CA1338808C - Cyclic amine compound - Google Patents

Cyclic amine compound

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Publication number
CA1338808C
CA1338808C CA000569944A CA569944A CA1338808C CA 1338808 C CA1338808 C CA 1338808C CA 000569944 A CA000569944 A CA 000569944A CA 569944 A CA569944 A CA 569944A CA 1338808 C CA1338808 C CA 1338808C
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Canada
Prior art keywords
compound
group
salt
benzyl
lower alkyl
Prior art date
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Expired - Lifetime
Application number
CA000569944A
Other languages
French (fr)
Inventor
Hachiro Sugimoto
Yutaka Tsuchiya
Kunizou Higurashi
Norio Karibe
Youichi Iimura
Atsushi Sasaki
Yoshiharu Yamanishi
Hiroo Ogura
Shin Araki
Takashi Kosasa
Atsuhiko Kubota
Michiko Kosasa
Kiyomi Yamatsu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eisai Co Ltd
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Eisai Co Ltd
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Application filed by Eisai Co Ltd filed Critical Eisai Co Ltd
Priority to CA000616996A priority Critical patent/CA1340192C/en
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Publication of CA1338808C publication Critical patent/CA1338808C/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

A cyclic amine compound is defined by the formula:

Description

Cyclic Amine Compound The invention relates to a cyclic amine compound, a therapeutical composition and medical treatment of senile dementia.

( Statement of Prior Arts ) With a rapid increase in the population of aged people, the establishment of the therapy for senile dementia, such as Alzheimer senile dementia, is eagerly desired.
Various attempts have been made to treat the senile dementia with a drug. So far, however, there has been no drug which is very useful for the treatment of these diseases.
Studies on the development of therapeutic agents for these diseases have been made from various aspects.
Particularly, since Alzheimer senile dementia is accompanied by the lowering in cholinergic hypofunction, the development of the therapeutic agent from the aspect of an acetylcholine precursor and an acetyl-cholinesterase inhibitor was proposed and is in fact attempted. Representative examples of the anti-cholinesterase inhibitor include physostigmine and tetrahydroaminoacridine. However, these drugs have drawbacks such as an unsatisfactory effect and the - ~ 1338808 occurrence of unfavorable side effects. At the present time, there are no decisive therapeutic agents.
In view of the above situation, the present inventors have made extensive and intensive studies on various compounds for many years with a view to developing a drug which has a persistent activity and a high safety.
As a result, the present inventors have found that a piperidine derivative represented by the following general formula (I) can attain the desired object.
Specifically, the compound of the present invention represented by the following general formula (I) has great advantages of having strong and highly selective antiacetylcholinesterase activity, increasing the amount of acetylcholine present in the brain, exhibiting an excellent effect on a model with respect to disturbance of memory, and having a persistent activity and a high safety when compared with physostigmine which is a conventional popular drug in the art, which renders the compound of the present invention very valuable.
The compound of the present invention was found based on the acetylcholinesterase inhibitory action and, therefore, is effective for treatment and prevention of various diseases which are thought to be derived from the deficiency of acetylcholine as a neurotransmitter in vivo.
Examples of such diseases include various kinds of dementia including Alzheimer senile dementia and further lnclude Huntington's chorea, Pick's disease, and ataxia.
Therefore, the objects of the present invention are to provide a novel piperidine dèrivative effective as a pharmaceutical, particularly for treatment and prevention of central nervous system diseases, to provide a process for preparing the same, and to provide a pharmaceutical comprising the same as an effective ingredient.

( Summary of the Invention ) The invention provides a cyclic amine compound having the following formuIa (XXV) and a pharmaceutically acceptable salt thereof:

J_ _s __T Q- K

\~CH2~J . (XXV) [in whlch J ls (a) a group, substltuted or unsubstituted, selected from the group conslstlng of (1) phenyl, (2) pyrldyl, (3) pyrazyl, (4) qulnolyl, (5) cyclohexyl, (6) qulnoxalyl (7) furyl and (8) naphthyl;
(b) a benzene rlng-contalnlng monovalent or dlvalent group, ln whlch the benzene rlng may have one or more substltuents, selected from the group consisting of (1) lndanyl, (2) lndanonyl, (3) lndenyl, (4) lndenonyl, (5) indanedionyl, (6) tetralonyl, (7) benzosuberonyl, (8) indanolyl and (9) lndanedlonylidenyl, (10) lndanonylldenyl, (11) benzosuberonylidenyl and (12) C6H5-CO-CH(CH3)-;
(c) a monovalent group derived from a cycllc amine or amide compound;
(d) a lower alkyl;
(e) a group of R21-CH=CH- ln whlch R ls hydrogen or a lower alkoxycarbonyl;
(f) a dlalkylamlnoalkylcarbonyl; or (g) a lower alkoxycarbonyl;
B ls -(CHR22)r-~ -CO-(CHR22) -, -NR4-(CHR22) - [ln whlch R ls hydrogen, a lower alkyl, an acyl, a lower alkylsulfonyl, phenyl, a substltuted phenyl, benzyl or a substltuted benzyl], -Co-NR5-(CHR22)r- [ln whlch R5 ls hydrogen, a lower alkyl, benzyl, pyrldyl or phenyl~, -CH=CH-(CHR22)r~, -OCOO-(CHR22)r~, -NH-CO-(CHR22)r~, -OOC-NH-(CHR22)r~, -CH2-CO-NH-(CHR22)r~, -(CH2)2-CO-NH-(CHR22)r~, -CH(OH)-(CHR22)r~ [ln each of whlch r ls zero or an lnteger of 1 to 10, R22 ls hydrogen or methyl so that one alkylene group may have no methyl branch or one or more methyl branch], =(CH-CH=CH)b- [in which b is an integer of 1 to 3], =CH-(CH2)C- [in which c is zero or an integer of 1 to 9], =(CH-CH)d= [in which d is zero or an integer of 1 to 5~, -CO-CH=CH=CH2-, -CO-CH2-CH(OH)-CH2-, -CH(CH3)-CO-NH-CH2-, ( 2)2 ' T is nitrogen, N-OH or carbon;
Q is nitrogen carbon or N->O; with the proviso that T and Q cannot be carbon simultaneously q is an integer of 1 to 3;
K is hydrogen, phenyl, a substituted phenyl, an aryl-alkyl (in which the aryl is for example, phenyl or naphthyl and the phenyl may have one or more substituents) cynnamyl, a lower alkyl, pyridylmethyl, a C3 8-cycloalkyl-C1 6-alkyl, adamantylmethyl, furylmethyl, a C3 8-cycloalkyl, a lower alkoxycarbonyl or an acyl (such as benzoyl and lower alkanoyl) and - - - - shows a single bond or a double bond].
The substituents on the benzene ring in the benzene ring-containing monovalent or divalent group (b) are for example, lower alkylenedioxy, halogen, hydroxyl, benzyloxy, lower alkyl having 1 to 6 carbon atoms and lower alkoxy having 1 to 6 carbon atoms.
Claimed, however, in this application are those in which J is benzene ring-containing monovalent or divalent group (b).
Novel compounds claimed in this application are those in which J is benzene ring-containing monovalent or ~_~ 65702-315 divalent group (b), provided that when J is (1) indanyl, (2) indanoyl or ~8) indanolyl, each of which may optionally have on the benzene ring 1 to 4 substituents selected from the group consisting of halogen, Cl 6 alkyl and Cl 6 alkoxy, B is -(CHR22)r- and r is 0, then K is other than hydrogen or a lower alkyl.
In the compounds having the formula (XXV~, J is preferably (a) or (b). In the definition (b), monovalent groups of (2), (3) and (5) and divalent groups of (2) are preferable. When R5 is phenyl, the phenyl may be substituted by lower alkoxy, halogen, lower alkyl or hydroxyl. In the definition of B, -(CHR )r~' =(CH-CH=CH)b~ =CH-(CH2)C- and =(CH-CH)d= are preferable. These preferable groups of (B) may be connected with - 5a -.1 (b) of J, in particular (2) or (b).
It is preferable in the formula (XXV) that Q is nitrogen, T is carbon and n is 1 or 3; and Q is carbon, T is nitrogen and n is 2. It is most preferable that Q is nitrogen, T is carbon and n is 2.
When K is a substituted phenyl or a substituted phenylalkyl, preferred substituents on the phenyl ring include hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy.
It is preferable that K is a phenyl-Cl 4-alkyl (part-icularly benzyl) or a phenyl-C1 4-alkyl (particularly benzyl) hav-ing one to three substituen~ on the phenyl.
Preferable compounds of the invention include:
l-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methyl-piperidine, l-benzyl-4-((5,6-dimethoxy-1-indanon)-2-ylidenyl) methylpiperidine, l-benzyl-4-((5-methoxy-1-indanon)-2-yl)methylpiperid-ine, l-benzyl-4-((5,6-diethoxy-1-indanon)-2-yl)methylpiper-idine, l-benzyl-4-((5,6-methylenedioxy-1-indanon)-2-yl) methylpiperidine, l-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanon)-2-yl) methylpiperidine, l-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanon)-2-yl) methylpiperidine, l-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanon)-2-yl) methylpiperidine, 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)propylpiperidine, 1-benzyl-4-'((5-isopropoxy-6-methoxy-1-indanon)-2-yl)methylpiperidine and 1-benzyl-4-'((5,6-dimethoxy-1-oxoindanon)-2-yl)propenylpiperidine, having the below shown formula, shown in Example 224.

CH ~ O ~CH-CH=CH GI-CH 2 ~

In addition, the invention provides a therapeutical composition which comprises a pharmacologically effective amount of the cyclic amine compound having the formula (XXV) or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier and then a method for preventing and treating a disease 'due to the acetylcholinesterase activ'ity by administering to a human patient the cyclic amine comp'ound having the formuIa '(XXV) or a pharmacologically acceptable salt thereof.

-8- 1338808 65702-3l5 A group of preferable compounds have the above shown formula in which J is the benzene ring-containing group (b). The group (b) includes groups having the formulae shown below. S is hydrogen or a substituent such as lower alkylenedioxy, halogen, hydroxy, benzyloxy, a lower alkyl having 1 to 6 carbon atoms and a lower alkoxy having 1 to 6 carbon atoms. Among the substituents, methoxy is most preferable. t is an integer of 1 to 4. The phenyl most preferably has 1 to 3 methoxy groups thereon. (S)t may form lower alkylenedioxy group such as methylene dioxy group or ethylene dioxy group on two adjacent carbon atoms of the phenyl group. The carbonyl group in the formulae may be in the hydrazino form =N-NH-U (where U is an amino such as 2,4-dinitrophenyl) or in the ketal or thioketal form < or ~ (such as ethylene;
O-- S--ketal or ethylene thioketal). O

(S)t ~ (S)t ~
indanyl tetralonyl (e.g. 2-indanyl) (e.g. 1-tetralon-2-yl) (S)t indanonyl (e.g. l-indanon-2-yl) (S)t benzosuberonyl (l-benzosuberon-(S)t ~ (S)t ~ 2-yl) indanonylidenyl indanolyl (l-indanon-2-ylidenyl) (1-indanol-2-yl) 9 1 3 3 8 8 0 8657o2-3l5 (S)t~ (S)t~

indanedionylidenyl benzosuberonyliden-(1,3-indanedion-2-ylidenyl) Y
(l-benzosuberon-2-yl-idenyl) ( )t ~ (S)t ~ -CO-CH(CH3)-(inden-2-yl) (l-benzoylethyl) O O
(S) t ~ (S) t{~

indanedionyl indenonyl (1,3 -indanedion-2-yl) (1-indenon-2-yl) A preferable definition of B includes -(CHR ) r~' -CO-(CHR )r~' =(CH-CH=CH) b-~ =CH-(CH2) - and =(CH-CH) d=. The group of -(CHR22)r~ in which R is hydrogen and r is an integer of 1 to 3 and then the group of =CH-(CH2)c- are most preferable.
In the above defined cyclic amine compound of the invention, it is preferable that J in the formula is (b) the monovalent or divalent group. In the definition (b), indanonyl, indanedionyl and indenyl are most preferable, optionally having a substituent (s) on the phenyl.
In the definition B, -(CHR ) r~ and =CH-(CH2) -are preferable.

In the ring including T and Q, it may be a 5-, 6-or 7-membered ring. It is preferable that Q is nitrogen, T is carbon or nitrogen and n is 2; Q is nitrogen, T is carbon and n is 1 or 3; and Q is carbon, T is nitrogen and n is 2.
In the definition K, phenyl, an arylalkyl and cynnamyl are preferable, optionally having a substituent (s) on the phenyl.
A group of preferred compounds among those of the formula (XXV) are represented by the formula:

J - ~~ Ba~~- ~ N Ka (Ia) [in which Ja is the benzene ring-containing group (b), Ba is (1) a single chemical bond, -(CHR )r~' -NH- or -CO(CHR )r~ when Ja is the monovalent group, or (2) is a double chemical bond, =(CH-CH=CH)b- or =CH-(CH2)c-, when Ja is the divalent group, Ta is nitrogen or carbon;
K is hydrogen, phenyl, naphthylmethyl, phenylethyl, benzyl (which on its phenyl ring may have one to three substitu-ents selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy), cvnnamyl, lower alkyl, pyridylmethyl, C3 6-cycloalkyl-methyl, adamantylmethyl, furyl-methyl, C3 6-cycloalkyl, lower alkoxycarbonyl or benzoyl;
S is lower alkylenedioxy, halogen, hydroxy, benzyloxy, lower alkyl or lower alkoxy;

~ 1338808 65702-315 t is l when S is lower alkylenedioxy or t is 1 to 4 when S is other than lower alkylenedioxy;
the keto group may be in 2,4-dinitrophenylhydrazino form or ethylene thioketal form;
R is hydrogen or methyl;
r is 1 to 3;
b is 1 or 2;
c is 0 or 1 to 3; and shows a single bond or a double bond, provid-ed that a double bond between Ba and Ta can be present only whenTa is carbon and B~ is a double chemical bond3:.~
In the above formula (XXV), when T is carbon, Q is nitrogen, and q is 2, the compound is a piper~dine compound. A

preferred group among such piperidine compounds are represented by the formula:

Rl._ _ _ _ X ~ R2 (I) wherein Rl is the following substituted or unsubstituted group:
phenyl, ~ pyridyl, ~ pyrazyl, ~ quinolyl, ~ indanyl, cyclohexyl, ~ quinoxalyl, ~ furyl or ~ naphthyl; a monovalent or divalent group derived from an indanone having an unsubstituted or substituted phenyl ring; a monovalent group derived from a cyclic amide compound; a lower alkyl group, a group represented by the formula R3-CH=C- (wherein R3 is a hy-drogen atom or a lower alkoxycarbonyl group), dialkylaminoalkyl-carbonyl or lower alkoxycarbonyl, X is a group represented by the formula -(CH2)n~, O R
-C-(CH2)n-, -N-(CH2)n- (wherein R is a hydrogen atom, a lower alkyl group, an acyl group, (such as formyl, acetyl or benzoyl) a lower alkylsulfonyl group, or a substituted (by for example, C methoxy)or unsubstituted phenyl or benzyl group~, Il 5 -C-N (CH2)n~ (wherein R is a hydrogen atom, a lower alkyl group, R O O
or a phenyl group), -CH=CH- (CH ) -, -O-C-O- (CH ) -, -O-C-NH-(CH ) -, O O
Il 11 -~CH-CH-CO-, -NH-C- (CH2)n~, -CH2-C-NH- ( CH2 ) -, -CH2NH ( CH2 ) -, O OH O O OH
Il l 11 11 1 -(CH2)2-C-NH-(CH2)n-~ -CH-(CH2)n-, -C-CH=CH-CH2-, -C-CH2-CH-CH2-, CH O

-CH-C-NH-CH2- or -CH=CH - C -NR -(CH2)2-, o n in the above definition of X is each independently an integer of 0 to 6, R is a substituted (by for example hydroxyl, lower alkyl, lower alkoxy, nitro, benzyloxy or halogen) or unsubstituted phenyl group, a substituted (by for example hydroxyl, lower alkyl, lower alkoxy, nitro, benzyloxy or halogen) or unsubstituted aryl-alkyl group, a cinnamyl group, a lower alkyl group, a pyridylmeth-yl group, a C3 8-cycloalkylalkyl group, an adamantylmethyl group, or a furylmethyl group, ~ -12a- 1 3 3 8 80 8 and a symbol, _ _ _ , in the above general formula, means a single bond or a double bond.
The term "lower alkyl group" used in the above definition of R , R , R and R with respect to the compound (I) of the present invention is intended to mean a straight-chain or branched alkyl group having 1 ` - 13 1338808 65702-315 to 6 carbon atoms, and examples thereo~ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, l-methylbutyl, Z-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, l-methylpentyl, 2-methylpentyl, 3-methylpentyl, l,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, l-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethyl-propyl, l-ethyl-l-methylpropyl, and l-ethyl-2-methyl-propyl groups. Among them, methyl, ethyl, propyl, isopropyl groups etc. are preferable. A methyl group is the most preferable.
Examples of the substituent involved in the expression "the following substituted or unsubstituted group: ~ a phenyl group, ~ a pyridyl group, ~ a pyrazyl group, ~ a quinolyl group, ~ an indanyl group, ~ a cyclohexyl group, ~ a quinoxalyl group, or ~ a furyl group" in the definition of Rl include lower alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups, lower alkoxy group corresponding to the above-described lower alkyl -groups, such as methoxy and ethoxy groups; a nitro group; halogen atoms such as chlorine, bromine, and ~ 133~808 65702-315 fluorine; a carboxyl group; lower alkoxycarbonyl groups corresponding to the above-described lower alkoxy groups, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-propoxycarbonyl, and n-~utyl-oxycarbonyl groups; an amino group; a lower mono-alkylamino group; a lower dialkylamino group, a carbamoyl group; acylamino groups derived from aliphatic saturated monocarboxylic acids having 1 to 6 carbon atoms, such as acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamlno, and pivaloylamino groups; C3 8cycloa1ky1oxycarbonYl groups such as a cyclohexyloxycarbonyl group; lower alkyl-aminocarbonyl groups such as methylaminocarbonyl and ethylaminocarbonyl groups~ lower alkylcarbonyloxy groups corresponding to the above-defined lower alkyl groups, such as methylcarbonyloxy, ethylcarbonyloxy, ~and n-propylcarbonyloxy groups, halogenated lower alkyl groups including a trifluoromethyl groupL a hydroxyl group; a formyl group; and lower alkoxy lower alkyl groups such as ethoxymethyl, methoxymethyl, -and methoxyethyl groups. The "lower alkyl groups"
and "lower alkoxy groups" in the above description of the substituent include all the groups derived --from the above-mentioned groups. The substituent may be one to three of them which may be the same or different.
Further, when the substituent is a phenyl group, the following group is within the scope of the substituted phenyl group:

G ~-wherein G is a group represented by the formula -C-, a group represented by the formula -O-C-, a group represented by the formula -O-, a group represented o by the formula -CH2-NH-C-, a group represented by the formula -CH2-0-, a group represented by the formula -CH2-S02-, a group represented by the formula -CH-, and a group represented by the formula -CH2-S- and E is a carbon or nitrogen atom.
Preferable examples of the substituents for the phenyl group among them include lower alkyl, lower alkoxy, nitro, halogenated lower alkyl, lower alkoxy-carbonyl, formyl, hydroxyl, and lower alkoxy lower alkyl groups, halogen atoms, and benzoyl and benzyl-sulfonyl groups. The substituent may be two or more of them which may be the same or different.

~ ~ 1338808 Preferable examples of the substituent for the pyridyl group include lower alkyl and amino groups and halogen atoms.
Preferable examples of the substituent for the pyrazyl group include lower alkoxycarbonyl, carboxyl, acylamino, carbamoyl, and cycloalkyloxycarbonyl groups.
With respect to Rl, the pyridyl group is preferably a 2-pyridyl, 3-pyridyl, or 4-pyridyl group;
the pyrazyl group is preferably a 2-pyrazinyl group;
the quinolyl group is preferably a 2-quinolyl or 3-quinolyl group; the quinoxalinyl group is preferable a 2-quinoxalinyl or 3-quinoxalinyl group; and the furyl group is preferably a 2-furyl group.
Specific examples of preferable monovalent or divalent group derived from an indanone having an unsubstituted or substituted phenyl ring include those represented by the following formulae (II) and (III):
O

(A)~

(A)Ja--wherein m's are each an integer of l to 4 and A's which may be the same or different are each one of the substituents described in the above items ~ to ~ of the definition of Rl or a hydrogen atom, preferably a hydrogen atom (i.e. unsubstituted), a lower alkyl group, or a lower alkoxy group, and most preferably the in-danone group is unsubstituted or substituted with 1 to 3 methoxy groups.
Examples of the monovalent group derived from a cyclic amine or amide compound include quinazolone, hexahydropyridinone, dihydroquinazalone, tetrahydroquinazolone, tetrahydroisoquinoli-none, tetrahydroisoquinoline, dihydroisoquinolinone, tetrahydro-benzoazepinone, tetrahydrobenzodiazepinone, and hexahydrobenzazoc-inone. However, the monovalent group may be any one having a cyclic amide group in the structural formula thereof and is not limited to the above-described specific examples only. The cyclic amide group may be one derived from a monocyclic or condensed heterocyclic ring. The condensed heterocyclic ring is preferably one formed by condensation with a phenyl ring. In this case, the phenyl ring may be substituted with a lower alkyl group having 1 to 6 carbon atoms, preferably a methyl group, or a lower alkoxy group having 1 to 6 carbon atoms, preferably a methoxy group.
Preferable examples of the monovalent group include the following groups:

1~3 65702-315 (a) (b) ~- ~,lj-(c) (d) ~0 H
(e) (f) ~- C~,-O O
(g) (h) ~ ~,f~

(i) (i) N ~/

(k) Y
(1) o WL \~ ,~-W

(m) (n) O

N--(r) g~-NrO ~
Y O y (s) (t) -19a- 65702-315 N- ~ O /
/~0 W (v) (u) ~ ~ N-~V

(w) In the above formulae, Y's in the formulae (i) and (1) are each a hydrogen atom or a lower alkyl group, V in the formula (k) is a hydrogen atom or a lower alkoxy group, W and W in the formulae (m) and (n) are each a hydrogen atom, a lower alkyl group, or a lower alkoxy group and W3 is a hydrogen atom or a lower alkyl group.
The right-hand ring in each of the formulae (j) and (1) is a seven-membered ring, while the right-hand ring in the -- formula (k) is an eight-membered ring.
The most preferable examples of the above-defined Rl include a monovalent group derived from an indanone having an un-substituted or substituted phenyl group and a monovalent group derived from a cyclic amide compound.

2~ 1338808 The most preferable examples of the above-defined X include a group represented by the formula -(CH2)n~, a group having an amide group, and groups represented by the above formulae wherein n is 2. Therefore, it is most preferable that any portion of a group represented by the formula R'-------X- have a carbonyl or amide group.
The substituents involved in the expressions "a substituted or unsubstituted phenyl group" and "a substituted or unsubstituted arylalkyl group" in the above definition of R2 are the same as those described in the above items ~ to ~ in the above definition of R .
The term "arylalkyl group" is intended to mean an unsubstituted benzyl or phenethyl group, etc.
Specific examples of the pyridylmethyl group include 2-pyridylmethyl, 3-pyridylmethyl, and 4-pyridylmethyl groups.
Preferable examples of R2 include benzyl and phenethyl groups. The symbol ---- means either a single or a double bond. This bond is a double bond only when Rl is the above-described divalent group (IIIJ derived from an indanone having an unsubstituted or substituted phenyl ring, while it is a single bond in other cases.

- 2~ 13~8808 In the present invention, the term "pharma-cologically acceptable salt" include those of inorganic acids, such as hydrochloride, sulfate, hydrobromide, and phosphate, and those of organic acids, such as formate, acetate, trifluoroacetate, methanesulfonate, benzenesulfonate, and toluenesulfonate.
Further, when a certain kind of substituent is selected, the compound of the present invention may form, e.g., alkali metal salts such as a sodium or potassium salt, alkaline earth metal salts such as a calcium or magnesium salt, organic amine salts such as a salt with trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, or N,N'-dibenzylethylenediamine.
Moreover, the compounds of the present invention may have an asymmetrlc carbon atom depending upon the kind of the substituent and, therefore, have stereo-isomers. They are, of course, within the scope of the present invention.
One specific example thereof will now be described.
When Rl has an indanone skeleton, the compound of the present invention has an asymmetric carbon atom and, therefore, may have stereoisomers, optical isomers, diastereomers, etc. All of these isomers are within the scope of the present invention.
The compound of the present invention may be prepared by various processes. Representative processes for preparing the compound of the present invention will now be described.
Process A
When X in the general formula (I) is a group o R5 represented by the formula -C-N-(CH2)n-, wherein n and R5 are as defined above, the compound of the present invention can be prepared by the following process:

Il ` (~) Rl--C--Hal Rs H~l-(CH2) n ~-R2 ( V ) a R'-C-~I-(CH2)rl Gl-R2 (~11) Specifically, a compound (VI) which is one of the object compounds of the present invention can easily be prepared by reacting an acyl halide represented by the general formula (IV) with a piperidine derivative represented by the general formula (V) in the presence of a demineralizing agent, such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or triethylamine, in an organic solvent, such as chloroform, benzene, toluene, dioxane, tetrahydrofuran, or dimethylformamide (DMF), while cooling the reaction mlxture or at room temperature or while heating the reaction mixture.
Process B
When Rl in the general formula (I) is a monovalent or divalent group derived from an indanone having an unsubstituted or substituted phenyl group and X is a group represented by the formula -(CH2)n~, wherein n is an integer of 1 to 6, the compound of the present invention can be prepared also by the following process:

O
~:-(OC2H;) 2 (~) tA)~

OHC- (CH2) n--C~-R2 ( ~[ ) - 2~ 1338808 NaH
v ~ ~(C Y 2) n ~b-R 2 ( D~ ) (A) .~

reduction O
~(CY2) r~ Gl-R2 ( X ) (A) .~

Specifically, a compound (X) which is one of the object compounds can be prepared by reacting a substituted l-indanon-2-ylphosphonate represented by the general formula (VII) with an aldehyde compound represented by the formula (VIII) (i.e., Wittig reaction) to prepare a compound (IX) which is one of the object compounds and then catalytically reducing said compound (IX).
Examples of the catalyst used in the Wittig reaction include sodium methylate (MeONa), sodium ethylate (EtONa), tert-BuOK, and NaH. Examples of the solvent used in this reaction include tetrahydrofuran 2~ 1338808 (THF), dimethylformamide (DMF), ether, nitromethane, and dimethyl sufoxide (DMSO). A reaction temperature ranging from room temperature to about 100C provides favorable results.
A catalytic reduction in the presence of a catalyst composed of palladium-carbon etc. provides favorable results.
The following scheme specifically shows a process for preparing the compound of the present invention, wherein Rl is a group represented by the formula ~ 6~ , wherein R6 and R may be the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkylalkoxy group, or a halogen atom among the groups defined by A, X is a group represented by the formula -(CH2)n~, wherein n is an integer of 1 to 6, R2 is a group represented by the formula -CH2 ~R ~ wherein R and R each have the same meaning as that of R6 and R7:
O ]

R6~ (OC2H;)2 (~

O H C - ( C H 2 ) rL ~--\~II ~ C H 2 ~ ( ~m) R6~ (CH2) n ~-CH2 ~ (~) ' 3~(CH2) n Gl-CH2 ~R ( X) Process C
When Rl in the general formula (I) is a monovalent or divalent group derived from an indanone having an unsubstituted or substituted phenyl group and X is a group represented by the formula -(CH2)n~, wherein n is an integer of 1 to 6, the compound of the present invention can be prepared also by the following process:

,(~ (~) .
(A).., OHC-(CH2) n ~1_R2 (~

L DA
(lithium diisopropylamide) O

~--(CH2) n ~_R2 (~X) (A) m ~H~
v ~(CH2) n {~ R2 ( X) (A) m Specifically, for example, diisopropylamine and n-butyllithium/hexane are added to a solvent such as tetrahydrofuran. A substituted l-indanone represented by the general formula (XI) and hexamethylphosphoric amide are added thereto at a temperature of preferably about -80C. Then an aldehyde compound represented by the general formula (VIII) are added thereto, followed by a reaction according to an ordinary method.
The reaction mixture is subjected to dehydration, thereby preparing a compound (IX). This compound may be catalytically reduced in the same manner as that of the Process B to prepare a compound (X).
A specific example of the Process C will now be described in the same manner as that described in the Process B.

~,6~ ( X[) ' OHC-(CH2) n Gl-CH2 ~ 9 (~m) L D A
o (CH 2) n ~N-CH 2 ~ 9 ( ~ ) - 2~3 1338808 R6 (CH2) n Gl-CH2 ~ (X)' Process D
When Rl is a monovalent group derived from a cyclic amide compound selected from among quinazolone, tetrahydroisoquinolinone, tetrahydrobenzodiazepinone, and hexahydrobenzazocinone, the compound of the present invention can be prepared also by the following process:

R ' ~
~(CH2) p~z ( ~ ) ~C H 2 H O

3~ 1338808 Hal- (CH~ r~-R

~'2 H - etc.
v R l c ~(CH2) (,~ ) S~ ~C H 2 Rl ' I r~
( C H 2 ) ~ 2 wherein Rl and Rll are each a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, n is an integer of 1 to 6, p is an integer of 1 to 3 and Z is a group represented by the formula -CH2-or a group represented by the formula -N- , wherein R12 is a hydrogen atom or a lower alkyl group.
Specifically, a substituted 1,2,3,4-tetrahydro-5H-l-benzazepin-2-one is allowed to condense with a substituted N-benzyl-4-(2-halogenoethyl)piperidine represented by the general formula (XIII) in a solvent, e.g., dimethylformamide, in the presence of, e.g., sodium hydride, thereby preparing a compound (XIV) which is one of the object compounds.
Process E
Wh~n Rl is a group represented by the formula and X is a group represented by the ~N~
formula -(CH2)n-, the compound of the present invention can be prepared also by the following process:
o ~3 (XO

H 2 N- (CH 2) n--CN~F~2 (~) ~- (CH2) A~ N'-R2 (~''L-'iil) Specifically, 2-hydroxymethylnicotinic acid lactone (XV) is reacted with a substituted N-benzyl(2-aminoethyl)-piperidine represented by the general formula (XVI) by an ordinary method to prepare a compound represented by the general formula (XVII) which is one of the object compounds. The reaction temperature is preferably about 200C.
Process F
When R in the general formula (I) is a group represented by the formula ~ I and X is R~3 a group represented by the formula -(CH2)n~, the compound of the presnet invention can be prepared also by the following process:

Rl2 11 ~H (~) -Hal- (CH2) ~--/ \N-R2 (~m) R
~3- (CH ~) ~N_~2 (.
R ' ~ .

Specifically, a substituted 2,3-dihydroxy-pyrrolo(3,4-b)benzene represented by the general formula (XVIII) is reacted with a substituted - 3~ 1338808 N-benzyl(2-halogenoethyl)piperidine represented by the general formula (XIII) in the presence of, e.g., sodium hydride, in a solvent, such as dimethyl-formamide, while heating the reaction mirture, thereby preparing a compound (XIV) which is one of the object compounds.
Process G
When R in the general formula (I) is a group epresented by the formula ~CDOCH / and X
\ CH 3 is a group represented by the formula -CONH-(CH2)n~, the compound of the present invention can be prepared also by the following process:

!~T ~1~
~N J~ ( XX ) H21~- (CH2) n{~l~l~R2 (,~) - 3~ 1338808 ~N ~CONH- (CH 2) n~N_~2 N C O~C~

Specifically, 2,3-pyrazylcarboxylic anhydride (XX) is added to, e.g., isopropyl alcohol, followed by reflux. The alcohol is distilled off, and the residue is reacted with a substituted N-benzyl(~-amino-alkyl) piperidine in a solvent, such as tetrahydrofuran, thereby preparing a compound (XXI) which is one of the object compounds.
Process H
When Rl in the general formula (I) is an unsubstituted or substituted phenyl group and X is a group represented by the formula -C-(CH2)3- or a roup represented by the formula -C-CH2-fH-CH2-, the OH
compound of the present invention can be prepared also by the following process:

~C O C H 3 ~ XX II) OHC-(CH2) n~N_~.2 (~

OH
~ca CH 2 CHCH 2 ~ 2 ( ~ ~) R ~3--COC'n 2 C~, 2 C il 2--~_,N-R 2 ( .~ r~) Specifically, diisopropylamine and n-butyl-lithium/hexane are added to a solvent such as tetrahydrofuran. In the presence of this mixture, an acetophenone represented by the general formula (XXII) is allowed to condense with a substituted N-benzyl (~-formylalkyl)piperidine, thereby preparing a compound (XXIII). This compound is dehydrated in the presence of, e.g., p-toluenesulfonic acid in a solvent, such as toluene, followed by catalytic reduction according to an ordinary method, thereby preparing a compound (XXIV) which is one of the object compounds.

Process I
procedure 1 The cyclic amine compound having the formula (XXV) in which J is (1) indanyl, (2) indanonyl, (5) indanedionyl, (6) tetralonyl, (7) benzosuberonyl or propyophenyl and B is -(CHR22)r-, =(CH-CH=CH)b-, =CH-(CH2)c- or =(CH-CH)d= can be produled by the following procedure.
B' is a group where the terminal group containing one carbon atom is excluded from B.

J~PO~O~C2H5)2 +

O~C-B' - T Q K

~ CH2 .~ b~s ~

J=CH-B'-T Q - K
~c~2~
reduction ~ CH2 ~

In this procedure, the phosphate is reacted with an aldehyde compound through the Wittig reaction and the product is catalytically reduced. The catalyst to use in the Wittig reaction, includes sodium methylate, sodium ethylate, potassium t-butyrate or sodium hydrideO
The reaction may be carried out in a solvent such as tetrahydrofuran~, dimethylformamide, ether, nitromethane and dimethylsulfoxide at a temperature of the room temperature to 100~c. In the catalytical reduction, it is preferable to use a catalyst such as a catalyst of palladium and carbon, Raney nickel and a catalyst of rhodium and carbon.
In the above shown procedure, one example in which J is indanonyl goes;

(S)t~

. (S)t V o (S)t ~ 1'~-~~2~5)2 - 3~ 1338808 0~ 13' - T Q K
~ CH2 ~

n (S)t ~ CH 13' ~ \

(S)t ~ -C~2-B'-7 ~ _ K

procedure 2 The compound as defined in the procedure 1 can be obtained also in the following way.

J-H

OHC-13' - T Q - K
~ CH
a base .J=(~ T Q K
~-CH

reduction J-('H2-B'-T Q _ K
~ CH2 ~

The compound of J-H such as indanone is reacted with an aldehyde by the conventional Aldole condensation to obtain an intended compound. The reaction may be carried out in a solvent such as tetrahydrofuran~ by first producing lithium di-isopropylamide from di-isopropylamine and a n-butylhexane solution of of lithium, adding thereto a compound of J-H at a temperature of preferably about minus 80c, then adding the aldehyde thereto, effecting the reaction in the conventional way, heating the production mixture up to the room temperature to conduct dehydration and obtain the enone body of the intended compound. In another manner, the two reactants are dissolved in a solvent such as tetrahydrofurane, a base such as sodium methylate is added to the solution at about ~ 1338808 0c and the reaction is effected at the room temperatureO
The enone body obtained this way can be reduced to obtain the intended compound.
One example in which J is indanonyl, B is -(CH2)r-and T is carbon, Q is nitrogen and q is 2 goes:

(S)t~

Ol-lC-(CH2)n-1 ~ - K

(S)t ~ CH-(CH2)n-l ~ - K

reduction v o (S)t ~ (CH2)n~ ~ - K
4~ 1338808 Process J
The compound having indanol is produced by the following procedure. This procedure applies to the compound having indanol having a substituent(s) on the phenyl group.

)t ~ B 'I Q - K

reduction with NaBH4 OH

( )t ~ ~ - K

The reduction is effected with sodium boron hydride at 0c to the room temperature in a solvent such as methanolO

Process K
The compound having indenyl is produced by the following procedure. This procedure applies to the compound having indenyl having a substituent(s) on the phenyl.

OH

(S)t - ~ B Q K

dehydration (S)t ~ B Q K

The dehydration is -effected conventionally, for example, with hydrochloric acid.

Process L
The compound having indenonyl is produced by the following procedure. This procedure applies to the compound having indenonyl having a substituent(s) on the phenyl.

)t ~ ~ 2 ~q NBS

, (S)t ~ B T Q K

DBU

(S)t ~ / - \

The above shown starting compound having indanone is heated for reflux in a solvent such as carbon tetrachloride in the presence of N-bromosuccinic imide'(NBS) and benzoyl peroxide to obtain its bromide and the bromide is heated for reflux in a solvent such as tetrahydrofuran~ with 1~8-diazabicyclo~5.4~o)undec-7-ene (DBu) to conduct the beta-elimination and obtain the indenone compound. The bromide may be replaced by another halogenated compound.

The indanone comp'ound, as used in the above shown processes I, J, K and L, is available in the commmertial market and is produced by the following procedures.

4~ 1338808 (S)t ~ -CHO

)t ~ - CH=CH-COO~

reduction with H2 (S)t ~ - C~2CH2COOH

SOCQ2 or others (S)t ~ ~ CH2CH2COCQ

by Friedel-Kraft reaction ~S)t-~

4~ 1338808 The aldenyde compound used above is produced by the following procedures.

O ~ - K or NC-CH2 ~ N- K

reduction with di-isobutyl aluminum hydride O~C-CH2 ~ - K

The above shown starting compound is converted to its aldehyde and the aldehyde is used for the Wittig reaction to increase the carbon number contained therein. The Wittig reaction is effected repeatedly or combined with another kind of the Wittig reaction. This is obvious to a man skilled in the art. The Wittig agent includes methoxymethylenetriphenylphosphorane to add one carbon atom and formylmethylenetriphenylphosphorane to add two carbon atoms. Methoxymethylenetriphenylphosphorane is obtained by the reaction between methoxymethylenetriphenylphosphonium chloride and n-butyl lithium in ether or tetrahydro'furanè. Then aketone compound or an aldehyde compound is added to the product mixture to obtain its methoxyvinyl compound and the resulting mixture is treated with an acid to obtain a corresponding aldehyde. One example goes:

o=~-CH2 ~;~

CH3-CH=C~-CH 2 OHC{~I-C~2 ~

When formylmethylenetriphenylphosphorane is used, a solution of a starting ketone or aldehyde in ether, tetrahydrofurane or bezene is mixed with this Wittig agent and the mixture is heated for reflux to obtain an intended compound.
The obtained unsaturated aldehyde compound may be converted to its sa'turated compound by the catalytic reduction using a catalyst of pallad'ium and carbon, Raney nickel or a catalyst of rhodium and carbon. One example goes.

OHC-C~2~-CH2 ~

OHC CH=CH CH2~-CH2 OHc-cH2-cH2-cH2~ cH2 ~

The compounds thus prepared and acid addition salts thereof represented by the general formula (I) are useful for treatment of various kinds of senile . ... ~

dementia, in particular senile dementia of the Alzheimer type.
The invention will be described in view of its therapeutical usefulness together with pharmacologically experimental data.
Experimental Example 1 In vitro acetylcholinesterase inhibitory action A mouse brain homogenate was used as an acetylcholinesterase source and the esterase activity thereof was determined according to the method of Ellman et al.

Ellman, G.L., Courtney, K.D., Andres, V., and Featherstone, R.M., (1961) Biochem.
Pharmacol., 7, 88-95.
Acetylthiocholine as a substrate, a sample to detect and DTNB were added to the mouse brain homogenate, followed by incubation. The amount of a yellow substance formed by the reaction between the thiocholine and DTNB was determined in the absorbance at 412 nm in terms of the acetylcholinesterase activity.

The acetylcholinesterase inhibitory activity of the sample was expressed in terms of inhibitory concentration 50~ (IC50).
The results are shown in Table l.

Table 1 AChE AChE
Compound inhibitory Compound inhibitory activity activity 50 (1~ ) IC50 (1 ) 0. 23 31 0. 02~
o . 0053 33 0. 030 0. 10 ~5 0. 36 6 0.017 48 0.019 8 0. 013 52 0. 80 9 O.O~i ~4 1.0 O. 009 ~,S 0. 017 11 O. 0~3 62 0. ~Q7 12 0. 040 6a 0. 0016 13 0. 026 67 0. 10 lA 0. 038 70 0. 28 0. 09l 72 0. 020 17 0. 052 89 0. 018 18 0. 68 90 0. 035 19 0. 06l 9~ 0. 085 0. 54 lQl 0. 11 21 50 120 0.19 23 0. 012 12 ' 2. 8 2~ 1. 1 176 0. 004 21 0.41 29 0. 15 Experimental Example 2 Ex vivo acetylcholinesterase inhibitory action A sample to detect was orally administered to rats. After one hour of the administration, the cerebral hemispheres were dissected and homogenized, followed by the determination of the acetylcholinesterase activity. The group of rats treated with physiological saline was used as the control. Inhibition of AChE
by samples ex vivo was expressed in terms of inhibition percent of the control value. Results are shown in Table 2.
Experimental Example 3 Action on passive avoidance learning impairment induced by scopolamine See Z.Bokolanecky & Jarvik:Int.J.Neuropharmacol, 6, 217-222(1967).
Male Wister rats were used as the test animal and a step-through light and dark box was used as an apparatus. A sample to detect was orally administered one hour before the training and the rats were treated with 0.5 mg/kg (i.p.) of scopolamine 30 min. before the training. In a training experiment, the animal was placed into a light room and, just after the animal had entered into a dark room, a guillotine - ~ ~ 1338808 door was closed, followed by delivery of an electric shock from the gid of the floor. After six hours, the animal was again placed into a light room for a retention experiment, and the time taken for the animal to enter the dark room was measured for evaluation of the effect of the sample.

The difference in the-response time between the physiological saline administration group and the scopolamine administration group was taken as 100%, and the effect of the sample was expressed in terms of the percentage antagonism by the sample (Reverse %).
The results are shown in Table 3.

Table 2 AChE
Compd. Dose inhibitory No. (mg/kg) action (%) Sal ine O
5 ~
3 17 *' 36 *
l7 100 la*~

~2 1338808 Table 3 Compd. Dose Reverse %
No. (mg/kg) 0.12~ 5 0. 25 36 0. 2~ 3g a.~ 27 1. 0 a L
lu 2.0 30 - 0. 5 37 1Ø 39 0.5 22 ~.0 38 The number of animals per dose was 10 to 17.
NE: non-effective - ~ 1338808 The above-described pharmacological experiments revealed that the compound of the present invention had a potent acetylchOlinesterase inhibitory action.
Among the compounds (I) of the present invention, the compound wherein R is a group (II) or (III) derived from an lndanone having an unsubstituted or substituted phenyl ring is preferable, and the compound wherein Rl is a group represented by the general formula (II) are the most preferable. Specifically, particularly a compound wherein Rl is a group derived from an indanone having an unsubstituted or substituted phenyl ring has characteristics such as remarkable difference from the conventional acetylcholinesterase inhibitor in the structure, advantages with respect to the manufacture of pharmaceutical preparations by virtue of the potent acetylcholinesterase inhibitory action, large width between the main and the side effects, persistent activity, high water solubility, excellent stability, advantage in formulating into .. ., . . " ... .. . ... ..
preparations, high bioavailability and excellent penetration into the brain.
Therefore, the objects of the present invention are to provide a novel compound effective for various . _ .
kinds of dementia and the sequelae of cerebrovascular diseases, to provide a process for preparing the same, and to provide a novel pharmaceutical comprising the same as an effective ingredient.
Representative compounds of the present invention (Compd. Nos. 4, 13, 15, 19, and 69 in the above Table 3) were applied to toxicity tests on rats. As a result, all the compounds exhibited a toxicity of 100 mg/kg or more, i.e., exhibited no serious toxicity.
The compound of the present invention is effective for treatment, prevention, remission, improvement, etc. of various kinds of senile dementia, particularly senile dementia of the Alzheimer type; cerebrovascuIar diseases accompanying cerebral apoplexy, e.g. cerebral hemorrhage or cerebral infarcts, cerebral arteri-osclerosis, head injury, etc.; and aprosexia, disturbance of speech, hypobulia, emotional changes, recent memory distllr~ncP, h~ c;n~to~paranoid syndrome, behavioral changes, etc. accompanying encephalitis, cerebral palsy, etc.
Further, the compound of the present invention has a strong and highly selective anticholinesterase action, which renders the compound of the present invention useful also as a pharmaceutical based on this kind of action.
Specifically, the compound of the present ~ 1338808 invention is effective for, for example, Huntington's chorea, Pick's disease and delayed ataxia or tardive dyskiaesia other than senile dementia of the Alzheimer type.

When the compound of the present invention is used as a pharmaceutical for these diseases, it may be orally or parenterally administered. In general, it is parenterally administered in the form of injections, such as intravenous, subcutaneous, and intramuscular injections, suppositories, or sublingual tablets. The does will remarkably vary depending upon the symptom;
age, sex, weight, and sensitivity of patients; method of administration; time and intervals of administration and properties, dispensing, and kind of pharmaceutical preparations; kind of effective ingredients, etc., so that there is no particular limitation with respect to the dose. Normally the compound may be administered in a dose of about 0.1 to 300 mg, preferably 1 to 100 mg, per day per adult, ordinarily in one to four portions.
Pharmaceutical preparations in the dosage form of, e.g., injections, suppositories, sublingual tablets, tablets, and capsules are prepared according to a method which is commonly accepted in the art.
In preparing injections, the effective ingredient is blended, if necessary, with a pH modifier, a buffer, a suspending agent, a solubilizing agent, a stabilizer, 1 3 3 8 8 08 65702-3l5 a tonicity agent, a preservative, etc., followed by preparation of an intravenous, subcutaneous, or intramuscular injection according to an ordinary method. In this case, if necessary, it is possible to lyophilize these preparations according to an ordinary method.
Examples of the suspending agents include methyl-cellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethyl-cellulose, and polyoxyethylene sorbitan monolaurate.
Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, and an ethyl ester of castor oil fatty acid.
Examples of the stabilizer include sodium sulfite, sodium metasulfite, and ether, and examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
CExamples]
The present invention will now be described in more detail with reference to the following Examples.
It is needless to say that the technical scope of the invention of the present invention is not limited * Trademark ~7 1338808 to these Examples only.
In the following examples, all of the NMR values are those of the compounds measured in free form.
Example 1 l-Benzyl-4-C2-C(l-indanon)-2-yl]]ethylpiperidine hydrochloride C H 2 C H 2--/--\Y - C H 2 ~3 H C 1 0.37 g of 1-benzyl-4-C2-C(l-indanon)-2-yl]]-ethylpiperidine was dissolved in 10 ml of methanol, followed by addition of 0.1 g of 5% rhodium-carbon.
The mixture was hydrogenated at room temperature under atmospheric pressure for 24 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by making use of a silica gel column (methylene chloride : methanol =
200 : 1). The eluate was concentrated in vacuo, and the residue was dissolved in methylene chloride.
A 10% solution of hydrochloric acid in ethyl acetate was added to the resulting solution, followed by concentration in vacuo to obtain a crystal, which was recrystallized from methanol/IPE to obtain 0.33 g (yield: 80%) of the title compound having the following ~ 1338808 properties:
m.p. (C): 224-225C
elementary analysis: C23H27NO HCl C H N
calculated (%): 74.68 7.63 3.79 found (%) : 74.66 7.65 3.77 Example 2 l-Benzyl-4-~2-~(1-indanon)-2-ylidenyl]]ethylpiperidine hydrochloride ~CH2 ~'-CH2 ~ HCI

.
0.32 g of 60% sodium hydride was washed with hexane, and 10 mQ of THF was added thereto. A solution of 2.12 g of diethyl 1-indanon-2-ylphosphonate in 30 mQ of THF was dropwise added thereto at 0C. The mixture was stirred at room temperature for 30 min and again cooled to 0C, followed by addition of a solution of 3.43 g of l-benzyl-4-piperidineacetoaldehyde in 10 mQ of DMF. The mixture was stirred at room temperature for 2 hr and at 50C for 2 hr and then refluxed for 2 hr while heating the mixture. Methanol and 20% sulfuric acid were added at 0C to the reaction mixture. 10 min after the addition, the reaction ~9 1338808 mixture was made basic with an aqueous sodium hydroxide solution and extracted with ethyl acetate.
The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by making use of a silica gel column (methylene chloride :
methanol = 500 : 1). The eluate was concentrated in vacuo, and the residue was dissolved in methylene chloride. A 10% solution of hydrochloric acid in ethyl acetate was added to the resulting solution, followed by concentration in vacuo to obtain 0.78 g (yield: 27%) of the title compound. 1.37 of diethyl l-indanon-2-ylphosphorate was also recovered.
molecular formula; C23H25NO HCl 'H~ (CDC13 ) ~ ;1.10~2.13(7H.m)~ 2.26 (2H. t) ~ 2. 88 (2H. bd) ~ 3. 48 (2H. s) ~ 6. 72 ~7. 07 (2H. m) ~ 7. 30 (5H, s) ~ 7. 10~8. 00 (~H, m) Example 3 1-benzyl-4-piperidine-carboaldehyde having the formula: OHC ~ ~-CH2 ~ ~ was prepared in the following way.

26 grams of methoxymethylene-triphenylphosphonium chloride was suspended in 200 ml of anhydrous ether.
1.6M solution in hexane of n-butyl lithium was added dropwise to the suspension at the room temperature.
The mixture was stirred at the room temperature for 30 minutes and cooled down to 0c. Then 30 ml of a solution in anhydrous ether of 14.35 g of 1-benzyl~
4-piperidone was added to the mixture. It was stirred at the room temperature for 3 hours and filtrated to remove out the insoluble. The filtrate liquid was concentrated at a reduced pressure. The obtained concentrate was dissoLved in ether and extracted with 1N hydrochloric acid. An aqueous solution of sodium hydroxide was added to the extract to have pH value of 12. The resultant was extracted with methylene chloride. The extract was dried with magnesium sulfate and concentrated at a reduced pressure. The residue was purified with a column filled with silica gel to obtain 5.50 g of an oil with a yield of 33 percent.

The oil was incorporated into 40 ml of methanol and 40 ml of 1N hydrochloric acid was added to the solution. It was heated so as to make reflux for 3 hours and then concentrated at a reduced pressure.
The residue was dissolved in water. An aqueous solution of sodium hydroxide was added to the solution to have a pH value of 12 and the solution was extracted with methylene chloride. The extract was washed with saturated salt solution and dried with magnesium suIfate. It was further concentrated at a reduced pressure and the residue was purified in a column charged with silica gel. 2.77 g of the intended compound was obtained with a yield of 54 percent. In analysis, its molecular formula was found to be C13H17NO and 1H-NMR (CDCQ3)~, 1.40-2.4~(7H,m), 2.78(2H, dt), 3.45(2H,S), 7.20(5H,S), 9.51 (1H,d).
The compound may be produced according to the methods shown in (1) Arm. K~,m. Zh., 36(9), 6l4-17 (1983) by R.A. Ruroyan, A.I. Markosyan, G.M. Snkhchyan and S.A. Vartangan and (2) Ind. Chim`. Belge, 32, 64-5 (1967) by B. Hermans and P. Van Daele.

l-Benzyl-4-c(5~6-dimethoxy-l-indanon)-2-ylidenyl]
methylpiperidine hydrochloride )~r `01- C H 2 ~ H C 1 This reaction was conducted in an argon atmosphere.
2.05 mQ of diisopropylamine was added to 10 mQ
of anhydrous THF, followed by addition of 9.12 mQ of a 1.6 M solution of n-butyllithium in hexane at 0C.
The mixture was stirred at 0C for 10 min and then cooled to -78C, and a solution of 2.55 g of 5,6-dimethoxy-l-indanone in 30 mQ of anhydrous THF and 2.31 mQ of hexamethyl-phosphoric amide were added thereto. The mixture was stirred at -78C for 15 min, and a solution of 2.70 g of 1-benzyl-4-piperidine-carboaldehyde in 30 mQ of anhydrous THF was added thereto. The temperature of the mixture was gradually raised to room temperature, followed by stirring for 2 hr. An aqueous 1% ammonium chloride solution was added thereto, and the organic phase was separated.
The water phase was extracted with ethyl acetate, and the organic phases were combined with each other.
The combined organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by making use of a silica gel column -- 6~ 1338808 (methylene chloride : methanol = 500 : 1 - 100: 1).
The eluate was concentrated in vacuo, and the residue was dissolved in methylene chloride. A 10~ solution of hydrochloric acid in ethyl acetate was added to the resulting solution, followed by concentration in vacuo to obtain a crystal, which was recrystallized from methanol/IPE to obtain 3.40 g (yield: 62%) of the title compound having the following properties:
~ m.p. (C): 237-238C (dec.) elementary analysis: C24H27NO3 HCl C H N
calculated (%): 69.64 6.82 3.38 found (%) : 69.51 6.78 3.30 Example 4 l-Benzyl-4-C(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine hydrochloride CH,D~CH2 {~ CH2 ~ HCi 0.4 g of 1-benzyl-4-~(5,6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine was dissolved in 16 mQ of THF, followed by addition of 0.04 g of 10% palladium-carbon. The mixture was hydrogenated at room temperature under atmospheric pressure for 6 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by making use of a silica gel column (methylene chloride : methanol = 50 : 1). The eluate was concentrated in vacuo, and the residue was dissolved in methylene chloride.
A 10% solution of hydrochloric acid in ethyl acetate was added to the resulting solution, followed by concentration in vacuo to obtain a crystal, which was recrystallized from methanol/IPE to obtain 0.36 g (yield: 82%) of the title compound having the following properties:
m.p. (C): 211-212C (dec.) elementary analysis: C24H29NO3~HCl C H N
calculated (%): 69.30 7.27 3.37 found (%) : 69.33 7.15 3.22 Example 5 2-C4'-(1'-Benzylpiperidine)ethyl]-2,3-dihydro-1-oxypyrroloC3,4-b]pyridine dihydrochloride .

~N-CH2CH2~N-CH2~ 2HCl 12.6 g of 2-hydroxymethylnicotinic acid lactone and 40 g of 4-(2-aminoethyl)benzylpiperazine were stirred in a sealed tube at 200C for 7 hr. Thereafter, the reaction mixture was purified by making use of a silica gel column, and a hydrochloride of the purified product was prepared by an ordinary method, thereby preparing 6.37 g of dihydrochloride of the object compound.
m.p. (C): 143.5-145C
elementary analysis: C21H25N3O 2HCl C H N
calculated (%): 61.77 6.66 10.29 found (%) : 61.49 6.68 9.98 Example 6 2-C4'-(1'-Benzylpiperidine)ethyl]-2,3-dihydro-5,6-dimethoxyoxypyrroloC3,4-b]benzene hydrochloride . .

CH30 ~ ~-CH2CH2 ~ N-CH2 ~ 2HCl 0.5 g of 2,3-dihydro-5,6-dimethoxyoxypyrrolo~3,4-b~benzene was dissolved together with a catalytic amount of potassium iodide in DMF. 0.21 g of sodium hydride (60%) was added to the resultlng solution while cooling and stirring the solution. Thereafter, g of 2,3-dihydro-5,6-dimethoxyoxypyrroloC3,4-b]-benzene was added thereto, and the mixture was stirred -- 6~ 1338808 at 80C for 4 hr. After the completion of the stirring, H2O was added thereto, followed by extraction with chloroform. The chloroform phase was washed with water and dried (over MgSO4). The solvent was distilled off, and the residue was purified with silica gel, thereby preparing an oleaginous object compound. A hydrochloride of the object compound was prepared by an ordinary method, thereby obtaining about 0.2 g of a creamy crystal.
molecular formula, C24H30N2O3 2HCl 'H~ R(CDCl 3) ~;
1. 12~3. 4 (9H, m), 2. 72 ~3. 00 (2H, m), 3. 48 (2H, s), 3. 62 (2H, t), 3. 9~ (6H, s), 4. 26 (2H, s), 6. 90 (lH, s), 1. 28 (6H, s) Example 7 4-~N-(o-Aminobenzyl)ethyl]-l-benzylpiperidine CH2~1HCH2CH; ~I-CH

.~H2 30 g of 2-nitrobenzaldehyde, 21.4 g of l-benzyl-4-aminoethylpiperidine, and 100 mQ of methanol were stirred in a nitrogen stream at room temperature for 3 hr. The resulting reaction mixture was cooled with ice, and a solution of 16 g of sodium borohydride in 30 mQ of MeOH was dropwise added thereto. The reaction was allowed to proceed at room temperature for an additional l hr. The reaction mixture was poured into water, extracted with methyl chloride, extracted three times with 150 mQ of 10% hydrochloric acid, and washed with methylene chloride. Sodium carbonate was added to the water phase to adjust a pH value to 10, followed by extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo, thereby preparing 28.4 g of 1-benzyl-4-CN-(o-nitrobenzyl)ethyl]piperidine.
This compound was dissolved in 100 mQ of methanol and hydrogenated in the presence of 3 g of 10%
palladium-carbon (hydrous) at a pressure of 4 kg/cm , thereby preparing 25.6 of the title compound.
molecular formula; C21H29N3 ~H~ R(CDCI 3) ~; 1. 0 ~2.1(9H,m) ~ 2.64 (2H. t) ~ 2. 90 (2H, m) ~ 3. d7 (2H. s) ~ 6. 6 (2H, m) ~ 7. 02 !2~, m), 7. 30 (vH, s) Example 8 3-C2-(1-Benzyl-4-piperidyl)ethyl-2-(lH,3H)-quinazolinone ~,~C ~1 2 C '~ 2 ~ .~ - C H 2 -~

25.6 g of 4-CN-(o-aminobenzyl)ethyl]-l-benzyl-piperidine, 15 g of l,l'-carbonyldiimidazole, and 100 mQ of methanol were heated under reflux for 12 hr.
After the completion of the reaction, the reaction mixture was poured into water, extracted with methylene chloride and dried over magnesium sulfate. The solvent was distilled off in vacuo therefrom.
The residue was purified by silica gel column chromatography (5% MeOH-CH2CQ2) and recrystallized twice from ethyl acetate, thereby preparing 3.0 g the title compound.
molecular formula; C22H27N30 ' H--!I'.lR (CDCl 3) ~; 1. 0 ~2. 1 (9H, m) ~ 2. 7 ~3. 0 (2H, m) ~ 3 2 ~3. 6 (~IH, m) ~ 4 4 (2H, s) ~ 6. 5 ~7. 4 (8H, ~ 7. 75 (lH, s) Example 9 l-C4'-(1'-Benzylpiperidine)ethyl-1,2,3,4-tetrahydro-4-methyl-5H-Cl,4]-benzodiazepin-2-one dihydrochloride - 6~ 1338808 C ~ 2 C H 2 ~N-C H 2--~

) 2~Cl C~3 0.35 g of sodium hydride was suspended in 0.5 mQ
of dimethylformamide (DMF). The suspension was stirred while cooling it with ice, and 0.52 g of 1,2,3,4-tetrahydro-4-methyl-5H-C1~4]-benzodiazepin-2-one dissolved in 3 mQ of DMF was dropwise added thereto, followed by stirring at room temperature for 30 min.
0.81 g of N-benzyl-4-(2-chloromethyl)piperidine hydrochloride dissolved in 3 mQ of DMF was dropwise added thereto, and the mixture was stirred at 60 to 70C for 7 hr. The reaction mixture was poured into ice/water and extracted with methylene chloride.
The extract was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography. A hydrochloride of the purified product was prepared by an ordinary method. Thus there was obtained 0.17 g of a pale yellow amorphous substance (yield: 13.5~).
molecular formula, C24H31N3O 2HCl 7~ 1338808 H -N~R (CDCl-3) ~; 1. 2J ~2. 02 (9U. c,) ~ 2. a2 (3H, s) ~ 2. 7g~2. 9a (2H, bd) ~ 3. 10 (2H, s) ~ 3. 48 (2,t. s) ~ 3. a ~ (2H. s) ~ 3. 91 (2H, b .) ~ 7. 14--7. ., (9H, m) Example 10 l-C4'-(1'-Benzylpiperidine)ethyl]-1,2,3,4-tetrahydro-5H-l-benzazepin-2-one hydrochloride CH2CH2{~N-CH2~
~0 HCI

0.27 g of sodium hydride was suspended in 0.5 mQ
of dimethylformamide (DMF). The suspension was stirred while cooling it with ice. 0.60 g of 1,2,3,4-tetrahydro-5H-l-benzazepin-2-one dissolved in 4 mQ
of DMF was dropwise added thereto. The mixture was heated at 60C for 15 min and then cooled with ice.
1.02 g of N-benzyl-4-(2-chloromethyl)piperidine hydrochloride was added thereto, and the mixture was stirred at 60C for 3.5 hr. The reaction mixture was left to stand for cooling, poured into ice/water, and extracted with methylene chloride. The extract was washed with water and dried over magnesium sulfate.

The solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography.
A hydrochloride of the purified product was prepared by an ordinary method. Thus there was obtained 1.40 g of the title compound (yield: 94.8%).
molecular formula; C24H30N2O HCl H~ R(CDCl3) ~; 1. 20~1. 92(11H,m) ~ 2. 20 ~2. 24 (dH, bs) ~ 2. 60 ~2. 88 (4H, m) ~ 3. 44 (2H. s) ~ 7. 12~1. 24(9H. m) Example 11 N-C4-(1'-Benzylpiperidyl)ethyl~-5,6,11,12-tetrahydrodibenzoCb,f]azocin-6-one hydrochloride O H 2 C H ~ C H 2 ~

~ HCI

2.24 g of 5,6,11,12-tetrahydrobenzoCb,f~azocin-6-one and 60~ sodium hydride were added to 20 mQ of dimethylformamide. The mixture was stirred at 60C
for 1 hr, and 0.7 g of 1-benzyl-4-chloroethylpiperidine was added thereto, followed by the reaction for an additional 3.5 hr.
The reaction mixture was poured into 20 mQ of - 7~ 1338808 water, extracted with ethyl acetate, washed with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off therefrom n vacuo.
The residue was purified by silica gel column chromatography (5% MeOH in CH2CQ2), thereby preparing 0.6 g of the title compound.
. molecular formula; C29H32N20 HCl ' H - .Y`.~R (C~Cl 3) ;1.1 ~2. 2 (9H, m) ~ 3. 7 ~4. 1 (4H. m) ~ L. 15~4. i ~2H. m) ~ 4. 46 (2H, s) ~ 6. 8 ~7. 4(13H. m) Example 12 10-C4'-(1'-Benzylpiperidine)ethyl]-10,11-dihydro-5-methyl-5H-dibenzoCb,e]Cl,4]diazepin-11-one hydrochloride .

HCl CH2CH2 ~.`,'-CH2~9 0.25 g of sodium hydride was suspended in dimethylformamide (DMF). The suspension was stirred while cooling it with ice. 0.58 g of 10,11-dihydro-5-methyl-5H-dibenzo[b,e]Cl,4]diazepin-11-one dissolved in 5 m~ of DMF was dropwise added thereto. The mixture was stirred at 40 to 50C for 20 min and then cooled with ice. 0.71 g of 4-(aminoethyl)-1-benzylpiperidine was added thereto, and the mixture was stirred at 45 to 55C for 6 hr. The reaction mixture was poured into ice/water and extracted with methylene chloride. The organic phase was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by silica gel column chromatograph~y. A hydrochloride of the purified product was prepared by an ordinary method. Thus there was obtained 0.78 g of a pale yellow amorphous substance (yield: 65.4~).
molecular formula; C28H31N3O HCl 'H--~3.~(CDCI3) ~; 1. 20 ~1. 91 (11H. m) 2. 60~3. 00 (2H. bs) ~ 3 22 (3H, s) ~ 3. 41 (2H. s) ~ 6. 87~1. 08 (3H, m) ~ 7. 08 (9H, m) 7. 64(1H, dd) Example 13 Isopropyl 3-CC4'-(1'-benzylpiperidine)propionyl]amino]-2-pyrazinecarboxylate hydrochloride -CO~IHCH2CH2 ~ ".~-CH2--C O~C~

18 g of 2,3-pyrazinecarboxylic anhydride was added to 200 m~ of isopropyl alcohol, and the mixture was refluxed for 1 hr. Thereafter, the alcohol was distilled off therefrom. The resulting solid was dissolved in THF, and 30.6 g of 4-(2-aminoethyl)-benzylpiperidine and 21 g of l-hydroxybenzotriazole were added thereto. The mixture was stirred while cooling, and 29.7 g of DCC was added to the mixture, followed by a reaction at room temperature overnight.
The reaction mixture was filtered and THF was distilled off from the filtrate, followed by addition of methylene chloride. The mixture was washed with an aqueous saturated potassium carbonate solution and then with a saline solution and dried. The solvent was distilled off therefrom. The residue was purified by making use of a silica gel column. The resulting crystal was recrystallized from ether-hexane, thereby preparing 8.81 g of a white crystal of the object compound. A hydrochloride of the compound was prepared by an ordinary method.
elementary analysis: Cz3H3oN4O3~HCl~l/2H2O

- 75 13388o8 C H N
calculated (%): 60.58 7.07 12.29 found (~) : 60.54 7.00 12.29 Exam~le 14 N-[4'-(1'-(p-Hydroxybenzyl)piperidine)ethyl]-2-quinoxalinecarboxylic amide hydrochloride ~Nq~ NncH2cli2~N-cH2 - ~oH HCI

2 g of 2-quinoxalinecarboxylic acid chloride was reacted with 2.52 g of 1-(p-methoxybenzyl)-4-piperidineethylamine in the presence of 2 g of triethylamine in THF at room temperature. The reaction mixture was post-treated by an ordinary method and purified by column chromatography, thereby preparing 2.5 g of N-C4'-(1'-(p-methoxybenzyl)piperidine)ethyl]-2-quinoxalinecarboxylic amide.
This compound was dissolved in 1 g of methylene chloride and reacted with BBr3 for demethylation.
The product was purified by column chromatography, thereby preparing 0.3 g of a product. A hydrochloride of the product was prepared to obtain 0.2 g of a creamy crystal.
molecular formula; C23H26N4O2 HCl - 7~ 1338808 H--N~.5R~CDCl3) ~; 1. 08~1. 92(9H, m) ~ 2. 84 ~3. 18 (2H, m) ~ 3, 24--3. 6d(2H, m) ~ 3, 52 (2H, s) ~ 6. 60 (2H, d) ~ 7. 05 (2H, d) ~ 7. i7 (2H, s) ~ 7. 64~8. 14 (4H, m) ~ 9. 53 (lH. m) Example 15 N-C4'-(1'-Benzylpiperidyl)ethyl]-2-quinoxaline-carboxylic amide ~ C~iHCH2CH2~ ~-CH2~

40 g of 2-quinoxaloyl chloride was added to a mixture of 4.6 g of 1-benzyl-4-aminoethylpiperidine, 50 mQ of pyridine, and 4-dimethylaminopyridine while .stirring the mixture at room temperature, followed by a reaction for 3 hr. Thereafter, the reaction mixture was poured into water, extracted with methylene chloride, and dried over anhydrous magnesium sulfate.
The solvent was distilled off therefrom.
The residue was purified by silica gel chroma-tography (5% MeOH-CH2CQ2) and recrystallized from ethyl acetate, thereby preparing 3.0 g of the title compound.

molecular formula; C23H26N4O2 HCl 'H~ (CDCl 3) ~; 1.16~2.20(9H.m)~ 2.76 ~3. 04 (2H. m) ~ 3. 49 (2H, s) ~ 3. 48 ~3. 68 (2H. t) ~ 1. 13~7. 40 (5H, m) ~ 7. 70~8. 26 (d~ 9. 6d(lH. s) Example 16 l-Benzyl-4-(N'-phenylaminoethyl)piperidine H ~3C H 2 CH 2 ~N-C H, 2 ~3 ~' .

47 g of 4-(N-benzoylpiperidyl) acetate, 8 mQ
of thionyl chloride, and 20 mQ of benzene were heated under reflux for 2 hr. Thereafter, the solvent was distilled off in vacuo.
The residue was dissolved in 20 mQ of THF. The resulting solution was dropwise added to a mixture of 1.86 g of aniline, 10 g of triethylamine, and 30 mQ
of THF while cooling the mixture with ice and, at the same time, stirring the mixture, followed by a reaction at room temperature for about 11 hr. The reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with a saturated saline solution and dried over - 78 1~38808 magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (5% MeOH in CH2CQ2) to prepare 0.9 g of 4-(N-benzoylpiperidyl)acetanilide.
0.9 g of 4-(N-benzoylpiperidyl)acetanilide was dissolved in 10 mQ of THF. A solution of 0.38 g of lithium aluminum hydride in 30 mQ of THF was dropwise added to the resulting solution while cooling and stirring the solution. The mixture was heated under reflux for additional 1 hr. After the completion of the reaction, water was added thereto. The resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to prepare 0.7 of 1-benzyl-4-(N'-phenylaminoethyl)-piperidine.
molecularformula; C20H26N2 ' H--~IYR (COCl ~) ~; 1. 0 ~2. 2 (9H, m) ~ 2. 85 (2H. m) ~ 3. 10 (2H. t) ~ 3. 44 (2H. s) ~ 3. 7 (lH. bs) ~ 6. 4 ~6. 8 (3H, m) ~ 7. 0 ~7 4 (7H, m) Example 17 N-C4'-(1'-Benzylpiperidyl)ethyl]acetanilide CH 3 C~l CH z CH 2 ~\N-C H 2 ~
~D
0.4 g of acetyl chloride was dropwise added to a mixture of 0.7 g of 1-benzyl-4-(N'-phenylaminoethyl)-piperidine, 2.0 g of triethylamine, and 20 mQ of THF
while cooling the mixture with ice under stirring.
The reaction was allowed to proceed at room temperature for 3 hr, and 20 mQ of water was added thereto, followed by extraction with methylene chloride.
The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off therefrom in vacuo. The residue was purified by column chromatography (5% MeOH
in CH2CQ2), thereby preparing the title compound.
molecular formula; C23H28N2O

'H~ R(CDC13) ~; 1. 0 ~2.1(12H.m) ~ 2. 6 ~3. 0 (2H. m) ~ 3. 39 (2H. s) ~ 3. 67 (2H. t) 6. 9 ~7. 5 (lOH. m) Example 18 N-(3'5'-Dimethoxyphenyl)-N-C4'-(1'-benzylpiperidyl)-ethyl]-4-fluorocinnamamide hydrichloride . 8~1 1338808 F ~-CH=CHC~ICH2CH2~;~-CH~ HCl CH 3 0 ~OCH 3 0.51 g of p-fluorocinnamoyl chloride was added to a mixture of 1.0 g of 1-benzyl-4-~N'-(3',5'-dimethoxyphenyl)aminoethyl~piperidine, 2.0 g of triethylamine, and 20 mQ of THF while cooling the mixture with ice under stirring. The reaction was allowed to proceed at room temperature for 2 hr.
Thereafter the reaction mixture was poured into water, extracted with ethyl acetate, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off therefrom in vacuo.
The residue was purified by silica gel chroma-tography (5% MeOH in CH2CQ2). A hydrochloride of the product was prepared by an ordinary method, thereby obtaining 0.9 g of the title compound.
molecular formula; C31H35N2O3F HCl H--~Y'.IR (CDCl 3) ~ ~2. 1 (9H, m) ~ 2. 7 ~3. 0 (2H, bd) ~ 3. 51 (2ff, s) ~ 3. 83 (8H, m) 6. l ~6. 4 (lff, m) ~ 6. 9 ~7. 8 (10ff, m) 8 1 13~8808 Example 19 N-C4'-(1'-Benzylpiperidine)ethyl~-N-phenylnicotinamid dihydrochloride o N~[~[H2CH2~\~1-CH2~ 2HCl 0.70 g of N-C4'-(1'-benzylpiperidine)ethyl]-aniline and a catalytic amount of 4-(N,N-dimethyl-amino)pyridine were dissolved in 30 m~ of pyridine.
The resulting solution was stirred while cooling it with ice. 0.85 g of isonicotinoyl chloride was added thereto, followed by stirring for 3.5 hr. The solvent was distilled off in vacuo. The residue was purified by making use of a silica gel column. A
dihydrochloride of the purified product was prepared by an ordinary method. Thus there was obtained 0.75 g of a pale yellow amorphous substance (yield: 73.0%).
molecular formula; C26H29N3O 2HCl I H--~IMR (C DC l 3) ~ ;1.1 3 ~2. 0 1 (9 H, m) ~ 2. 8 1 (2H, bd) ~ 3 4A (2H. s) ~ 3. 88(2H. bt) 6. 84~7. 26 (12H, m) ~ 8. 31 (2H. d) Example 20 4-(1-Benzylpiperidine)propananilide hydrochloride ~IYHCCH2CH2~N-CH2-~ HCI

0.5 g of aniline and 1 g of triethylamine were dissolved in THF. 1 g of 4-(1-benzylpiperidine)-propionyl chloride was dropwise added to the resulting solution while stirring the solution, followed by a reaction at room temperature for 5 hr.
Thereafter the solvent was distilled off and methylene chloride was added to the residue. The resulting solution was washed with water and dried over MgS04. The solvent was again distilled off and the residue was purified by making use of a silica gel column, thereby preparing the object compound in the form of oleaginous matter. A chloride of this compound was prepared by an ordinary method, thereby obtaining 0.14 g of a white crystal.
m.p. (C): 197.5-198C
elementary analysis: C21H26N2C-HCl C H N
calculated (~): 70.28 7.58 7.81 found (%) : 70.50 7.58 7.83 Example 21 N-C3'-(1'-Benzylpyrrolidine)methyl]benzamide hydrochloride O
~eNHCH2 ~I-CH2--~ HCl 0.74 g of benzyl chloride was reacted with 1 g of 3-(2'-aminomethyl)benzylpyrrolidine in the presence of 1.5 g of triethylamine in THF at room temperature while stirring the reaction system. The reaction mixture was post-treated by an ordinary method and purified by column chromatography, thereby preparing 0.32 g of the object compound. A hydrochloride of the compound was prepared by an ordinary method.
molecular formula; ClgH22N2O HCl 'H~ R(CDC13) ~;
1. 48 ~3. 08 (7','. ~) ~ 3. 44 (2H. d) ~ 3. 62 (2 H, d) ~ 7. 04~7. 88 (lOH. m) Example 22 4-C4'-(N-Benzyl)piperidyl~-3-hydroxy-p-methoxy-butyrophenone O OH
~D~C C H 2 C H C H 2 ~ N-C H 2 4 -- 8~ 1338808 2 mQ of diisopropylamine was added to 7 mQ of THF in a nitrogen stream. 7.6 mQ of a 1.6 M solution of n-butyllithium in hexane was added thereto at 0C.
The mixture was stirred for 10 min and then cooled to -78C. A solution of 1.65 g of p-methoxyacetophenone in 10 mQ of THF was added thereto, and the mixture was stirred for 20 min. Further, a solution of 2.4 g of l-benzyl-4-piperidinecarboaldehyde in 10 mQ of THF was added thereto, and the mixture was stirred for 10 min. An aqueous 1% ammonium chloride solution was added to the reaction mixture, followed by extraction with methylene chloride. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (5~ MeOH-CH2CQ2), thereby preparing 2.0 g of the title compound.
molecular formula; C23H29NO3 'H~ R(CDCl 3) ~; 1. 0 ~2. 2(9H. m) ~ 2. 6 ~3. 4 t5H, m) ~ 3. ~3 (2H, s) ~ 3. 81 (3H, s) 4. 1 (lH) ~ 8. 83 (2H, d) ~ 7. 17 (5H, s) 7. 82 (2H, d) Example 23 4-C4'-N-Benzyl)piperidyl]-p-methoxybutyrophenone ~ 1338808 hydrochloride o ~CCH2CH2CH2~N-CH2~ HCl CH .0 0.54 g of 4-C4'-(N-benzyl)piperidyl]-3-hydroxy-p-methoxybutyrophenone, 0.1 g of p-toluenesulfonic acid, and 30 mQ of toluene were heated under reflux for 5 hr by making use of a Dean-Stark reflux condenserO
After the completion of the reaction, the reaction mixture was poured into an aqueous potassium carbonate solution, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by column chromatography (5% MeOH-CH2CQ2) to prepare 0.45 g of 1-benzyl-4-C4-(p-methoxyphenyl)-4-oxobutyl]-piperidine. This compound was dissolved in 20 mQ
of MeOH and 40 mg of 10% palladium-carbon (anhydrous) was added thereto to effect hydrogenation at room temperature under atmospheric pressure for 1.5 hr.
The insolubles were filtered off, and the solvent was distilled off in vacuo. A hydrochloride of the product was prepared by an ordinary method. The hydrochloride was recrystallized from MeOH-IPE, thereby preparing 0.2 g of the title compound.

~ 1338808 molecular formula; C22H29N02 HCl ' H--N',-IR (CDCl 3) ~; 1. 4 ~2. 3 (11H. m) ~ 2. 4 ~2.1 (2H. m) ~ 2. 95 (2H. t) ~ 3. 55 (2H. s) 3. 87 (3H, s) ~ 6. 93 (2H. d) ~ 7. 1 ~7. 5 (5H, m)~ 7.94(2H.d) Example 24 N-C4'-(1'-Benzylpiperidine)ethyl~-3-furancarboxylic amide hydrochloride ~CNHCH 2~ H 2--\ ,N-CH 2~ HC1 1.64 g of 4-(2-aminoethyl)-1-benzylpiperidine and 2.67 g of potassium carbonate were added to a mixture comprising 40 mQ of chloroform and 40 mQ of water. The mixture was stirred for 1 hr while cooling it with ice. The organic phase was separated, washed with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off in vacuo and the residue was purified by making use of a silica gel column. A hydrochloride of the product was prepared by an ordinary method, thereby obtaining 1.60 g of the title compound in the form of a pale yellow amorphous substance (yield: 61.1~).

87 1338808 65702-3l5 molecular formula; ClgH24N202 HCl IH~ .IR(CDCl3) ~; 1 4~~2~10(9H~m)~ 2.81 (2H. bd) ~ 3. 25~3. A7 (A~{, m) ~ 5. 80 (1H.
bs) ~ 6. 51 (lH. dd) ~ 7. la~l. 19 (6H. m) 7. 82 (1H, dd) Example 25 N-[4'-Adamantylmethylpiperidine)ethyl]benzamide ~CNHCH 2CH 2 r N-CH 2 ~

1.47 g of N-(l-adamantanemethyl)-4-(2-aminoethyl)-piperidine and 0.73 g of potassium carbonate were added to a mixture comprising 15 mQ of chloroform and 15 mQ of water. The mixture was vigorously stirred while cooling it with ice.~~O.90 g of benzoyl chloride was added to the mixture, followed by stirring at room temperature overnight. The organic phase was separated, washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by making use of a silica gel column. The purified product was recrystallized from benzene-n-hexane, thereby preparing 1.47 g of the title compound in the form of a pale yellow plate crystal (yield:
72.6%).
olecular formula; C25H36N2 IH~ (COCl 3) ~; 1. 29~2.28(27H.m) 2.12 (2H, bs) ~ 3. 43 (2H. q) ~ ~. 01 (~H, bs) 7. 31~7. 43 (3H, m) ~ 7 (lH. dd) Example 26 N-Methyl-N-[4'-(1'-Adamentylmethylpiperidine)ethyl]benzamide hydrochloride 11 r ~3,CIC.2CH2 ~_~N-CH2 ,~ HCl 0.18 g of sodium hydride was suspended in 2 mQ
of tetrahydrofuran (THF). The suspension was stirred while cooling it with ice. A solution of 1.45 g of N-~4'-(1'-benzylpiperidine)ethyl]benzamide dissolved in 5 mQ of THF was dropwise added thereto. The mixture was stirred at room temperature for 1 hr and again cooled with ice. 0.36 mQ of methyl iodide was added thereto, followed by stirring at room temperature overnight. The reaction mixture was poured into ice/water, extracted with chloroform while conducting salting out, washed with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off in vacuo and the residue was purified by silica gel chromatography. Thus there was prepared 0.60 g of yellow oleaginous matter (yield: 47.0~).
The starting material (0.22 g) remaining unmethylated was recovered (recovery: 15.2%).
A hydrochloride of the obtained oleaginous matter was prepared by an ordinary method, thereby obtaining 0.52 g of the title compound in the form of a yellow amorphous substance (yield: 37.6%).
molecular formula; C26H38N2O HCl H ~ R(COCl 3) ~, O,9 2 ~3.60(63H,m) 7.29(~H,s) Example 27 N-C4'-(1'-Cyclohexylmethylpiperidyl)ethyl]-N-methylbenzamide hydrochloride Il CNCH2CH2 ~ N-CH2 ~
~ CH3 HCI

0.6 g of N-methyl-N-(4'-piperidylethyl)benzamide, 1.2 g of cyclohexyl bromide, 2.0 g of sodium bicarbonate, and 30 m~ of methyl ethyl ketone were heated under reflux for 7 hr. After the completion of the reaction, water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (5% MeOH-CH2CQ2), thereby preparing 0.3 g of the title compound.
molecular formula; C22H34N20 HCl 'H~ R(CDCl3) ~ ;0.8 ~1.1(20H,m)~ 1.1 ~1. ~(4H, m) ~ 1. 8 --2. ~ (~H, m) ~ 7 4 (5H, s) Examples 28 to 177 The compounds synthesized in the same manner as that of Examples 1 to 27 are shown in Tables 4 to 8.

~q U~
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c)a~ ~ o ~ m _I R C~ 5~
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ocn ~ In 51 ~ 5, ~ 5, ~ --U ~ U r r~
^ ~ U ~ 5' --~ _I In m _I
N ~ ` ` 5:~ ` 5 a) o ~o o ~r ma) O cr) 0 ~ 5 - ,o~ z r~r-- Z ~ ~~ Z In In ~ ~ m r~
~ ~ U ~ nU -- ~U ~ ~ ^----O ~-- O
~ :O 'J ~ ~ ~ _I ~i~ m In 2 _ m Z
E3 ~ 5 ~s7C. 1~ 1~ ~r :C r r~ E a~ E t~ a~
~ ~ r ~ O ~ ^ ~ ~ N `
~ ~ 5~m ~
~ ~ -- -- ~ -- -- o -- -- ~ ~ u -- -- ^ u ~ . ~ ....... ~ ........ ~ o u~ R ~ O u~
r ~ .~ u ~ u ~ ~
¢J ~ ~ ~ ¢l ~ ~ ¢l ~ Ec~ ~ ~ E
c , ~ U ~ , ~ U c~ U c~ ~ ~
o ¢l ¢ o o ¢l ¢ o o ¢l ¢ o _ o In ~ o _ In In o s~
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E ~ E ~ ~ E
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s g3 ~ ~, ~ s ~ s J =~
n ~ ==~ ~ =n~ C~
O C ~ O O
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X O C~ o U~
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Z ~ Z Z Z
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U ~1 ' ' U r~) ~,) N
O ~r~ ~ ~ O U O O O
-- ~IS ~ z ~ r ~ Z ~ Z Z
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tC ~ N~r ` ~ `
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2 ~ ~ ~1 o co ~ ~ ~ `-- ` N ~ _ _ z s,R ~1 -- R ` ~D R
Z ` O `~ ~ ~ ~ I~
N _ .N ' Ul N ` O ~ O O
; _i O ~ O U~ U~ U ~ r co ~
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-- n~N N R o-- N O` Il) O -- -- O 1` t'') a~ --I
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E ~ --~ N E N ` ~D t`') E
, ~0 r` -- ~N ~ 1~ ` ~ N 'O _I _ N ~0 G~ ` ' '`I :11 U` ----~U------~V ----~--U --------~_ ~ ------~o R ~D ~ 0 0 ~ ~ '13 u~ ~N UJ Ul _I - dP dP dP
V ~ ~ ~ V ~ ~1 ` ------E N N ~ E a N ~r~ N E . N tr~ m E a N ~ --I E --0 N
-- V c' --Q ~ V c' ~-- ~V c' ~-- ~ V c' ---- ~ V ~: ~i ~ ~
--O --~ ~ O --O O ~D O -- ~r 1~ ~ O --o a~ ~r o o ~ ~ ~ o s . . . ~ r O
-LJ z ~ -- Z ~ O Z ~ ~ ~ Z ~ E
O _~ E --I E ~: - OEI ~ --ol ~ a ~r s Q = _ -. '' s ~ . .
s s . s n o~ o~ o~ o~
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o o o o o S L~

X z ~ V, ~r Table 4 (cont'd) Ex. Physicochemical constant No. Structural formula (m.p., elem. anal., NMR, etc.) H-NMRtcDcl3)~;
IH 1.80~2.03(13H,m), 2.80(3H,bd), 3.43(2H,s), 43 ~CHCII,CH,CH,~H-CH,-~ HCI 4.60(1H,t), 7.28(5H,s), 7.30(5H,s) mol. form.; C22H29NO-HCl H-NMR(CDC13) IS;
Inl 1.10~2.13(7H,m), 2.26(2H,t), 2.88(2H,bd), 44 ~-CCH=CHCH.~-CH~ HCI 3.48(2H,s), 6.72~7.07(2H,m), 7.30(5H,s), 7.10~8.00(5H,m) mol. form.; C22H2sNO HCl : m-.p. (C); 176~178 n elem- anal- C21H26N2 H9- CCH,CH,CU, { H-CH, ~ 2HCI C H N
found (%~ 63.13 7.43 6.88 3/lOH20(% 62.94 7.19 6.99 ~-~
lH-NMR(cDcl3)~;
~ OH 1.05~2.15(9H,m), 2.85(2H,bd), 3.02(2H,d), C~
4G H~-CCH,lltCU,~-CH.~ 7 21(5H s), 7.62(2H,dd) 8 70(2H,dd) CX~
mol. form-; C21H26N22 lH-NMR(CDC13)~;
Il 1.10~2.10(7H,m), 2.25(2H,bd), 2.85(2H,bd), 41 N~CCH=CHCH,~N-CH~ 2HC1 3.45(2H,bs), 6.59~7.10(2H,m), 7.20(5H,s), 7.56(2H,dd), 8.67(2H,dd) mol- form-; C21H24N2 2HCl Table 4 ( cont ' d ) Ex. Structural formula Physicochemical constant No. (m.p., elem. anal., NMR, etc.) m.p. (C); 240~240.7 n , elem. anal.: C20H2sN3O-2HCl 1~ N~NHCC~,CH,~N-CN,~ 2~CI calcd. (~ 66.75 7.28 11.68 foùnd (%~ 66.26 7.42 11.37 3/20H20(% 66.25 7.31 11.59 lH-NMR(CDC13) 0;
1l 1l 1.80~2.24(9H,m), 2.96(2H,d), 3.64(1H,m), 49 H~-NHCCIJ,~N-C~ HCI 4.60(1H,m), 7.20~7.58(6H,m), 8.34(2H,d) mol- form-; Cl9H21N32 HC1 H-NMR(CDC13)~; C~
~ O ~ Dr~ 1.12~2.20(7H,m), 2.34(2H,d), 2.74~3.01(2H, O,N ~NNCCH,~N-CN,~ HCI m), 3.50(2H,s), 7.29(2H,s), 7.71(2H,d), CY~
8.20(2H,d) ' ' 00 Table 5 Ex. Physicochemical constant No. Structural formula ~=.p., elem. anal., NMR,etc.) m.p. (C); 135~140 (dec.) Q elem. anal.: C22H2sN30-2HCl 51 ~ CH,CH,~N-CH,~ 2HCI C H N
N found (%) 59.22 6.639.14 3/2H20 (%) 59.06 6.76 9.39 m.p. (C); 80~82 (dec.) n elem. anal.: C22H27N3O-2HC1 52 ~-CU,CH,~H-CH,~ 2HCI calcd. (%) 62 56 6H92 gN95 found (%) 60.14 7.313 9.21 l-H20 (%) 60.00 7.099.54 lH-NMR(CDCl 2) IS;
1~ 1.1~2.2(~H,m), 2.7~3.1(2H,m), 3.50(2H,s) 53 ~-CH,CH,~H-CH,~ HCI 4.03(2H t), 6.50(1H,m), 6.9~7.9(9H,m), mol. form.; C23H26N2O HCl ~_~
H-NMR (CDC13 ) ~;
1 r~ ~ 1.1~2.2(9H~m)~ 2.7~3.1(4H,m), 3.4~3.7 C~
54 ~ ~-CH,CH,~N-CH,~ ~CI (6H,m), 7.0~7.6(8H,m), 8.06(1H,m) CX~
~J'-' mol. ; 23 28 2 0 n lH-NMR(CDC13)~; CP~
J~ r~ ~ 1.10~2.20(11H,m), 2.27(3H,m), 2.93(2H,bd), -CH,CH,~H-CH,-~ HCI 3.48~3.70(4H,m), 7.27(5H,s), 7.28~8.12 N ( 4H,m) C=O
CH, mol. form.; C24H2gN3O2-HCl Table 5 ~cont ' d) E Physicochemical constant NoStructural formula (m.p., elem. anal., NMR, etc.) H-NMR(CDC13)~;
~ r~ 1 10~2.20(9H,m) 2.93(2H,bd), 3.40~3.65 56~-CH,CH,- ,N-CH.- ~ HCI (6H,m), 4.43(2H,s), 7.00~7.50(4H,m), 7.31(5H,s) mol. form.; C23H2gN2O-HCl lH-NMR(CDC13)~;
r~ ~ 1.10~2.20(9H,m), 2.22~2.97(8H,m), 3.45(2H, 57~J-CH,CH,~N-CH,~ 2HCI s), 3.55(2H,s), 6.90~7.20(4H,m), 7.20(5H,s) mQl. form.; C23H30N2-2HCl lH-NMR(CDCl3)~;
r~ ~ 1.10~2.16(13H,m), 2.16~2.50(2H,m), 2.87 58~-CH,CH,~N-CH,~ HCI (2H;bd), )3.03~3.43(4H,m), mol. form.; ClgH20N2o-H
lH-NMR(CDC13)~;
r~ R~\ 1.10~2.10(9H,m), 1.46(3H,d), 2.87(2H,bd), ~_~-CH,CH,~N-CH,-~ HCI 3.35~3.72(3H,m), 3.46(2H,s), 4.40(2H,dd), C~
0 7.00~7.38(4H,m), 7.28(5H,s) C~
CH, mol- form-; C24H30N2 HCl CXO

-/~N CH ~ lH-NMR(CDC13)~; 00 H,CH,-\~ =J 1.20~2.84(2H,m), 3.44(2H,s), 7.14~7.25 /o IICI (9H,m) ~ mol- form-; C25H32N2 ~D 0 0 '_ 0 S e ~ e N . C~ N ~ _ -- N ~ --r ~ r N -- N
~r 00-- 0 ~--u In ~D CO ~ _ CO
N N ~9 e ~
a~ N ~ In ~ .
~ 0 0 -- ~ ~ N ~?
0 -- ~ D -- -- N
~ R Ul :C r~ In ~ _ N t~
z Q ~ In e o -N N 1~ N --I N N r "
~ I -- UCO -- -- U ~ I ~ -- U
d ~ U a~n 0 0 ::~ ~ ~ U co 0 X
~ C . ,m, ,~
_ ~ N . ~ ~ NN m r, NN . . N ~
O N _ _ o~ In O 1~ 0 ~ C
N 0 ~a N~-- -- N
. e -- Z Z--In _I Z--CD z _~ , ~3 e ~ E N r ~e ~ N ~ e O ~ E o _ ~1 ,m, r r~ ~ m ~
~ In ~ ~ r ~ n~ ,n n N ~ In r, n -- -- -- -- U
~C a;~0 O r-~O ~ ~ ~0 0 ~~'7N e ~ u~
n ~ N ~ I O
e ~ u _ :c u :q u ~ -- ~ _I r~ea N _ _e a N N ~1 ea N ~r E a N N r E
-- U C~ e e h U C~ U C~ U C~
~ --~r co o --~ O --~n ct~ o O--a) ~ o --N ~ O O
-- ~; ~r O ~ C; N r 5: 4~ ~ N ~ o q~~ ~ ~ ~ ~ ~ ,n N ~
Z --I ~ Z ~ Z ~ ~~ Z _I ~ z _I ~ ~ -C~ ~C e ~r e ~ e 5~ e ~r ~OE
Lr a~
.4 .
E~

y = .

O

X Z ~o ~ ~q U~

Table 5 ( cont ' d ) Ex Physicochemical constant Structural formula No. (m.p., elem. anal., NMR, etc.) H-NMR(CDC13)~;
~ . 1.10~2.10(11H,m), 2.60~3.00(4H,m), 3.45 66 C~,0 ~ ~ (2H,s), 3.45~3.80(1H,m), 3.86(6H,s), 6.22 ~ ~ ~ ~ ~CI (lH,bs), 6.57(1H,s), 7.20(5H,s), 7.46(1H,s) CH,C CH,CH.- ~H-CH.- =
mol. form-; C25H32N23 HCl lH-NMR(CDC13)~;
1.08~2.10(11H,m), 2.50~2.95(4H,m), 3.01 67 CH~o~l~ CH (3H,s), 3.45(2H,s), 3.45~3.60(1H,m), 3.85 ,~ ~ n Hl:l (6H,s), 6.52(1H,s), 7.10(1H,s), 7.20(5H,s) CH,O CH,CH.- JN-CH.- = ~L
- mol. form.; C26H34N2O3 HCl H-NMR(cDcl3)~;
~ , 1.02~2.12(9H,m), 2.50~3.05(4H,m), 3.43(2H, ~_~
68 CH~O~ J ~H s), 3.43~3.85(1H,m), 3.88(6H,s), 6.58(1H, C~
~CH ~N H ~ Hl:l s), 6.50~6.82(1H,m), 7.20(5H,s), 7.46(1H, C~3 CH,O~ ~ -C, ~J s ) ~
mol. form.; C24H30N23 Hcl CX3 ,~ lH-NMR(cDcl3) ~i;
f~,CH,~N-CH, -~ 1.17(3H,t), 1.10~2.15(9H,m), 2.68(2H,q), ~N ~IJ 2.89(2H,bd), 3.14(2H,s), 3.51(2H,s), 6~ ~ ~ ZHCI 3.55(2H,s), 3.87(2H,bt), 7.07~7.35(9H,m) J ~ N/
CH,CH. mol- form-; C25H33N3O-~U 1338808 uJ E~
O N o E
_ _ o r~ ' ~D O ' ~ ' ~
~r N ~ ,~ c ~, c' E c'~D ' N
O E :C N ~ N
' NN -- r ^ ~
E ~ ~ o ~ ~ 0 c' ~D N ~D~ ~) ~ :C E
E ~r ~ o J~ ~ E ~
z~ _ ~ o ~ ~ '~ ~ ~
o o e I ' ~
~ N :1:~ ~N ' O :~ O ' UJ ~
~J C5~1 0 0N r~ N ~ N 5: :C
r~ N ON N_I -- t` _ N -- U7 --1 ~--N c~O -- --C N q~ z~ ~
E ~ D ^~ ~ ~ o -- ' O N E ~ E~
E ~ ~ ~ N a~
u ~ u~ -- ^ -- ^ -- ^ ^ ^ ^ ^
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G C ~ o UJ u :C U ~ ~ ~ C
EC3 N N r~ a N ~ ~
U :C ~U c ~ cU c E ~ E ~ -- E ~---- N N O-- N O ~-- CO ' I" ' -- I-') ' ~SI 1 I Ul ~ N U~ ~ ~ N -Z O U~ Z _~ ~ I`Z _~ --~ -- Z O --Il~ Q
E ~ ~m Q

E~
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x o o c~ z lOl 1338808 o ~" _ o c' E-- --co u _ _ ~ ~
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u - ~ E ~ D E c~ E~ ~ m m m u ~
~: ~ u . m . ~ u . m u . ~ _I u o . u a~--o . _l ~ o a ~ c~ h ~ ~ C~ ~-- a o N (~
E U c' ~ c' ~ U c' ~ c' U c' ~ N U c' ~ ~ E U N ~ 5 U C ~ ~m -- --~r ~) o ~ -- ) co o -- o~ c~ -- o N CJJ - -- N CO O U f~ ~ C ~ C CO
~o ~ _I m o: o ~9 o ~ ; o _1 ~ m ~ ~ O . ~ N
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m m m :c m -~ E ~ O _~
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_ ~r7--01 e~ UO N UO ~ UO In _I
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tll r` ~ r` ~. N t` ``I
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Table 7 (cont 'd) Ex Physicochemical constant No Structural formula (m.p., elem. anal., NMR, etc.) Q lH-NMR(CDC13)~;
N '~- !NIH H -~N-CH R~ 1.1~2.1(9H,m), 2.6~3.0(2H,m), 3.50(2H,s), J ~ 2HLI 3.83(2H,m), 6.58(4H,dd), 7.04(2H,d), 7.19(5H,s), 8.28(2H,d) IIH mol- form-; C26H29N32 2HCl n lH-NMR(CDCl )~; Oq~ 11 \ ~ 1.07~2.35(~H,m), 2.99(2H,bd), 3.62(2H,s), 112N~-l:N(:H,l:H,- ,N-CH,- = ZHCI 3.81(2H,bt), 6.31~6.56(3H,m), 6.84~7.11 (3H,m), 7.25(5H,s), 8.31(2H,bs) ~H mol. form.; C26H2gN302-2HCl O lH-NMR(CDC13)~
N ~-LNCH,CH,-~II-(`H -~ 1.1~2.1(9H,m), 2.6~3.0(2H,m), 3.44(2H,s), C~
113 ~ J ZHCI 3.68(3H,m), 3.85(2H,m), 6.78(4H,dd), CP~
U l 7.02(2H,d), 7.23(5H,s), 8.37(2H,d) CX3 O(:H, mol- form-; C27H31N32-2HCl CX~
H-NMR(CDC13)~i ~ -NCH,CH.- C N-CH,- ~ 7 20(11H~m)~ 8.05(1H~m), 1.2~1.83(9H,m), 11~ f~ 2HCI 2.65~2.81(2H,d), 3.4(2H,s), 3.90(2H,m), W 6.20~6.52(2H,m) mol. form.; C25H29N3 2HCl Table 8 Ex. Structural formula Physicochemical constant No. (m.p., elem. anal., NMR, etc.) ~ I~H, lH-NMR(CDC13)~;
115 ~-C-N--CH,CH,~N-CH-~ HCI 0.80~2.12(12H,m), 2.52~3.64(8H,m), 1 7.06~7.52(lOH,m) L'H, lH-NMR(CDCl )~;
R-~ 1I r~ R~ 1. ~8~2.13(9H~m) 2.80~2.92(2H,d), 3.00 IIC 11,11-~-C-7 CH,CH,-~N-CH,-/~ ZHCI 6-~0(2H,dj 7325742H8m(7H 3j9o(2H~s)~
CH, mol. form.; C22H2gN30 2HCl Il lH-NMR(CDC13) ~i;
117 ~-C-IN-CH,CH~-cN-CH,-~ UCI . 1 0 2 1(9H m) 2 31(3H,s) 2.5~3.1(5H,m), O
l:H, CH, mol- form-; C23H30N20-C lH-NMR(CDC13)~;
118 ~-CH,-~'-NHI:H,CH,-CN-CH,-~ HCI 1 0 2 2(9H m),812(2H3S) 5.8(iH,s), 7.25 Nn~ (5H,s), 7.3~7.7(3H,m), 8.03(1H,d) C~
mol. form.; C22H27N303 HCl C~
Q lH-NMR(CDCl3)~; (in free form) CXO
ll ~ 1.10~2.06(17H,m), 2.10~2.32(3H,m), 2.96 CX~
119 R -C-IN-CH,CH,- ~N-CH,- = ' HCI (3H,s), 3.20~3.52(4H,m), 4.08~4.16(2H,d), CHJ 7.36~7.76(5H,m) CXD
mol. form.; C22H34N20 HCl Il ¦¦ l~, lH-NMR(CDC13)~;
12U IJ ~ N-CH,CH,-CN-CR.-~ RCI (3H,s); 3.46~3.64(4H,m); 6.42(1H,ddj, o 7.00(lH,dd), 7.26~7.45(6H,m) mol- form-; C20H26N202-HCl Table 8 (cont ' d) Ex Physicochemical constantNo Structural formula (m.p., elem. anal., NMR, etc.) O lH-NMR(CDC13)~;
21 ~ -C-IN-CH,CH,- ~ N-CH,CH=CN- ~ HCI 6 16~6 54(2H,m), 7 10~7 55(10H,m) CH, mol. form.; C24H30N20-HCl lH-NMR(CDC13) ~;
~ 1.1~2.1(7H,m), 2.8~3.05(2H,m), 3.05~3.15 12Z ~-UCNHCH,-~N-CH- V HCI (2H,m), 3.49(2H,s), 5.1(1H, ), 7.0~7.5 (lOH,m) ~_~
mol. form.; C20H24N2o2-Hcl ~
lH-NMR(CDC13) ~i;
z3 ~-C-N-CH,CH,-C~N-CH,CH~ HCI 1.00~3.08(20H,m), 7.22(5H,bs), 7.37(5H,s) CH, mol. form.; C23H30N20 HCl D lH-NMR(CDC13) ~ 11 ~ 1 30~2 24(9H,m), 2.86(2H,bd), 3.32~3.60 C~
12~ CRHCH,1~ ~R-CH,~ HCI ( 4H,m) 6.08~6.28(2H,m), 7.20~8.02(6H,m) mol. form.; Clg 24 2 2 CX~
Q . lH-NMR(CDC13) ~; o 125 ~ -DCOCH,-- C N-CH, ~ HCI 1.1~2.2(9H,m), 2.8~3.1(2H,m), 3.50(4H,s), ~X~
7.30(lOH,s) mol. form.; C20H23N03 HCl O ` lH-NMR(CDC13)~; (in free form) CHJQ 1I r~ or~ 1.20~2.16(9H,m), 2.64~3.0(2H,bd), 3.46 120~CRHCIl,CH,-~II-CH,-~ H~'l (2H,s), 3.36~3.60t2H,m), 3.80(6H,s), 5.60 (lH,bs), 6.50~6.60(2H,d), 7.16~7.40(6H,m) IJCH~ moo. form.; C23H30N203 HCl Table 8 ( cont ' d ) Ex. Structural formula Physicochemical constant No. (m.p., elem. anal., NMR, etc.) ~ lH-NMR(CDCl~)~; (in free form) l27 ~ ,CNHCH,CH,-CN-CH,-~ HCI (2H~S); 3 32~3)6o2(2H6~3;o(2H~bd)~ 3 48 6.32~7.40(8H,m), 8.26(1H,bs), 14.0(1H,s) OlH, mol. form.; C22H2gN203-HCl lH-NMR(cDcl3)~;
12a ~ ,nCIlHCH,CH~-CN-CH.-~ HCI ljl~2 2(9H,m), 2 7~3 0(2H,m), 3 1~3 4(2H, ~_~

mol. form.; C21H26N202-HCl ~-`
O lH-NMR(cDCl3)~-12U ~ CH,~NH~H,I:H,-~Y-CH.-~ HCI 1.1~2.2(9H,m), 2.7~3.0(4H,m), 3.1~3.6 (2H,m), 3.55(2H,s), 5.5(1H), 7.30(10H,s) ~_~
mol. form.; C22H28N20-HCl C~
H-NMR(CDC13)~; CXO
13U ~ CH=CHCIIH~,CH,-CN-CH,-~ HCI 1.1~2.2(9H,m), 2.7~3.0(2H,m), 3.2~3.4 CX~
I 1~ (2H,m), 3.40(2H,s), 5.9(1H), 6.39(1H,d), ~~~
7.1~7.8(11H,m) CX~
mol. form.; C23H2gN20-HCl O lH-NMR(CDC13)~; (in free form) n ,~ R-~ 1.1~2.2(9H,m), 2.6~3.0(2H,bd), 3.44(2H,s), 131 ,~n~CNHcH.cH~ -cH~-v ~CI 3.36~3.6(2H,m), 3.90(3H,s), 6.9~8.30 (lOH,m) IICH, mol. form.; C22H20N2o2-H

Table 8 (cont ' d) .. ... ._............ . .. . . ... . ,_ . ... .. . . _ Ex. Physicochemical constant Structural formula No. (m.p., elem. anal., NMR, etc.) O lH-NMR(CDC13)~;
132 L'H,CH,CIIHCH,CH,-CN-CH,-~ HCI 1.1~2.2(9H,m), 2.3~2.7(4H,m), 2.7~3.0(2H, m), 3.0~3.5(4H,m), 6.1(1H), 7.0~7.7(10H,m) mol- form-; C23H30N20-lH-NMR(CDC13)~;
1.17~3H,t), 1.2~2.1(9H,m), 2.17(2H,q), CH,CH,I IIHCH,CH.~N-CH. ~ HCI 5 3(1H), 7.21(5H;s) mol. form., C17H26N20-HCl H-NMR(CDC13)~;
ll _\ 1.1~2.0(12H,m), 2.6~3.0(2H,m), 3.0~3.3 13~ "~IHL'NHCH,I:H,_ ~N-Clt.-' = I HL'I (2H,m), 3.41(2H,s), 3.3~3.4(lH,m), 7.23 b 11 CH, (lOH,s) mol. form.; C23H30N20-HCl ~_~
H-NMR(CDCl3)~; C~
D ~ 0.90~2.10(9H,m), 2.78(2Hjbd), 3.00~3.70 C~
135 ~b~c-N--cH~LH~- ~N-CH.- = I HCI (2H,m), 3.43(2H,s), 4.40~4.85(2H,m), CXO
CH, R~ 7.27(10H,s), 7.38(5H,s) CX~
~=~ mol. form.; C2gH32N20-HCl O
~ lH-NMR(CDC13)~;
]:]C ,CIJCH,CH.- C Il-CU. ~ 1.0~2.1(9H,m), 2.7~3.0(2H,m), 3.48(2H,s), 4.36(2H,t), 7.0~7.7(8H,m), 7.8~8.2(2H,m) mol. form-; C21H25N2 Table 8 ( cont ' d ) Ex. Structural formula Physicochemical constant No. (m.p., elem. anal., NMR, etc.) Il lH-NMR(CDC13)~;
111 C-N-CH,I:H, ~ N-CH.- ~ HCI 0.86~1.90(9H,m), 2.56~3.05(4H,m), 3.38 I ~ ~ I (2H,d), 4.56(1H,s) 4.68(1H,s), 7.00~7.56 ~ylJ CH,-~ = ~ (12H,m), 8.10(2H,m) 0,N mol. form.; C28H31N33-lH~NMR(CDCl3)~;
0 _\ 1.0~2.1(9H,m), 2.7~3.0(2H,m), 3.1~3.4 CH,=I:NC~H,C~,-( N-lH.-~ ~ HCI (2H,m), 3.47(2H,s), 5.58(1H,dd), 5.9~6.1 (2H,m), 7.29(5H,s) mol. form.; C17H24N2 Hcl ~-~
H-NMR(cDcl3) ~;
1 3!1 ~C- ~t-C;H,CH,- ~ N-C- ~ 1.00~4.08(16H,m), 7.38(10H,s) mol. form-; C22H26N22 -NMR(CDC13)~
~,C-N-CH,C~ N-CH.- ~ -N~, HCI 0.90~2.10(9H,m), 2.55~3.50(7H,m), bJI ~. 3.52(2H,s), 7.38(5H,s), 7.80(4H,ABq) C~
mol- form-; C22H27N33 HCl CX~
- lH-NMR(CDC13)~;
,~-tlCH,CH,-(~N -CH- -~ O . 96~2.08(3H,m), 2.60~3.10(6H,m), l:H, 3.48(2H,d), 7.16~7.92(14H,m) ~-0 ll~ 1338808 O ' N
N t`
~) ' ) U~
~ E N,~ t~l E ~ O 0 Z
r r ~r ~ r co o~ ~
o t~
z a~ N r~ r 1~ ~
'` ~ ~ ~ u u~ a~
~N ~ ,0 Vl c~ E ^ r~ r r 'D
c~~ ~ N
~ d ~ o N ~ rN ~ LO r ~ O
_ ~ N 5~ 0-- O N -- O 1:~ Z
N' a:) N ~O tr) -- ~ '1 IJ') z~ N æ ~ ~o z ~ N a~
E ~ ~ fi N ~ E O ^ ` 1` 5 C) a) E E '-- r~ E 1` ~ --I ~I ~'7 N
r N ~ r r ~ ,~ r N t~
~1 ` 5. r ~ r o N ~ rl2 ~ N dQ dP
C~ ^5~ U r c~
E a N r~ ~ N ~) U1 E C~ r E ~ N ^ E ^
-- --O N --~ n O --O N O --O ' O O 11] C
o r ~ o o ~ o~ ~ r ~ -- .~ ~
~ ~ . N rr O
.~ Z O ~) Z _I--~` Z --I 1` Z O -- E
r r E _~r E ,~r E E
t) -r ~ ~ ~ 3~

O=~ =O C~ O=C-- C~=~l 0=0 < D ~7 <~ 7 x o c ~ e e e .c m m U N O
m m ~ ~ ~ ~ m ~ C~ m ~ ~ a~ ~
o ~o ~ ~ C~ 1`
'` m ~ ~ E^ C`l -o u ~a --2. e E ~ m m m -- . . m m (~J) ~ ` ~1 N ') ` N ~`I
i co u co ê u ~ ~ u c~ ~ -' ~~
~ ~ ~ m N ` m c~ e m o o m r ~ m ~, ~ ~ O N ~ O m G ~ 0 ~ ~
e o m 2. ~1 co 2; ~ 2 ~ ~ 2~ ~ ~ 20 , ~ ~ In c" ( r m _ ~J e ~ e e m ~ m m U ` _ _ U _ ~ ~ U -- ~ ----N ~r ~ U
P~ u m ~ u m m U N ` U ~D~ U 0 e c~ _ e ~ e ~ . _ e a~ . . e ~ , E
-- u--e ~ u---- ~ U ~ e ~ uc~ u c~
-- N ` O-- u~ 1 0-- C~ ` O --o O _ o o t'~l o ~ ~; co m ~~ c~ o m ~ ~; o ~ o _l ~ ~
2~; 0--~2~; 0 ~ ~ 2~ 2~;_1 U2 U~ Ut~ æ ~
o ~m e _,m e _,m e ~m e _,m e -r ~`

~ _ ~ .
= ,S"=~ S\ 1=/~ ~ ~

S ~-S :_~ = = Z~
~ r~

U~ = n:.~ S r~ = ~, Cl=
O= ~J 0=~0= L~ 0=

X O

Tab le 8 ( cont ' d ) Ex. Physicochemical constant Structural formula No. tm.p., elem. anal., NMR, etc.) O lH-NMR(CDC13)~;
ll r~ /r~ 1.00~2.00(9H,m), 2.03(3H,s), 2.80(2H,bd), 152 CH,CII l:H,lH. - ~N -CH, -~ HC I 2.88,2.91(total 3H, each s), 3.05~3.40 (2H,m), 3.43(3H,s), 7.20(5H,s) LU, mol. form.; C17H26N20-HCl q - lH-NMR(cDcl3)~;
15:J CH=LHLNICH,CH.-cH-CH.-~ IH'I (4H,mj, 6.8~7 1(iH mj2(75H3m)~ 3j2~3 6 ,l~ tH, 7.5~7.8(3H,m), 8.24(2H,d) ~-~
C,ll mol. form.; C26H2gN303 HCl I) lH-NMR(CDC13)~;
~5~ NIH,CH.-CI~ CH. I - I 1.00~2.08~lOH,m), 2.72~3.08(5H,m), ~ CU loJ ~ HCI 3.33(2H,bd), 6.16(1H,bs), 7.07(7H,bs) _ mol- form.; C20H26N202 HCl I
1l lH-NMR(cDcl3)~; C~
,INCH,CH-- ~ N-C~ 0.15(2H,m), 0.56(2H,m), 0.90~2.23(10H,m), CX~
155 ~ UCI 3.00(5H,m), 3.34(4H,m), 7.40(5H,s) CX~
mol- form-; Cl9H28N2 HCl CX~
O lH-NMR(cDcl3)~;
ISG ~,CNIl:~,CH.-cN-CH.-~ 2HCI (4H,m); 7 1s(lH~m)2;647~23;00(5H~m)~ 3 41 CH, 7.50(lH,d), 8.41(2H,m) mol- form.; C21H27N3 2HCl .

Table (cont ' d) Ex. Physicochemical constant Structural formula No. (m.p., elem. anal., NMR, etc.) Il lH-NMR(CDC13)~;
Il ,~ n - 1 . 04~1.04(11H,m), 2.64~3 00(5H,m), 3.58 l57 ~ ,CIIIII,CII.- ~ NCII,_~ ~ 211CI (2H,s), 7.01(1H,m), 7.27(5H,s), 7.58 bJI lllJ (2H,m), 8.44(1H,d) mol- form-; C21H27N30-Il lH-NMR(CDC13)~;
H /-~ 1.00~2.00(4H,m), 2.83(2H,bd), 3.24(2H,bd), 15a ~ -Cll,CIIIICII,CII,- ~ N-CII,- ~ 3.45(2H,s), 3.59(2H,s), 5.85(1H,bs), J~y~ IICI 7.27(5H,s), 7.77(4H,ABq) ~~~
U,N mol. form.; C22H27N3O3 HCl ~~~
lH-NMR (CDC13 ) 15~171~ N-CII,-~ IICI 1 0~2jl(9H2m5)5H2s)6 ; 3~8.1(7H,m) ~"J Cll, mol. form.; C26H30N2O HCl ~_~

lH-NMR(cDcl3) ,llll.ll,CII~- C NCII~ ~ 1.00~2.10(9H,m), 2.25(3H,s), 2.81(2H,bd), CX~
1l;0 1 ¦1 1 IICI 2.97(3H,bs), 3.10~3.45(2H,m), 3.43(2H,s), CX~
/`~J Cll, 7.23(4H,ABq), 7.27(5H,s) Cll,CllU mol- form-; C24H30N23 HCl Il lH-NMR(cDcl3)~;
,~ ~NI:II,CII.-~ CII, - ~N 211CI 1.06~1.92(9H,m), 2.70~2.99(5H,m), 3.44 l;l J ! ~ (2H,s), 7.22(2H,d), 7.38(5H,s), 8.50(2H,d) `~" ~,11, i mol- form-; C21H27N3-2HCl 11~ 1338808 ~ C _ ~ E u~
m ~ C ~ ~ ~ N ~
N ~ L~') c ~ ~ ~ ~ 0 ~ _ N ~r ~ ~ ~
O Ul ~a ~
O ~ E
. m ~ m N ~ N m N
_ _ _ N ~ ~ ~
E r~ ~ ~ -- E~
~ Ul E ~ D .4 Z ~ E ~ a~
_Ic ~ ~ N ~
_ _ _ _I _ C ~ ~ ~ ~
_ _I o u~ m~ u 0 . ~r~ ~ m .
(1~N _I 1~ O N O CJ~) N C ~
-- N N ~ (~~ N ~9 ~ ~ ~ CD
E E ~ E 7 ~ ~~ ~ ~E ~ E ~ ~) N ~o m ~ N ~ N CO N
~ ~ _ ~ V V ~ t~ N~_)-- ~-- -- -- -- --P. ~ N u m ~c v . m Ea _I N ~` E a ,I E a E a ~ N N a N N C:1 ~ ~. -- h V N ~ ~1U C~ -- -- ~,) C~ ---- -- O N CO O-- c~ u7 0 -- c~ O -- ~ D Ln z o ~ I` z o u~ z _I ~ ~ z o ~ a) z _i E _I E --I

- ~3 J

-- z l _~ _ J I _ . ~ _ = ~3 ~ 1 4_ <~ z ~7 'i~,i "~D

x z Table 8 (cont ' d) Ex. Structural formula Physicochemical constant No. (m.p., elem. anal., NMR, etc.) 0 1H-NMR(CDC13)~;
I! . . / ' R ~ 1.08~1.94(9H,m), 2.68~3.02(7H,m), 3.40 IG7 ~H'~ JN~~ . HCI (oHod(), 7j27(5H,s), 7.41(2H,d), 7.78(2H,d), C~U mol. form.; C23H2gN202-HCl lH-NMR(CDC13)~;
IG~ Nl:ll,Cll, -CN CII~ ~ 1.10~1.98(15H,m), 2.77~2.98(6H,m), c~.~ b ~ Cll . IICI 3 12~3 46(4H~m)~ 7.26(9H,m) ~
~H /CII mol- form-; C25H34N2O-IJ lH-NMR(CDC13)~
I G~ l!NCII'CII~ -CN~CII' ~~ 1.00~2.00(9H,m), 2.60~3.00(7H,m), 3.45 C~
~ I IICI (2H,m), 6.95(2H,d), 7.26(5H,s), 7.90(2H,d) C~
E,l: mol- form-; C23H27N2OF3-HCl CX~
U lH-NMR(CDCl3)~; _ I! . . ~', . R~ 1.00~2.10(3H,m), 2.87(2H,bd), 2.99(3H,s), CX~
17U ~Il~ \-J~ IICI 3.10~3.50(2H,m), 3.48(3H,s), 6.35~7.35 )~JI ~1l, (5H,m), 7.83(5H,s) HU mol. form.; C22H2gN202-HCl IJ lH-NMR(CDC13)~;
171 l~ cll~-~N-rll~-~ 1.10~1.88(12H,m), 2.80(2H,d), 2.98(3H,s), IICI 3.23~3.44(4H,m), 4.02(2H,m), 6.84(2H,d), ~J lll. 7.26(7H,m) ElO mol. form.; C24H32N2O2-HCl Table 8 (cont'd) Ex. Structural formula Physicochemical constantNo. (m.p., elem. anal., NMR, etc.) lH-NMR(CDC13)~;
q ~ 1.00~2.08(9H,m), 2.83(2H,bd), 2.98(3H,s), 172N ~ -lll,U- ~ -CN(:II,CII, ~ N-CII, ~ 3.12~3.50(2H,m), 3.47(2H,s), 5.08(2H,s), CIIJ ~ 211ll 7.15(4H,ABq), 7.38(5H,s), 7.96(2H,ABq) ~_~
r~
q 1I r H-NMR(CDC13)~;
N ~-CRCII,CII,- ~ N- ~ 1.04~1.98(7H,m), 2.20~3.80(7H,m), 17~ ~ ~J I ~J =~ IICI 6.60~7.34(7H,m), 8.67(2H,d) ~_~
C~
lH-NMR(CDCl~)~; CX~
Il ll 0.90~2.20(11H,m), 2.60~3.30(2H,m), 2.85, CY~
17~ Cll,UC- ~ -LINIII,CII,- ~ NCII, ~ IICI 3 03(total 3H; each bs), 3j48,3j55(total O
mol. form.; C24H30N2O2-HCl H-NMR(CDC13)~;
0.90~2.06(9H,s), 2.70~3.02(10H,m), 3.20 Cll,CII,UC11,- ~ -1:71:11,CII,- ~ N-CII,- ~ IICI 3.62(4H,m), 4.50(2H,s), 7.21~7.30(9H,d) Cll, mol- form.; C2SH34N22 HC

Table 8 (cont ' d) Ex. Structural formula Physicochemical constant No. (m.p., elem. anal., NMR, etc.) lN-NMR(cDcl3) ~i;
G~ \ ~ 1J 9.90~2.10(9H,m), 2.81(2H,bd), 3.45(2H,s), 17G b~H~ HCI 4.11(2H,t), 6.98~7.82(8H,m), 7.21(5H,s) OH~l H2 {~N-~H,-~ ~
mol- form-; C27H28N22 HCl H-NMR~CDC13) 1l . 1.29(3H,s), 1.40(3H,s), 1.40~2.20(9H,m), C~
177 . ~H-O-~-CNCH2~H.-CN-~'H.-~ H~l 2.83(2H,bd), 3.00(3H,s), 3.20~3.50(2H,m), CX~
~J~ I 3.48(2H,s), 4.56(1H, quirtet), 7.08 CPD
~HJ (4H, ABq), 7.28(5H,s) mol. form.; C2sH34N2O2-HCl CX~

Example 178 l-Benzoyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl~iperidine 0.85 g of 5,6-dimethoxy-1-indanone and 1.38 g of l-benzoyl-4-piperidinecarbaldehyde were dissolved in 20 ml of anhydrous THF to obtain a solution.
1.02 g of 28 % sodium methylate was added to the solution at 0C. The obtained mixture was stirred at a room temperature for 2 hours, diluted with ethyl acetate, washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum. The obtained residue was purified through a silica gel column to obtain 1.23 g of 1-benzoyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine (yield : 71 %).
1.23 g of this compound was dissolved in 20 ml of THF, followed by the addition of 0.3 g of 10 %
palladium/carbon. After the hydrogenation had been carried out at a room temperature under an ordinary pressure for one day, the catalyst was filtered out and the filtrate was concentrated in a vacuum. The residue was recrystallized from methylene chloride/

hexane to obtain 1.10 g of the title compound (yield : 89 %). The characteristics thereof are as follows:
m.p.(C) : 151 to 152 elemental analysis as C24H27'`~01 C H N
calculated(%) 73.26 6.92 3.56 found(%) 73.30 6.85 3.32 Example 179 4-[(5,6-Dimethoxy-l-indanon)-2-yl]methylpiperidine hydrochloride c'~C~
9.00 g of 1-benzoyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine was dissolved in 90 ml of dioxane, followed by the addition of 90 ml of 6N
hydrochloric acid. The obtained mixture was heated under reflux for 10 hours and concentrated in a vacuum. The residue was diluted with water and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 12 with a 50 %
aqueous solution of sodium hydroxide and extracted with methylene chloride. The organic layer was 12~ 1338808 washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum. The obtained residue was converted into its hydrochloride by an ordinary method. The obtained product was recrystallized from methanoliethanol to obtain 6,30 g of the title compound (yield : 85 %). The characteristics thereof are as follows:
m.p.(C): 249 to 250 (dec.) elemental analysis as C17H23NO3 HCl C H N
calculated(%) 62.67 7.42 4.30 found(~) 62.75 7.31 4.52 Example 180 1-(3-Fluorobenzyl)-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride 0.25 g of 4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine was dissolved in 6 ml of THF, followed by the addition of 0.29 ml of triethylamine and 0.13 ml of 3-fluorobenzyl bromide. The obtained mixture was heated under reflux for 2 hours and 125 1~8808 concentrated in a vacuum. The residue was diluted with ethyl acetate, washed with a 10 % aqueous solution of sodium carbonate and a saturated aqueous solution of common salt successively, dried over magnesium sulfate and concentrated in a vacuum.
The obtained residue was purified through a silica gel column and converted into its hydrochloride by an ordinary method. The obtained product was recrystallized from methylene chloride/IPE to obtain 0.27 g of the title compound (yield : 72 %).
The characteristics thereof are as follows:
m.p.(C): 230 to 232 (dec.) elemental analysis as C24H28NO3 HC1 C H N
calculated(%) 66.43 6.74 3.23 found(%) 66.18 6.79 3.11 Example 181 l-Benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine dihydrochloride cu~ t~ ~ ~ 2 ~

1.00 g of 5,6-dimethoxy-1-indanone, 0.31 g of paraformaldehyde and 0.90 ml of l-benzylpiperazine were suspended in a mixture comprising 30 ml of ethanol and 2 ml of water. The pH of the obtained suspension was adjusted to 3 with concentrated hydrochloric acid, heated under reflux for 3 hours, cooled by allowing to stand and filtered to obtain a white solid. This solid was suspended in methylene chloride, washed with a 10 % aqueous solution of sodium carbonate and a saturated aqueous solution of common salt successively, dried over magnesium sulfate and concentrated in a vacuum.
The obtained residue was purified through a silica gel column and converted into its hydrochloride by an ordinary method. The product was recrystallized from methanol to obtain 0.55 g of the title compound (yield : 23 %). The characteristics thereof are as follows:
m.p.(~C) 227 to 228 (dec.) elemental analysis as C23H29N2O3-2HCl C H N
calculated(%) 60.79 6.88 6.16 found(%) 60.31 6.95 6.06 Example 182 4-[t5,6-Dimethoxy-l-indanon)-2-yl]methyl-1-ethoxycarbonylpiperidine ~ C~{~J ~ C~Ct!

0.50 g of 1-benzyl-4-[(5,6-dimethoxy-'-ircanon)-2-yl]methylpiperidine was dissolved in 8 mi o,~
benzene, followed by the addition of 0.15 ml of ethyl chloroformate. The obtained mixture was heated under reflux for 3 hours, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous soltuion of common salt successively, dried over magnesium sulfate and concentrated in a vacuum. The obtained residue was recrystallized from ethyl acetate/hexane to obtain 0.45 g of the title compound (yield : 94 %). The character-istics thereof are as follows:
m.p.(C): 132 to 133 elemental analysis as C20H27N05 C H N
calculated(%) 66.46 7.53 3.88 found(%) 66.79 7.53 4.00 Example 183 4-[(5,6-Dimethoxy-l-indenon)-2-yl]methyl-1-ethoxycarbonylPiperidine ~le~c4~

2.00 g of 4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl-l-ethoxycarbonylpiperidine was dissolved in 30 ml of carbon tetrachloride, followed by the addition of 0.98 g of N-bromosuccinlmide and 0.02 g of benzoyl peroxide. The obtained mixture was heated under reflux for 5 hours, diluted with carbon tetrachloride, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of common salt successively, dried over magnesium sulfate and concentrated in a vacuum.
The obtained residue was dissolved in 20 ml of THF, followed by the addition of 1.66 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene. The obtained mixture was heated under reflux for 30 minutes and concentrated in a vacuum. The residue was diluted with ethyl acetate, washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum. The obtained residue was purified through a silica gel column to 12g 1338808 obtain 1.12 g of the title compound as an oil (yield : 56 ~).
molecular formula: C20H25NO5 H-NMR(CDC13) ~; 1.23(3H,t), 1.41~2.90(11H,m), 3.84(3H,S), 3.88(3H,S), 4.10(2H,g), 6.60(1H,S), 6.97(lH,S), 7.03(lH,S).

Example 184 l-Benzyl-4-[(1,3-indanedion)-2-ylidenyl]-methylpiperidine ~,u~
~, .

0.17 ml of diisopropylamine was added to 3 ml of anhydrous THF. 0.75 ml of a 1.6 M solution of n-butyllithium in hexane was added to the obtained mixture at 0C. The obtained mixture was stirred at 0C for 10 minutes and cooled to -78C, followed by the addition of a solution of 0.18 g of 1,3-indanedione in 8 ml of anhydrous THF and 0.21 ml of hexamethylphosphoramide. The obtained mixture was stirred at -78C for 15 minutes, followed by the addition of a solution OL 0.35 g -- ~30 1338808 of l-benzyl-4-piperidinecarbaldehyde in 3 ml of anhydrous THF. The obtained mixture was gradually heated to a room temperature, stirred at that temperature overnight, diluted with methvlene chloride, washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum. The obtained residue was recrystallized from methylene chloride/IPE
to obtain 0.12 g of the title compound (yield : 29 %). The characteristics thereof are as follows:
m.p.(C): 173 to 174 (dec.) elemental analysis as C22H21NO2 C H N
calculated(%) 79.73 6.39 4.23 found(%) 79.43 6.20 4.31 Example 185 l-Benzyl-4-[(5,6-dimethoxyinden)-2-yl]methyl-piperidine hydrochloride C~'~ ~"~

0.24 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanol)-2-yl]methylpiperidine was dissolved in 5 ml of methylene chloride, followed by the addition of a 10 % solution of hydrochloric acid in ethyl acetate.
The obtained mixture was concentrated in a vacuum.
The obtained residue was recrystallized from methylene chloride/IPE to obtain 0.24 g of the title compound (yield : 95 %). The characteristics thereof are as follows:
m.p.(C): 216 to 217 (dec.) elemental analysis as C24H29N02.HCl C H N
calculated(%) 72.07- 7.56 3.50 found(%) 71.82 7.63 3.33 Example 186 l-Benzyl-4-[3-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]]propylpiperidine hydrochloride ~30 ~ ~C~ C~

0.31 ml of diisopropylamine was added to 5 ml of anhydrous THF. 1.39 ml of a 1.6 M solution of n-butyllithium in hexane was further added to the obtained mixture at 0C. The obtained mixture was stirred at 0C for 10 minutes and cooled to -78C, followed by the addition of a solution of 0.39 g of 5,6-dimethoxy-1-indanone in 5 ml of anhydrous THF

and 0.35 ml of hexamethylphosphoramide. The obtained mixture was stirred at -78C for 15 minutes, followed by the addition of a solution of 0.50 g of 3-(1-benzyl-4-piperidine)propionaldehyde in 5 ml of anhydrous THF. The obtained mixture was gradually heated to a room temperature, stirred at that temperature for 3 hours, diluted with ethyl acetate, washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum. The obtained residue was purified through a silica gel column and converted into its hydrochloride by an ordinary method of obtain 0.55 g of the title compound as an oil (yield : 61 %).
molecular formula : C26H31NO3-HCl H-NMR(CDC13) ~; 1.10~3.00(13H,m), 3.45(2H,S), 3.50(2H,S), 3.90(3H,S), 3.95(3H,S), 6.58~7.20 (3H,m), 7.27(5H,S).

Example 187 l-Benzyl-4-[3-[(5,6-dimethoxy-1-indanon)-2-yl]]-propylpiperidine hydrochloride 13~ 8808 0.40 g of 1-benzyl-4-[3-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]]propylpiperidine was dissolved in 15 ml of THF, followed by the addition of 0.1 g of 10 % palladium/carbon. After the hydrogenation had been carried out at a room temperature under an ordinary pressure for 2 hours, the catalyst was filtered out and the filtrate was concentrated in a vacuum. The residue was purified through a silica gel column and converted into its hydrochloride by an ordinary method to obtain 0.37 g of the title compound as an oil (yield : 84 %j.
molecular formula: C26H33NO3-HCl H-NMR(CDC13) ~; 1.00~ 3.30(18H, m), 3.38, 3.43 (total 2H, each S), 3.85(3H,S), 3.90(3H,S), 6.77, 6.83 (total lH, each S), 7.05, 7.10 (total lH, each S), 7.18, 7.20 (total 5H, each S).
Examples 188 to 249 The compounds listed in Table 9 were each synthesized and analyzed.

Table 9 13i~ 1338808 Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) lH-NMR(cDcl3) ~;
1.00~ 3.40(14H,m), 3.47(2H,S), ~ 3.78(3H,S), 6.90~7.50(3H,m), 188 C~o ~ ~ 7.23(5H,S).

molecular formula: C23H27N2 HCl lH-NMR(CDC13) ~;
f~ 1.05~2.12(9H,m), 2.50~3.40(5H,m), ~ R ~ 3.48(2H,S), 3.88(3H,S), 6.98(1H,q), 189 ~ ~ ~ ~ 7.15~7.32(2H,m), 7.23(5H,S), C'~ f~ molecular formula: C23H27NO2-HCl m.p.(C) : 199 to 200 (dec.) elemental analysis as C24H29NO3 HCl 190 ~ ~ ~ ~- ~ calculated(%) 69.30 7.27 3.37 H'~ found(%) 69.24 7.40 3.38 m.p.(C) : 198 to 199 ~ ~ elemental analysis as C24H29NO3 HCl 191 G~ ~ ~ ~ ~ calculated(%) 69.30 7.27 3.37 .~ found(%) 69.15 7.42 3.47 - m.p.(C) : 200 to 201 C~ elemental analysis as C25H31N04HCl 19 2 G~ ~ C H N
G~ calculated(%) 67.33 7. 2 3 3.14 ~ ~ found(%) 67.10 7.16 3.00 13~ 1338808 Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) H-NMR(CDC13)~;
1.05~2.15(9H,m), 2.55~3.43(5H,m), 3.48(2H,Sl, 7.23(5H,S), 7.23~7.43 193 F~ ~ (3H,m).

molecular formula: C22H24NOF HCl m.p.(C): 175 to 177 - elemental analysis as C23H27NO.HCl 194 C~ ~ calculated(%) 74.68 7.63 3.79 - h'~ found(%) 72.77 7.64 3.62 1/2 H2O (%) 72.90 7.71 3.70 m.p.(C): 211 to 213 (dec.) elemental analysis as C23H27NO HC1 195 ~ ~ ~5~ ~ calculated(%) 74.68 7.63 3.79 c~ H~ found(%) 72.68 7.49 3.70 1/2 H2O (%) 72.90 7.71 3.70 -- m.p.(C): 153 to 154 ~ elemental analysis as C23H27NO3 196 ~ ~ C H N
C~ calculated(%) 75.59 7.45 3.83 found(%) 75.77 7.28 3.64 m.p.(C): 170 to 171 (dec.) elemental analysis as C23H27NO3 197 ~ ~ ~X ~ C H N
- calculated(~) 75.59 7.45 3.83 found(%) 75.61 7.47 3.55 .

13~ 1338808 - Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) m.p.(C): 175 to 176 elemental analysis as C26H33NO3 HCl 198 ~ ~ _~ ~ calculated(%) 70.33 7.72 3.15 ~3 foundt%) 70.20 7.46 3.35 m.p.(C): 236 to 237 (dec.) elemental analysis as C23H25NO3.HCl 199 ~r~ calculated(%) 69.08 6.55 3.50 found(%) 68.97 6.82 3.29 m.p.(C): 195 to 196 a elemental analysis as C23H27NO HC1 200 ~ ~ ~ C H N
~ calculated(%) 74.68 7.63 3.79 found(%) 74.72 7.77 3.78 H-NMR(CDC13) ~;
~ r~ 1.10~2.10(13H,m), 2.60~3.08(5H,m), ~ ~ ~ 3.41(2H,S), 7.00~7.85(4H,m), 201 ~ ~ 7.19(5H,S).

molecular formula: C24H29NO-H-NMR(CDC13) ~;
~ 1.17(3H,d), 1.12~2.10(9H,m), 202 ~ ~- ~ ~ 2.60~2.93(2H,m), 3.41(2H,S), -~Cl 3.51(1H,q), 7.20(5H,S), 7.30~7.92 (5H,m).
molecular formula: C22H27NO HCl Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) m.p.(C): 126 to 127 elemental analysis as C26H33N03-HCl 203 a~ ~) calculated(%) 70.33 7.72 3.15 C~ ~ found(%) 70.41 7.48 2.85 H-NMR(CDC13) ~;
1.00~3.40(2OH,m), 3.50(2H,S), C~ ~ ~ 3.90(3H,S), 3.97(3H,S), 6.88(lH,S), C~ 7.18(1H,S), 7.31(5H,S).

; molecular formula: C27H35N03-HCl H-NMR(CDC13) ~;
1.05~3.36(22H,m), 3.45(2H,S), C~r~c~r~ ~ 3 85(3H S) 3 90(3H S), 6.78(1H,S), HC~.
molecular formula: C28H37N03 HCl , - 1H-NMR(CDC13) ~;
1.10~2.50(7H,m), 2.70~3.02(2H,m), ~ 3.48(2H,S), 3.56(2H,S), 3.79(3H,S), 206 ~ ~ ~ 6.69(lH,dt), 7.02~7.50(3H,m), .~ ~ 7.21(5H,m).
molecular formula: C23H25N02 HCl ~H-NMR(CDC13) ~;
1.50~3.57(llH,m), 3.48, 3.50~total ~~~4 r~ 2H, each S), 3.83, 3.85 (total 3H, 207 ~ ~-C~ ~ each S), 6.57~7.39(4H,m), 7.22(5H,m).
G~a ~C2 molecular formula: C23H25N02-HCl - 13~ 1338808 Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.

H-NMR(CDC13)~;
1.58~2.55(7H,m), 2.79~3.02(2H,m), 208 ~ ~~~ r 3.50(2H,S), 3.63(2H,d), 3.90 G~ (6H,S), 6.63(1H,dt), 6.93(1H,d), . ~ 7.22(5H,S), 7.57(1H,d).
molecular formula: C24H27NO3-HCl H-NMR(CDC13) ~;
1.50~2.55(7H,m), 2.78~3.03(2H,m), C~ ~ 3.48(2H,S), 3.56(2H,d), 3.85(3H,S), 209 C~ 4.00(3H,S), 6.62(1H,dt), 7.07(1H,d), 7.21(1H,d), 7.22~5H,S).
molecular formula: C24H27NO3 HCl H-NMR(CDC13) ~;
1.50~2.50(7H,m), 2.78~3.03(2H,m), 210 C~ 3.48(2H,S), 3.53(2H,d), 3.82(3H,S), G~ - 3.90(3H,S), 4.03(3H,S), 6.58(1H,dt), -~ 6.61(1H,S), 7.25(5H,S).
- molecular formula: C25H29NO4-HCl .
lH-NMR(CDC13) ~;
O 1.52~2.55(7H,m), 2.78~3.02(2H,m), F~ "~ ,r~ 3.50(2H,S), 3.59(2H,S), 6.72(1H,dt), 211 ~ ~ ~ ~ ~ 7.05~7.55(3H,m), 7.22(5H,S).
.Lr~
"~, molecular formula: C22H22NOF HCl lH-NMR(CDC13) ~;
a - 1.50~2.55(7H,m), 2.38(3H,S), 212 ~ ~ ~ 2.78~3.02(2H,m), 3.48(2H,S), 3.57(2H,S), 6.66(lH,dt), 7.38~7.60 (3H,m), 7.21(5H,S).
molecular formula: C23H25NO-HCl Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) H-NMR(CDC13) ~;
1.48~2.60(7H,m), 2.32(3H,S), 213 ~ r 2.77~3.02(2H,m), 3,49(4H,S), C~ 6.69(1H,dt), 7.10~7.67(3H,m), C~ ~C2 7.22(5H,S).
molecular formula: C23H25NO HCl m.p.(C~: 174 to 175 elemental analysis as C23H25NO3 214 C~ J~G~ ~ calculated(%) 69.08 6.55 3.50 - - found(%) 69.12 6.41 3.43 m.p.(C): 175 to 176 ~ elemental analysis as C30H31NO3 215 ~ calculated(%) 79.44 6.89 3.09 found(%) 79.04 6.87 2.77 m.p.(C): 180 to 181 elemental analysis as C26H31NO3 HCl C ~ calculated(%) 70.65 7.30 3.17 ~CQ found(%) 70.34 7.05 3.07 m.p.(C): 228 to 230 (dec.) elemental analysis as C23H23NO3 HC
~ C H N
217 ~ ~ ~ ~ ~ calculated(%)69.436.08 3.52 found(%) 67.895.97 3.45 1/2 H2O (%) 67.896.19 3.44 .

l~O 1338808 Physicochemical constants Example Structural formula tm.p., elemental analysis, NMR etc.) H-NMR(CDC13) ~;
2.48~3.02(13H,m), 3.48(2H,S), 218 ~ C~ ~ ~ ~ 6 73(lH,dt), 7.10~8.10(4H,m), ~CQ
- molecular formula: C23H25NO HCl - m.p.(C): 211 to 213 (dec.) elemental analysis as C24H27NO-HCl 219 ~ ~ ~ C H N
~ .yr~ calculated(%)75.47 7.39 3.67 - - found(%) 75.22 7.41 3.57 ,. . .
1H_NMR(CDC13) ~;
1.20~2.60(7H,m), 1.96(3H,d), 220 ~ ~ ~ ~ 2.70~2.97(2H,m), 3.46(3H,S), C~ 6.67(1H,dd), 7.21(5H,S), 7.21~7.61(5H,m).
molecular formula: C22H25NO HCl m.p.(C): 170 to 171 elemental analysis as C26H31NO3 221 ~ ~ ~ ~ ~ ~ ~ calculated(%) 77.01 7.70 3.45 C~ found(%) 77.10 7.67 3.43 H-NMR(CDC13) ~;
~ 1.10~2.40(13H,m), 2.70~3.00(2H,m), 222 ~ C~C~ ~ J~ 3.45(2H,S), 3.48(2H,S), 3.86(3H,S), c~ 3.91(3H,S), 6.68(lH,tt), 6.80(lH,S), 7.20(6H,S).
molecular formula: C27H33NO3~HCl 14~ 1338808 Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) lH-NMR(CDC13) ~;
- 1.10~2.40(15H,m), 2.68~3.00(2H,m), ~ 3.46(2H,S), 3.50(2H,S), 3.88(3H,S), 223 ,~ ~ 3.93(3H,S), 6.68(1H,tt), 6.83(1H,S), n'~ 7.19(1H,S), 7.21(5H,S).
molecular formula: C28H35NO3-HCl m.p.(C): 130 to 135 elemental analysis as C26H29NO3-HCl 224 ~ ~~ calculated(~) 70.98 6.87 3.18 3 ,,~ found(%) 70.81 6.72 3.10 lH-NMR(CDC13) ~;
a 1.10~3.50(16H,m), 3.87(3H,S), 225 ~ ~ 3 93(3H,S), 6.80(1H,S), 7.00~7.25 molecular formula: C24H29NO3 HCl m.p.(C): 186 to 188 (dec.) H-NMR(CDC13) ~; 1.65~2.10(7H,m), ia 2.65~2.75(2H,m), 3.25~3.83(5H,m), 226 ~ ~ ~ 3.92(3H,S), 3.98(3H,S), 4.60(2H,S), O 6.88(1H,S), 7.19(1H,S), 7.26 7.60(5H,m).
molecular formula: C24H29NO4 m.p.(C): 220 to 221 elemental analysis as C25H31NO3-HCl 227 ~ calculated(%) 69.83 7.50 3.26 found(%) 70.03 7.51 3.26 Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) m.p.(C): 212 to 213 elemental analysis as C2SH31NO3 HCl 228 C~a'} ~ ~ ~ 91 calculated(%) 69.83 7.50 3 26 G~ ~ found(%) 69.62 7.38 3.15 m.p.(C): 229 to 230 (dec.) elemental analysis as C25H31NO3-HCl 229~ ~ J~ ~ C~ calculated(%) 69.83 7.50 3.26 - - Y,C~ found(%) 69.91 7.48 3.28 H-NMR(CDC13) ~;
1.00~3.50(14H,m), 3.73(2H,S), - ~ ~ -- 3.86(3H,S), 3.93(3H,S~, 6.82~1H,S), 230C~ ~ C~ ~ 7.12(lH,S), 7.22~7.80(4H,m).
molecular formula: C24H28N2O5-HCl m.p.(C): 210 to 211 elemental analysis as C24H28N2O5-231 C~ ~ ~ ~ ~ C H N
~ calculated(%) 62.54 6.34 6.08 found(%) 62.48 6.34 5.96 m.p.(C): 234 to 236 (dec.) elemental analysis as C24H28N2O5 HCl C~q~ C H N
C~ .~ calculated(5) 62.54 6.34 6.08 found(%) 62.56 6.25 ~.83 .

Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) lH-NMR(cDcl3) ~;
1.10~3.43(14H,m), 3.52(2H,S), C~> ~ _rJ~ r~ 3;84(3H,S), 3.91(3H,S), 6.35~7.08 nU molecular formula: C24H29NO4 HCl m.p.(C): 146 to 148 elemental analysis as C24H29NO4 HCl C H N
234 C~ ~ C~ ~ a~ calculated(~) 66.51 7.29 3.53 -H~ found(%) 66.73 7.00 3.24 m.p.(C): 193 to 194 O ~ elemental analysis as C25H31NO4-HCl 235 o~Q ~ G~ ~ C H N
~C ~C~ calculated(%) 67.33 7.23 3.14 found(%) 67.43 7.22 3.13 m.p.(C): 226 to 228 (dec.) ~ elemental analysis as C25H31NO4 HCl 236 o~ C H N
c~5 v_~ H~ calculated(%) 67.33 7.23 3.14 found(%) 67.21 7.29 2.97 H-NMR(cDcl3) ~;
~ 0.78~3.40(14H,m), 3.46(2H,S), 237 C~ ~ ~ 3.85(3H,S), 3.91(3H,S), 5.01(2H,S), C~ 6.78(lH,S), 6.80~7.43(9H,m), 7.09(lH,S).

m~lecular formula: C31H35N4 HCl - 14~ 1338808 Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) m.p.(C): 224 to 226 ~dec.) elemental analysis as C23H28N2O3 2HCl 238 CY~ ~ J' calculated(%) 60.93 6.67 6.18 ~,~C~ found(%) 58.72 6.98 5.56 H2O(%) 58.60 6.84 5.94 m.p.(C): 253 to 256 (dec.) c elemental analysis as C25H31NO3 HCl C~ G~ ~ c H N
239 C~'~~ calculated(5) 69.83 7.50 3.26 found~) 69.60 7.49 3.27 m.p.(C): 225 to 226 (dec.) elemental analysis as C24H35NO3 HCl ~ ~ C H O
240 C~O ~C1 calculated(%) 68.31 8.60 3.32 found(%) 68.17 8.49 3.51 m.p.(C): 226 to 227 (dec.) elemental analysis as C28H31NO3-HCl 241 ~ ~ $ calculated(%) 72.17 6.92 3.01 found(%) 71.71 7.07 2.85 m.p.(C): 243 to 245 (dec.) elemental analysis as C28H31NO3-HCl 242 C~ calculated(%) 72.17 6.92 3.01 ~ found(%) 71.75 6.92 3.01 Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) - m.p.(C): 191 to 192 elemental analysis as C26H33N05-HCl 243 ~ C H N
C~ calculated(%) 65.60 7.20 2.94 ~ found(%) 65.34 7.27 2.79 - m.p.(C): 219 to 221 elemental analysis as C27H35N06. HCl 244 ~ calculated(%) 64.09 7.17 2.77 ~ H~ cc~ found(%) 63.27 7.19 2.51 1/2 H2~(%) 62.96 7.24 2.72 H-NMR (D2O) ~;
~ 1.10~3.12 (14H,m), 3.84 (3H,S), 245 ~ ~ 6.70 (1H, S), 6.84 (1H, S) .
molecular formula: C16H21NO3. HCl .

~L . ~ m.p.(C): 182 to 183 ~ elemental analysis as C30H33N506 246 ~5i~ C H N
C~ calculated(%) 64.39 5.94 12.51 found(%) 64.42 5.78 12.52 m.p.(C): 240 to 241 (dec.) n elemental analysis as C26H33N02S2.HCl 247 ~ "~ C H N
.~ calculated(%) 63.46 6.96 2.85 found(~) 63.18 6.78 2.80 I- 14~ 1338808 Physicochemical constants Example Structural formula (m.p., elemental analysis, NMR etc.) m.p.(C): 180 to 185 (dec.) elemental analysis as C23H28N2O3 2HCl 248 ~r~ C H N
calculated(%) 60.73 6.45 6.25 found(%) 60.92 6.67 6.18 m.p.(C): 230 to 232 (dec.) elemental analysis as C35H39NO6 HCl 249 ~ C~ calculated(%) 69.35 6.65 2.31 ,~ found(%) 69.21 6.59 2.33 The compounds obtained in Examples 178 to 249 were each examined according to the above shown experimetal test in view of the inhibitory activity. Results are shown in Table 10.

~47 Table 10 Inhibitory effect against acetylcholinesterase in vitro Inhibitory Inhibitory Inhibitory activity activity activity Compound on AChE Compound on AChE Compound on AChE
IC50(1~M) IC50(~M) IC50(11M) 178 >10 202 1.2 226 0.0049 179 5.4 203 0.009 227 . 0.01 180 0.001 204 0.035 228 0.002 181 0.094 205 0.014 229 0,04 182 0.8 206 0.41 230 0.16 183 5.3 207 0.049 231 0,004 184 >5 208 0.062 232 0.1 185 0.00082 209 0 43 233 0.046 186 0.0015 210 0.06 234 0.0018 187 4,4 211 2 235 0.22 188 0.081 212 0.5 236 3.6 189 0.012 213 0.05 237 2.6 190 0.02 214 0.0084 238 0.072 191 0.085 215 0.0042 239 0.18 192 0.013 216 0.017 240 0.0089 193 0.2 217 0.14 241 0.22 194 0.069 218 20 242 2.9 195 0.0071 219 19 243 4 196 1 0.0013 220 11 244 4.9 197 0.38 221 0.033 245 5 198 0.0054 222 0.011 246 4.4 199 0.023 223 0.0054 247 200 2.1 224 0.003 248 1.4 201 15 225 0.48 249 0.62

Claims (36)

1. A piperidine compound having the following formula:

[in which J is a benzene ring-containing group selected from the group consisting of (1) indanyl, (2) indanonyl, (3) indenyl, (4) indenonyl, (5) indanedionyl, (6) tetralonyl, (7) benzosuberonyl, (8) indanolyl, (9) indanedionylidenyl, (10) indanonylidenyl, (11) benzosuberonylidenyl and (12) C6H5-CO-CH(CH3)-; wherein the benzene ring in each of the groups may optionally be substituted by methylenedioxy, ethylenedioxy, or 1 to 4 substituents selected from the group consisting of halogen, hydrogen, benzyloxy, C1-6alkyl and C1-6alkoxy;
B is -(CHR22)r-, -CO-(CHR22)r-, -NR4-(CHR22)r-, -CO-NR5-(CHR22)r-, -CH=CH-(CHR22)r-, -OCOO-(CHR22)r-, -OOC-NH-(CHR22)r-, -NH-CO-(CHR22)r-, -CH2-CO-NH-(CHR22)r-, -(CH2)2-CO-NH-(CHR22)r-, -CH(OH)-(CHR22)r-, =(CH-CH=CH)b-, =CH-(CH2)c-, =(CH-CH)d=, -CO-CH=CH-CH2-, -CO-CH2-CH(OH)-CH2-, -CH(CH3)-CO-NH-CH2-, -CH=CH-CO-NH-(CH2)2-, -NH-, -O- or -S-(in which R22 is hydrogen or methyl; R4 is hydrogen, lower alkyl, formyl, acetyl, benzoyl, lower alkylsulfonyl, phenyl, methoxy-substituted phenyl, benzyl or methoxy-substituted benzyl; R5 is hydrogen, lower alkyl, benzyl, pyridyl or phenyl which may be substituted by lower alkoxy, halogen, lower alkyl or hydroxyl; r is 0 or an integer of 1 to 10; b is an integer of 1 to 3; c is 0 or an integer of 1 to 9; and d is 0 or an integer of 1 to 5); and K is hydrogen, phenyl (which may have a substituent selected from the group consisting of hydroxyl, lower alkyl, lower alkoxy, nitro, benzyloxy and halogen), aryl-lower-alkyl (in which the aryl is phenyl or naphthyl and the phenyl may have a substituent selected from the group consisting of hydroxyl, lower alkyl, lower alkoxy, nitro, benzyloxy and halogen), cynnamyl, a lower alkyl, pyridylmethyl, a C3-8 cycloalkyl-lower alkyl, adamantylmethyl, furylmethyl, a C3-8 cycloalkyl, a lower alkoxycarbonyl, a lower alkanoyl or benzoyl; and _______ - - - - shows a single bond or a double bond, provided that when J is (1) indenyl, (2) indanoyl or (8) indanolyl, each of which may optionally have on the benzene ring 1 to 4 substituents selected from the group consisting of halogen,C1-6 alkyl and C1-6 alkoxy, B is -(CHR22)r- and r is 0, then K is othef than hydrogen or a lower alkyl]
or a pharmaceutically acceptable salt thereof.
2. The compound or salt as claimed in claim 1, in which J is selected from the group consisting of monovalent groups of (2) indanonyl (3) indenyl and (5) indanedionyl.
3. The salt as claimed in claim 1, in which B is -(CHR)r-, =(CH-CH=CH)b-, =CH-(CH2)c- or =(CH-CH)d=, wherein R, r, b, c and d are as defined in claim 1.
4. The compound or salt as claimed in claim 1, in which J is (2) indanonyl and B is -(CHR)r-, =(CH-CH=CH)b-, =CH-(CH2)C- or =(CH-CH)d=, wherein R, r, b, c and d are as defined in claim 1.
5. The compound or salt as claimed in claim 1, in which K

is a phenyl-lower alkyl in which the phenyl may have at least one substituent selected from the group consisting of hydroxyl, lower alkyl, lower alkoxy, nitro, benzyloxy and halogen.
6. The compound 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
7. The compound 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
8. The compound 1-benzyl-4-1(5-methoxy-1-indanon)-2-yl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
9. The compound 1-benzyl-4-[(5,6-diethoxy-1-indanon)-2-yl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
10. The compound 1-benzyl-4-[(5,6-methylenedioxy-1-indanon)-2-yl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
11. The compound 1-(m-nitrobenzyl)-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
12. The compound 1-cyclohexylmethyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
13. The compound 1-(m-fluorobenzyl)-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
14. The compound 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]propylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
15. The compound 1-benzyl-4-[(5-isopropoxy-6-methoxy-1-indanon)-2-yl]methylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
16. The compound 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]propenylpiperidine or a pharmaceutically acceptable acid addition salt thereof.
17. The compound 1-benzyl-4-(1-indanon-2-yl)methylpiperidine of the formula:

or a pharmaceutically acceptable acid addition salt thereof.
18. A therapeutical composition for treating senile dementia, which comprises an acetylchlolinesterase inhibitory effective amount of the compound or salt as defined in any one of claims 1 through 17 and a pharmaceutically acceptable carrier.
19. A piperidine compound of the formula:

(in which Ja is (1) a monovalent benzene ring-containing group selected from the group consisting of:

(2-indanyl) (1-tetralon-2-yl) (1-indanon-2-yl ) (1-benzosuberon- (1-indanol- (inden-2-yl) 2-yl) 2-yl) (1-benzoylethyl) (1,3-indanedion- (1-indenon-2-yl) 2-yl) or Ja is (2) a divalent benzene ring-containing group selected from the group consisting of:

(1-indanon-2-yl- (1,3-indanedion- (1-benzosuberon-idenyl) 2-ylidenyl) 2-ylidenyl), Ba is (1) a single chemical bond, -(CHR22)r-, -NH- or CO(CHR22)r- when Ja is the monovalent benzene ring-containing group, or (2) is a double chemical bond, =(CH-CH=CH)b- or =CH-(CH2)C- when Ja is the divalent benzene ring-containing group, Ka is hydrogen, phenyl, naphthylmethyl, phenylethyl, benzyl (which on its phenyl ring may have one to three substituents selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy), cynnamyl, lower alkyl, pyridylmethyl, C3-6cycloalkyl-methyl, adamantylmethyl, furylmethyl, C3-6cycloalkyl, lower alkoxycarbonyl or benzoyl;
S is methylenedioxy, ethylenedioxy, halogen, hydroxyl, benzyloxy, lower alkyl, lower alkoxy or hydrogen;
t is 1 when S is methylenedioxy or ethylenedioxy or t is 1 to 4 when S is other than those;
the keto group in Ja may be in 2,4-dinitrophenyl-hydrazino form or ethylene thioketal form;
R22 is hydrogen or methyl;
r is 1 to 3;

b is 1 or 2;
c is 0 or 1 to 3; and _______ - - - - shows a single bond or a double bond, provided that (i) a double bond between Ba and the piperidine ring can be present only when Ba is a double chemical bond and (ii) when Ja is 2-indanyl, 1-indanon-2-yl or 1-indanol-2-yl, Ba is a single chemical bond, S is halogen, lower alkyl, lower alkoxy or hydrogen and t is 1 to 4, then Ka is other than hydrogen or lower alkyl) or a pharmaceutically acceptable acid addition salt thereof.
20. The piperidine compound or salt as claimed in claim 19, wherein Ja is the monovalent benzene ring-containing group (1) and Ba is -(CHR22)r- or -CO(CHR22)r-, R22 is hydrogen and r is 1 to 3.
21. The piperidine compound or salt as claimed in claim 20, wherein Ja is 2-indanyl, 1-indanon-2-yl, 1-indanol-2-yl, inden-2-yl, 1,3-indanedion-2-yl or 1-indenon-2-yl, each of which may have on its benzene ring one methylenedioxy or ethylenedioxy substituent or one to three substituents selected from the group consisting of halogen, hydroxyl, benzyloxy, lower alkyl and lower alkoxy.
22. The piperidine compound or salt as claimed in claim 20, wherein Ja is 1-indanon-2-yl, inden-2-yl, or 1,3-indanedion-2-yl, each of which may have on its benzene ring one methylenedioxy substituent or one to three substituents selected from the group consisting of halogen, hydroxyl, benzyloxy, lower alkyl and lower alkoxy.
23. The piperidine compound or salt as claimed in claim 21, wherein each of the radical defined for Ja has on its benzene ring one methylenedioxy substituent or one to three lower alkoxy substituents.
24. The piperidine compound or salt as claimed in claim 21, wherein Ka is benzyl which on its phenyl ring may have one to three substituents selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy.
25. The piperidine compound or salt as claimed in claim 22, wherein Ka is benzyl which on its phenyl ring may have one to three substituents selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy.
26. The piperidine compound or salt as claimed in claim 19, wherein Ja is the divalent benzene ring-containing group (2) and Ba is =CH-CH=CH- or =CH-(CH2)c- and c is 0 or 1 to 3.
27. The piperidine compound or salt as claimed in claim 26, wherein Ja is 1-indanon-2-ylidenyl or 1,3-indanedion-2-ylidenyl, each of which may have on its benzene ring one methylenedioxy or ethylenedioxy substituent or one to three substituents selected from the group consisting of halogen, hydroxyl, benzyloxy, lower alkyl and lower alkoxy.
28. The piperidine compound or salt as claimed in claim 27, wherein each of the radicals defined for Ja has on its benzene ring one methylenedioxy substituent or one to three lower alkoxy substituents.
29. The piperidine compound or salt as claimed in claim 27, wherein Ka is benzyl which on its phenyl ring may have one to three substituents selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy.
30. The piperidine compound or salt as claimed in claim 28, wherein Ka is benzyl which on its phenyl ring may have one to three substituents selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy.
31. A therapeutical composition for treating senile dementia, which comprises an acetylchlolinesterase inhibitory effective amount of the compound or salt as defined in any one of claims 19 through 30 and a pharmaceutically acceptable carrier.
32. The compound or salt as claimed in claim 1, in which B is as defined in claim 1 other than CH2.
33. The compound or salt, as claimed in claim 1, in which J is (1) indanyl, (2) indanonyl or (8) indanolyl, B is -(CHR22)r-, r is O and K is as defined in claim 1 other than hydrogen and a lower alkyl.
34. The compound or salt as claimed in claim 19, in which Ja is 1-indanon-2-yl, B is -(CHR22)r- and Ka is phenyl, naphthylmethyl, phenylethyl, benzyl (which on its phenyl ring may have one to three substituents selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy), cinnamyl, pyridylmethyl, C3-6 cycloalkyl-methyl, adamantylmethyl, furylmethyl, C3-6 cycloalkyl, lower alkoxycarbonyl or benzoyl.
35. The compound or salt as claimed in claim 34, wherein Ka is benzyl which on its phenyl ring may have one to three substituents selected from the group consisting of hydroxyl, lower alkoxy, lower alkyl, halogen, nitro and benzyloxy.
36. A therapeutical composition for treating senile dementia, which comprises an acetylchlolinesterase inhibitory effective amount of the compound or salt as defined in any one of claims 32 through 35 and a pharmaceutically acceptable carrier.
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