [α] _D ²⁴ + 9.0 ° (c = 0.56, methanol); EA: C ₁₆ H ₂₄ N ₂ S
Calculated for: C, 69.52; H, 8.74; N, 10.13; Found: C, 69.11; H, 8.79; N, 9.8
Four.

This base (0.26 g) was dissolved in 1.7 mL of ethanol and treated with 20 mL of an ether solution saturated with maleic acid. Resulting in solid collected and dried to give the following substances 0.36g: mp 194.5-195.1 ℃; EA: Calculated for _{C 16 H 24 N 2 S ·} 2C 4 H 4 O 4: C, 5
6.68; H, 6.34; N, 5.51; Found: C, 56.46; H, 6.33; N, 5.42.

Example 29 (S) -4-N-isoamylamino-1- (3,4-dihydro-2-H-benzo
Pyran-4-yl) dried flask under piperidine nitrogen (S) - (-) - 1- (3,4- dihydro -2-H-
Benzopyran-4-yl) -4-piperidone (Method I) (1.06 g, 4.58 mm)
ol), 17 mL of THF and 8.5 mL of methanol. To this was added isoamylamine (0.44g, 5.0mmol) followed by sodium cyanoborohydride (0.43g, 6.9mmol). 0.34 mL (6.4 mmol) acetic acid was added and the solution was stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue was partitioned with sodium bicarbonate solution and ethyl acetate. The aqueous portion is extracted again with ethyl acetate,
The combined organic extracts were washed with brine and dried. Removal of solvent gave a residue (1.52g) which was purified by Kugelrohr distillation to give a yellow oil (0.90g).
g) was obtained (bp 151-157 ° C. (air bath temperature) at 100 mtorr). This is TLC
Homogeneous with (silica gel, ethyl acetate); R _f 0.11; m / z 303 (M + H) ⁺ ; [α] _D ²⁴ + 29 ° (c = 0.48, methanol); EA: C ₁₉ H ₃₀ N ₂ Calculated value for O: C, 75.45; H, 10.00;
N, 9.26; Found: C, 74.87; H, 10.03; N, 9.31.

This base (0.83 g) was dissolved in 4 mL of ethanol and treated with 45 mL of ether solution saturated with maleic acid. The resulting solid was collected and dried to give 1.20 g of the following material: mp 176.5-177.6 ° C; EA: C ₁₉ H ₃₀ N ₂ O.1.7C ₄ H ₄ O ₄ calcd: C,
62.00; H, 7.42; N, 5.61; Found: C, 61.88; H, 7.55; N, 6.01.

Preparation of Starting Materials The starting materials for the above examples are either commercially available or can be readily prepared from known materials by standard methods. For example, the following reaction is exemplified, but the production of the starting materials used in the above reaction is not limited thereto. Method A 1- (1,2,3,4-Tetrahydro-1-naphthalenyl) -4-piperidone Under a nitrogen atmosphere, oxalyl chloride (1.5 mL, 23.1 in 15 mL DCM ).
The flask was charged with (mmol) and cooled to -76 ° C. Dichloromethane (15 mL
) In DMSO (3.0 mL, 42.2 mmol) was added dropwise over 15 minutes. 4-Hydroxy- (1,2,3,4-tetrahydro- in dichloromethane (20 mL)
1-Naphthalenyl) piperidine (Method B) (2.0 g, 8.6 mmol) was added over 15 minutes. After 25 minutes, triethylamine (10.0 mL, 71.7 mmol) was added dropwise. The reaction was warmed to ambient temperature and stirring was continued overnight. The reaction is water (30
quenched with mL), dried extracted twice with DCM, then dried (MgSO _4). A yellow oil (1.95 g) was obtained by filtration and removal of solvent. TLC: R _f 0.70 (
Ethyl acetate); NMR (CDCl ₃ ) 1.62-1.72 (m, 2H), 1.96-2.02 (m, 2H), 2.43-2.48 (m
, 4H), 2.74-2.94 (m, 6H), 4.00-4.05 (m, 1H), 7.03-7.32 (m, 3H), 7.77-7.85 (d
, 1H).

Method B 4-Hydroxy-1- (1,2,3,4-tetrahydro-1-naphthalenyl) pipet
Lysine According to the method of Example 1, 1,4-hydroxypiperidine (2.5 g, 12
mmol) and potassium iodide (0.25 g) in DMAC (10 mL)
Reacted with 1-chloro-1,2,3,4-tetrahydronaphthalene in (10 mL). The product (2.7 g) was heated on a Kugelrohr at 150 mtorr at 90 ° C. and the volatiles removed to leave a beige solid (2.2 g). This material was triturated twice with ethyl acetate (2 x 5 mL) to give a gray solid. 5 at 150 mtorr
After drying at 5 ° C., 1.38 g of a substance having the following properties was obtained. Mp 109.5-110.5 ℃; TLC
: R _f 0.40 (ethyl acetate); NMR (CDCl ₃ ) 3.65-3.69 (m, 1H), 3.83-3.85 (m, 1H);
EA: Calculated for C ₁₅ H ₂₁ NO: C, 77.88; H, 9.15; N, 6.05; Found: C, 77.58; H, 8.
94; N, 5.99.

Method C 1- (1,2,3,4-Tetrahydro-1-naphthalenyl) -4-piperidone Condenser, addition funnel and three necked 250 mL equipped with stirring magnet rod.
The flask was charged with 1-amino-1,2,3,4-tetrahydronaphthalene (7.50 g,
50.7 mmol), potassium carbonate (0.5 g, 3.6 mmol) and ethanol (60 m)
L) was charged and the contents were refluxed. N-methyl-N-ethyl-4-oxo-piperidinium iodide (Taschaen et al, J. Org. Chem.
60: 4324-4330 (1995)) (20.5 g, 76.2 mmol) was added drop by drop over 45 minutes resulting in a reddish brown coloration. After 1 hour, heating was discontinued and the reaction was allowed to proceed overnight at ambient temperature. After concentration, the residue was partitioned with water and dry ether. Remove the solvent 10
Obtained 0.28 g of oil. TLC: R _f 0.58 (1: 1, ethyl acetate: hexane); NMR (CDCl ₃ ) 1.62-1.72 (m, 2H), 1.94-2.01 (m, 2H), 2.40-2.51 (m, 4H), 2.47- 2.93 (m, 6H)
, 4.00-4.04 (m, 1H), 6.92-7.45 (m, 3H), 7.76-7.88 (d, 1H).

Method D (S) -1- (1,2,3,4-tetrahydro-1-naphthalenyl) -4-piperi
Using the procedure of Don Method C, N-ethyl-N-methyl-4-oxo-piperidinium iodide (8.21 g, 30.5 mmol) was added to S (+)-1-amino-1,2,3. , 4
-Reaction with tetrahydronaphthalene (3.0 g, 20.3 mmol) gave the title compound (4.60 g). NMR (300 MHz) can be superimposed on that of Method C.

Method E (R) -1- (1,2,3,4-tetrahydro-1-naphthalenyl) -4-piperi
Using the procedure of Don Method C, N-ethyl-N-methyl-4-oxo-piperidinium iodide (8.20 g, 30.48 mmol) was added to R (-)-1-amino-1,2,3. ,
Reaction with 4-tetrahydronaphthalene (2.9 g, 19.62 mmol) gave the title compound (4.49 g). TLC: _Rf 0.70 (ethyl acetate); NMR (CD
Cl ₃ ) can be superposed with that of method C.

Method F 1- (3,4-Dihydro-2-H-benzothiopyran-4-yl) -4-piperi
Using the procedure of Don Method C, N-ethyl-N-methyl-4-oxo-piperidinium iodide (8.53 g, 31.7 mmol) was added to 4-amino-3,4-dihydro-2-.
React with H-benzothiopyran (3.5 g, 21.2 mmol) to give the title compound (4
0.53 g) was obtained. TLC: _Rf 0.78 (ethyl acetate); NMR (CDCl ₃ ) 2.16-2.21 (m, 2H)
, 2.44-2.49 (m, 4H), 2.71-2.79 (m, 2H), 2.88-2.96 (m, 2H), 3.08-3.18 (m, 2H)
, 3.85-3.89 (m, 1H), 6.97-7.12 (m, 3H), 7.85-7.62 (d, 1H).

Method G (S) -1- (3,4-dihydro-2-H-benzothiopyran-4-yl) -4
-N-ethyl-N-methyl-4-oxo-piperidinium iodide (11.9 g, 44 mmol) was added to S-(-)-4-amino-3,4-dihydro using the procedure of Piperidone Method C. Reaction with 2-H-benzothiopyran (4.87 g, 29.5 mmol) gave the title compound (6.76 g). NMR (300 MHz) can be superimposed on that of racemic material (Method F).

Method H 1-Chloro-1,2,3,4-tetrahydronaphthalene 1,2,3,4-tetrahydro-1-naphthol (34.3 g, in dry diethyl ether (420 mL) under a nitrogen atmosphere. The flask was charged with 0.23 mmol). Pyridine (4.7 mL) was added and the flask was cooled to 16 ° C in an ice water bath.
Then thionyl chloride (50.7 mL, 0.70 mol) in ether (140 mL)
Solution was added dropwise over 25 minutes and stirred overnight, during which time the bath warmed to ambient temperature. The reaction mixture was subsequently poured into cold brine (400 g ice and 800 mL brine) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (2 x 150 mL) and the combined organic extracts dried over sodium sulfate. Filter and remove the solvent in vacuo to give the title compound as an oil (36.9g). This material was used without further purification.

Method I (S) -1- (3,4-dihydro-2-H-benzopyran-4-yl) -4-pi
Using the procedure of Peridone Method C, N-ethyl-N-methyl-4-oxo-piperidinium iodide (10.93g, 40.6mmol) was added to S-(-)-4-amino-3,4-.
Reacted with dihydro-2-H-benzothiopyran (4.04 g, 27.1 mmol),
The title compound (6.40 g) was obtained. TLC (silica gel, ether: hexane, 1
: 1) R _f 0.50; m / z 231 (M + H) ⁺ .

[0104] according to general methods well known in Examples 28 pharmaceutical art, can be prepared the following representative dosage form containing a compound of formula (I): the compound of (a) Tablet mg / tablet formula (I) 50.0 Mannitol, USP 223.75 Croscarmellose sodium 60 Corn starch 15.0 Hydroxypropyl methylcellulose (HPMC), USP 2.25 Magnesium stearate 3.0 (b) Capsule mg / Compound of formula (I) 10 0.0 Mannitol, USP 448.5 Croscarmellose sodium 15.0 Magnesium stearate 1.5 (c) Injection For intravenous administration, the compound of formula (I) is dissolved in an isotonic sterile solution (5 mg /
mL).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/10 A61P 9/10 25/00 25/00 25/02 25/02 25/16 25/16 25 / 28 25/28 31/18 31/18 43/00 111 43/00 111 123 123 123 C07D 405/04 C07D 405/04 409/04 409/04 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), A E, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI , GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA , UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Richard Elliott Simon-Bilenbaum Delaware, USA 19850-5437. Wilmington. Concord Pike 1800 F Term (Reference) 4C054 AA02 CC02 DD01 EE01 FF28 4C063 AA01 BB01 CC79 CC95 DD10 EE01 4C086 AA01 AA02 AA03 AA04 BC21 GA02 GA03 GA07 GA12 MA01 MA04 NA14 NA15 ZA01 ZA15 ZA16 C35 Z36C35 Z36C20

Claims (12)

[Claims] 1. The following formula (I):   [Chemical 1] [In the formula, R¹And R²Are each independently hydrogen, C_1-6Alkyl, C_3-6Archeni
Le and C_3-6Selected from alkynyl, where C_1-6Alkyl, C_3-6Arche
Nil and C_3-6Alkynyl is optionally halo, nitro, hydroxy, C_1-6 Alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy,
Ruboxy, carbamoyl, mercapto, sulfamoyl, mesyl, NC_1-6A
Rukiruamino, N, N- (C_1-6Alkyl)₂Amino, C_1-6Alkoxy carbonyl
, N-C_1-6Alkylcarbamoyl or N, N- (C_1-6Alkyl)₂Carbamoy
Le, B- (CH₂)_q-Substituted with one or more selected from the group of formula (IA)
Is   In formula (IA), B is aryl, carbon-linked heteroaryl, carbon-linked heterocycle, C _3-12 C fused with cycloalkyl or benzene ring_3-12Cycloalkyl; q is 0
1, 2, 3, 4, 5 or 6; further wherein said aryl, heteroaryl,
Is a heterocycle optionally a halo, nitro, cyano, hydroxy, trifluoro
Chill, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto
, Sulfamoyl, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6 Alkoxy, C_1-6Alkanoyl, C_1-6Alkanoyloxy, N- (C_1-6Al
Kill) amino, N, N- (C_1-6Alkyl)₂Amino, C_1-6Alkanoylamino,
N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6Alkyl)₂Carbamoyl
, C_1-6Alkyl S (O)_a(A is 0, 1 or 2), C_1-6Alkoxy carbonyl
, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6Alkyl)₂Sulfa
Moyl and phenyl C_1-6A ring with one or more groups selected from alkyl
A heterocycle or heteroaryl substituted on the inner carbon; and further containing a —NH— group is
In some cases C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Arca
Noil, C_1-6Alkylsulfonyl or phenyl C_1-6Alkyl and R ¹ And R²But together with the nitrogen atom to which they are attached, a heterocycle or
Optionally substituted on the nitrogen with a group forming a lower aryl ring, in which case
The heterocycle or heteroaryl ring is optionally halo, nitro, cyano,
Droxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,
Carbamoyl, mercapto, sulfamoyl, C_1-6Alkyl, C_2-6Alkenyl
, C_2-6Alkynyl, C_1-6Alkoxy, C_1-6Alkanoyl, C_1-6Alkanoyl
Oxy, N- (C_1-6Alkyl) amino, N, N- (C_1-6Alkyl)₂Amino, C_{1 -6} Alkanoylamino, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6
Alkyl)₂Carbamoyl, C_1-6Alkyl S (O)_a(A is 0, 1 or 2), C_{1- 6} Alkoxycarbonyl, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_{1 -6} Alkyl)₂Sulfamoyl or phenyl C_1-6One selected from alkyl
Or may be substituted on the ring carbon with two or more groups;
The heterocycle or heteroaryl ring may be C_1-6Alkyl, C_2-6Arche
Nil, C_2-6Alkynyl, C_1-6Alkanoyl, C_1-6With alkylsulfonyl
Optionally substituted on the nitrogen;   R³Is halo, hydroxy, C_1-6Alkyl, C_1-6Alkoxy, halo C_1-6Archi
Le, cyano, nitro and C_2-6Selected from alkenyl;   R^FourIs C_1-6With alkyl;   X is -CH₂-, -O-, or -S-;   r is 0, 1, 2, 3 or 4, in which case each R³The parts are the same but different
Well; further   s is 0, 1, 2 or 3 and in this case R^FourThe parts may be the same or different
] Or a pharmaceutically acceptable salt thereof, or an
Stell, amide or carbamate. 2. R ¹ and R ² are each independently selected from hydrogen and optionally substituted C _1-6 alkyl, or R ¹ or R ² is a group of formula (IA) wherein B is aryl. And q is 1), or R ¹ and R ² and the nitrogen atom to which they are attached together form a heterocycle; r is 0; s is 0; and X is _2. A compound according to claim 1, selected from CH2, S or O, a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester, amide or carbamate. 3. R ¹ and R ² are each independently selected from hydrogen, optionally substituted C _1-5 alkyl and benzyl, or R ¹ and R ² and the nitrogen atom to which they are attached are together. 3. A compound according to claim 2 which forms a heterocycle, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester, amide or carbamate. 4. R ¹ and R ² are each independently selected from hydrogen, methyl, n-propyl, isopropyl, isoamyl and benzyl, or R ¹ and R ² and the nitrogen atom to which they are attached are taken together. 4. A compound according to claim 3 which forms a piperidine ring, a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester, amide or carbamate. 5. A compound according to claim 1 selected from: 4-piperidino-N- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine; 4- (N-benzyl-N-methyl) ) Amino-1- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine; 4-N, N-dimethylamino-1- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine; (S) -4-N, N-Dimethylamino-1- (1,2,3,4-tetrahydro-1
-Naphthalenyl) piperidine; 4- (N-isopropyl-N-methyl) amino-1- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine; 4-N-n-propylamino-1- (1 , 2,3,4-Tetrahydro-1-naphthalenyl) piperidine; (S) -4-Nn-propylamino-1- (1,2,3,4-tetrahydro-
1-naphthalenyl) piperidine; (R) -4-N-n-propylamino-1- (1,2,3,4-tetrahydro-
1-naphthalenyl) piperidine; 4-N-isoamylamino-1- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine; (S) -4-N-benzylamino-1- (1,2, 3,4-tetrahydro-1-
Naphthalenyl) piperidine; (S) -4-N-isoamylamino-1- (1,2,3,4-tetrahydro-1)
-Naphthalenyl) piperidine; 4-N, N-dimethylamino-1- (3,4-dihydro-2-H-benzothiopyran-4-yl) piperidine; 4-N-n-propylamino-1- (3,4 -Dihydro-2-H-benzothiopyran-4-yl) piperidine; 4-N-isoamylamino-1- (3,4-dihydro-2-H-benzothiopyran-4-yl) piperidine; 4- (N-benzyl- N-methyl) amino-1- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine bismaleate; 4-N, N-dimethylamino-1- (1,2,3,4-tetrahydro -1-Naphthalenyl) piperidine bismaleate; (S) -4-N, N-dimethylamino-1- (1,2,3,4-tetrahydro-1)
-Naphthalenyl) piperidine bismaleate; 4- (N-isopropyl-N-methyl) amino-1- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine bismaleate; 4-Nn -Propylamino-1- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine bismaleate; (S) -4-N-n-propylamino-1- (1,2,3,4 -Tetrahydro-
1-naphthalenyl) piperidine bismaleate; (R) -4-Nn-propylamino-1- (1,2,3,4-tetrahydro-
1-naphthalenyl) piperidine bismaleate; 4-N-isoamylamino-1- (1,2,3,4-tetrahydro-1-naphthalenyl) piperidine bismaleate; (S) -4-N-benzylamino -1- (1,2,3,4-tetrahydro-1-
Naphthalenyl) piperidine bismaleate; (S) -4-N-isoamylamino-1- (1,2,3,4-tetrahydro-1)
-Naphthalenyl) piperidine bismaleate; 4-N, N-dimethylamino-1- (3,4-dihydro-2-H-benzothiopyran-4-yl) piperidine bismaleate; 4-N-n-propyl Amino-1- (3,4-dihydro-2-H-benzothiopyran-4-yl) piperidine bismaleate; 4-N-isoamylamino-1- (3,4-dihydro-2-H-benzothiopyran-4) -Yl) piperidine bismaleate; (S) -4-N, N-dimethylamino-1- (3,4-dihydro-2-H-benzothiopyran-4-yl) piperidine, and (S) -4- N-isoamylamino-1- (3,4-dihydro-2-H-benzopyran-4-yl) piperidine. 6. The following steps: a) A compound of the following formula (II) (wherein L is a leaving group): Reacting with a compound of formula (III) below, wherein R ^a and R ^b are R ¹ and R ² excluding hydrogen, or R ^a and R ^b are amino protecting groups; ] Or b) a compound of the following formula (IV) (wherein L is a leaving group): R ^a -NH-R ^b becomes a compound of formula (V) (R ^a and R ^b in the formula is as defined above) is reacted with; not hydrogen or c) R ¹ and R ² are both formula (I ), The following formula (
A compound of VI) is reacted with R ^d -L of formula (VII), or Where L is a leaving group and further i) R ^c is R ¹ excluding hydrogen, or R ^c is an amino protecting group and R ^d is R ² excluding hydrogen; or ii R ^c is R ² excluding hydrogen, or R ^c is an amino protecting group, and R ^d is R ¹ excluding hydrogen); or d) a compound of the following formula (VIII): ] Or reacting with a compound of formula (III); or e) a compound of formula (IX): F) reacted with a compound of formula (V); or f) ^one of R ¹ and R ² is optionally substituted C _1-6 alkyl or a group of formula (IA) as defined in claim 1 wherein q is 1, 2, 3, 4, 5, or 6) and the other is not hydrogen, the compound of formula (VI) is: By reacting with a compound of formula (X) (Wherein i) R ^c is R ¹ excluding hydrogen, and R ^c is optionally substituted C _1-5 alkyl or a group of formula (IA) as defined above, wherein q is 1, 2, 3, 4, 5 or 6), or ii) R ^c is R ² excluding hydrogen, and R ^c is optionally substituted C _1-5 alkyl or a group of formula (IA) as defined above. (Where q is 1
, 2, 3, 4, 5 or 6)); or g) R ¹ and R ² are optionally substituted C _1-6 alkyl or a group of formula (IA) as defined in claim 1 where q is In the case of a compound of formula (I) which is 1, 2, 3, 4, 5 or 6), a compound of formula (XI): Wherein i) R ^f is R ¹ and R ^g is optionally substituted C _1-5 alkyl or a group of formula (IA) as defined above, wherein q is 1, 2, 3, 4 5 or 6), or ii) R ^f is R ² and R ^g is optionally substituted C _1-5 alkyl or a group of formula (IA) as defined above, wherein q is 1 2, 3, 4, 5 or 6)); and, if necessary, then converting a compound of formula (I) to another compound of formula (I); removing any protecting groups Or a pharmaceutically acceptable salt or forms an in vivo hydrolysable ester, amide or carbamate, a compound of formula (I) as defined in claim 1, a pharmaceutically acceptable salt thereof, or A method for producing an ester, amide or carbamate which is hydrolyzed in vivo. 7. A compound of formula (I), a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester, amide or carbamate of claim 1 together with a pharmaceutically acceptable excipient or carrier. A pharmaceutical composition comprising: 8. A compound of formula (I) according to claim 1 for use as a medicament for inhibiting the [ ³ H] -emopamil binding site of warm-blooded animals, a pharmaceutically acceptable salt thereof or in vivo hydrolysis. Possible esters, amides or carbamates. 9. A compound of formula (I) according to claim 1 in the manufacture of a medicament for use in inhibiting a [ ³ H] -emopamil binding site in a warm-blooded animal, or a pharmaceutically acceptable salt thereof, or Use of in vivo hydrolysable esters, amides or carbamates. 10. A compound of formula (I) according to claim 1, a pharmaceutically acceptable salt thereof, or hydrolyzed in vivo in a therapeutically effective amount for a subject suffering from a neurological disease. A method for treating a neurological disease as described above, which comprises administering an ester, amide or carbamate. 11. Stroke, head trauma, transient cerebral ischemic stroke, and Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia. Claim 1 for the treatment of various chronic neurodegenerative diseases
The method described in 0. 12. The method of claim 10 for treating a neurological disorder by inhibiting the [ ³ H] -emopamil binding site.