JPS6251650A - Hydropyridine derivative and 3-aminopropionic acid derivative, manufacture and use as drug - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to formula 1: where R1 is carboxy, lower alkoxycarbonyl,
represents carbamoyl (carbamyl), N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl, R2 represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amine group, R3 is the formula R-(Ia), R-a 1 kl
-(Ib) or alk2-(Ic), where R is unsubstituted or in the benzene moiety one or more of hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or R′ represents a benzocycloalkenyl residue substituted with trifluoromethyl and/or substituted with lower alkyl in the α position and having a total number of ring carbon atoms of 8 to 12 bonded via saturated carbon atoms; benzocycloalkylidene residues having a total number of ring carbon atoms of 8 to 12, unsubstituted or substituted in the benzene moiety by one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl; represents a group, al
k represents lower alkylene or lower alkylidene, a
lk2 represents lower alkyl-ω-ylidene, and has the above formula (
I) new hydropyridine-derivative compounds, their tautomers and/or salts, uses of these compounds, in which the dotted line represents that there may be single or especially double bonds; Methods for their preparation and compounds of formula I or their tautomers and/or
Or, it relates to a pharmaceutical preparation containing a pharmaceutically usable salt.

The residue R or R' may carry one or more, for example one or two or three, identical or different substituents as mentioned above.

The residue R according to the above definition is 1, for example a benzocyclobutenyl residue, for example benzocyclobuten-1-yl, an indanyl residue, for example indan-1-yl or a
is an indan-2-yl residue, or a 1,2,3,4-tetrahydronaphthyl residue, such as 1,2,3,4-tetrahydronaato-1-yl or secondly a 1,2,
3.4-tetrahydronaphth-2-yl.

A residue R' according to the above definition is, for example, a penzocyclobutenylidene residue, such as benzocyclobuten-1-ylidene.

The present invention can be applied, for example, to formula 1 (wherein R3 is group 1a or Ib
R is unsubstituted or in the benzene moiety, one or more of hydroxy, lower alkoxy, lower alkanoyloxy,
represents a benzocyclobuten-1-yl residue substituted with halogen, lower alkyl and/or trifluoromethyl and/or substituted with lower alkyl in the α-position;
R1 is carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N.

Represents N-dilower alkylcarbamoyl; R2 is hydrogen,
represents an optionally etherified or acylated hydroxy group or an optionally acylated amino group;
a l kl represents lower alkylene or lower alkylidene), tautomers and salts thereof, uses of these compounds, processes for their production, and compounds of formula 1 or tautomers and salts thereof and/or pharmaceutical preparations containing pharmaceutically usable salts.

Etherified hydroxy R2 is, for example, lower alkoxy or optionally substituted phenyl lower alkoxy.

Acyl in acylated hydroxy or amino R2 is 1
For example, acyls derived from half esters of organic carboxylic or sulfonic acids or carbonic acids.

Acyl derived from organic carboxylic acids is, for example, the residue of an aliphatic or monocyclic aromatic carboxylic acid, such as lower alkanoyl or, for example, substituted benzoyl,
Furthermore, it is pyridryl.

Acyl derived from organic sulfonic acids is, for example, lower alkanesulfonyl.

In the acyl derived from a half ester of carbonic acid, the hydroxyl group of $2 is esterified with one, eg, aliphatic or aryl, eg, phenylaliphatic alcohol. Acyl groups derived from half-esters of carbonic acid include, for example, lower alkoxycarbonyl and optionally substituted phenyl lower alkoxycarbonyl.

For example, tautomeric forms of compounds of formula I exist when R2 represents hydroxy or amino and the dotted line represents the presence of a double bond. That is, the dinol or enamine of formula 1 is a 0 representative compound which exists in equilibrium with the corresponding keto- or ketimine-tautomer of the formula T':\R0, where R2' represents oxo or imino. Both tautomeric forms can be isolated.

The compounds according to the invention may furthermore exist in stereoisomeric forms.
atom (e.g., their α-C atom if the residues R or R' are substituted with lower alkyl, or the C-i atom at the 3-position of a 4-unsubstituted piperidine residue) Therefore, they can be used, for example, as pure enantiomers or enantiomeric mixtures, e.g. racemates, and even if there is at least one further chiral center (e.g. C- in position 4 of a 4-unsubstituted piperidine residue). carbon), diastereomers or diastereomeric mixtures; thus, for example, with respect to R1 and R2, if R2 is different from hydrogen, this may also be a geometric isomer, e.g. -1 i.e. 3S, 4
S- and 3R, 4R1 and trans-1, i.e. 3S
, 4R- and 3R,4S-isomers may also be formed.

Salts of compounds of formula 1 or their tautomers are in particular the corresponding acid addition salts, preferably pharmaceutically usable acid addition salts. These include, for example, strong, strong, and weak acids, such as
For example, using sulfuric acid, phosphoric acid or hydrohalic acid to form a strong organic carboxylic acid, such as a lower alkane carboxylic acid, such as acetic acid, an optionally unsaturated dicarboxylic acid, such as malonic acid, maleic acid or fumaric acid. acids, or hydroxycarboxylic acids, such as tartaric acid or citric acid, or with sulfonic acids, such as lower alkane- or optionally substituted benzenesulfonic acids, such as methane- or P-)luenesulfonic acids. It is formed by If RI represents, for example, carboxy, the corresponding compounds can form salts with bases. Suitable salts with bases are, for example, the corresponding alkali metal or alkaline earth metal salts, such as the sodium, potassium or magnesium salts,
Pharmaceutically usable transition metal salts, e.g. zinc- or copper salts, or ammonia or organic amines, e.g.
Salts with cyclic amines, such as heptano, di- or trihydroxy lower alkyl amines, hydroxy lower alkyl lower alkyl-amines or polyhydroxy lower alkyl amines. Cyclic amines are, for example, morpholine, thiomorpholine, piperidine or pyrrolidine. As the mono-lower alkylamine, for example, ethyl-
Alternatively, t-butylamine, di-lower alkylamine includes, for example, diethyl- or diisopropylamine, and tri-lower alkylamine includes, for example, trimethyl- or triethylamine. The corresponding hydroxy lower alkylamines are, for example, mono-,
di- or triethanolamine, and the hydroxy lower alkyl-lower alkyl amine is, for example, N,
N-dimethylamine- or N.

N-diethylaminoethanol, and examples of the polyhydroxy lower alkylamine include glucose amine.

Also included are salts which are unsuitable for pharmaceutical use, since they can be used, for example, for the isolation or purification of the compounds according to the invention as well as their pharmaceutically usable salts. There is C.

Residues or compounds referred to above and below as "lower" are, unless otherwise defined, particularly understood to contain up to 7 and especially up to 4 carbon atoms (C-atoms).

Lower alkoxy is, for example, methoxy, xyloxy, n
-propoxy, isopropoxy, n-butyroxy, isobutyroxy and tert-butyroxy.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, inbutyl, 5ec
-butyl or tert-butyl, further including the corresponding pentyl-, hexyl- and heptyl residues.

Lower alkylene Alk, has both ring systems first of all 1
bridging via 3 to 3 C atoms, especially l
up to 4, especially up to 2 to 3 C-atoms from
For example, linear, e.g.
-propylene, 1,2- or 1,3-(2-methyl)propylene or 1,2- or 1,3-butylene, in a lower alkyl-nodene a2 □ connects both ring systems to one C-
bridged through atoms, in particular having 1 to 4, especially 1 to 3 C atoms, such as methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1 - or 2,2-butylidene.

The lower alkyl-ω-ylidene a l k2 bridges both ring systems primarily via 2 to 3 C atoms, in particular 2 to 4 C atoms, especially 2 or 3 C atoms. It has a C-atom, for example ethyl-2-ylidene or propyl-3-ylidene.

Lower alkanoyl is, for example, acetyl, propionyl, butyryl, imbutyryl or pivaloyl.

Lower alkanesulfonyl is, for example, methane- or ethanesulfonyl, phenyl lower alkoxy is
For example, up to 4 alkyl-C- optionally substituted with lower alkyl, lower alkoxy and/or halogen.
α-phenyl lower alkoxy atoms, especially benzyloxy.

Halogen is in particular a halogen with an atomic number of 35 or less, e.g.
Fluorine, chlorine and bromine, and also iodine.

The compounds of formula 1, their tautomers and their pharmaceutically usable salts, for example, have useful pharmacological, especially nootropic, properties. That is, in the case of mice, Mondadori (Mondadori)
) and Classen's two-compartment passive avoidance (Two-Compartment Pa5s
ive avoidance) test model (Acta
Neurol, 5cand, 69, Expanded Edition 99.1
25-129 (1984)), about 0,1
Administration of mg/kg intraperitoneally and orally resulted in a reduction in the amnestic effects of brain electric shock.

In this test model, a first-order anti-amnestic effect was determined.

Cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride is 0.3 to 3 mg/
Trans-4-hydroxy-1-[2-(-methoxybenzocyclobuten-1-yl)-ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride was effective when administered intravenously up to 0,3m
Effective at intravenous doses of 3 to 30 mg/kg
The effect was even greater when administered intravenously up to 1 kg; 4-amino-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,2,5,6-titrahydropyridine-3 -Carboxylic acid ethyl ester-hydrochloride is 0
, showed efficacy with intravenous administration of 3 mg/kg, and 30 eg
The effect was even greater when administered intravenously at a dose of 1-((6-methoxyindan-1-yl)methyl]-
1.2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester-oxalate group at 3 and 30 mgl
Oral administration of kH showed effects; 4-hydroxy-[(5-methoxy-1-methyl-benzocyclobuten-1-yl)-methyl]-1.2,5,
6-titrahydropyridine-carboxylic acid ethyl ester-hydrochloride was effective at intravenous doses of 0.3 to 30 mg/kg; 4-hydroxy-1-(benzocyclobuten-1-yl)-1, 2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester-hydrochloric acid ester was effective at oral doses of 0.3 and 30 mgl kg; 1-[(7-medicine 1,2,3. 4-tetrahydronaphth-2-yl)methyl]-1,2°5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride was effective at oral doses of 0.3 and 30 mgl kg; 4 -Hydroxy-1-[(4-methoxybenzocyclobuten-1-yl)methyl]-1,2°5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride at 0.3 mgl kHz orally and 4-hydroxy-1-[(7-medoxy 1°2.3.
4-tetrahydronaphth-2-yl)-methyl]-1.
2,5,6-titrahydropyridine-3-carboxylic acid methyl ester-hydrochloride was effective at oral doses of 3 and 30 mgl Itg.

The compounds of the invention also show significant memory-improving effects, which have been shown in mice by Mondadori.
and step down by Wasar.
Passive avoidance (Step-dowr+ Pa5siveA
voidance test (Psychopharmac)
63, pp. 297-300 (1979)) when administered at approximately 0.1 mg/kg intraperitoneally and orally.

In this test model, for example, 4-hydroxy-
1-[5-methoxy-benzocyclobuten-1-yl)
methyl]-1,2,5,8-tetrahydropyridine-3
-carboxylic acid ethyl ester-salt at showed great efficacy when administered intravenously (0,1 100 ffig/kg + 7) and orally at doses of 1 to 100 mgl kg.

The compounds of formula 1 or their tautomers and their pharmaceutically acceptable salts can be suitably used as medicaments, for example as psychedelics, eg as prophylactic and therapeutic treatments for memory disorders. A further subject of the invention is the formula I
, their tautomers and their pharmaceutically usable salts for the manufacture of medicaments, in particular stimulants, and for the treatment of memory disorders. Commercial preparations of the active substances may also be included here.

The present invention particularly relates to formula 1 (wherein R or R' is unsubstituted or has one or more in the benzene moiety, e.g.
Benzocyclobuten-1-yl residues substituted with 2 or 3 hydroxy, lower alkoxy, lower alkanoyloxy and/or halogen and/or substituted with lower alkyl in the α-position, benzocyclobutene -1-ylidene residue, indan-1-yl- or indan-2-yl residue or 1,2,3,4-tetrahydronaphth-niyl or 1,2,3°4-tetrahydronaphth-2-yl residue represents a group, R1 represents carboxy, lower alkoxycarbonyl or carbamoyl,
R2 represents hydrogen, hydroxy, lower alkoxy, lower alkanoyloxy, lower alkanesulfonyloxy, phenyl lower alkoxy or amino optionally substituted with lower alkyl, lower alkoxy and/or substituted with halogen in the phenyl moiety, alk, each represents lower alkylene or lower alkylidene linking both ring systems via 1 or 2 up to 3 C-atoms, and a l R2 represents 2 or 3 C-
lower alkyl connecting both ring systems via an atom -ω-
(representing ylidene), and their tautomers and/or salts.

The invention particularly relates to compounds of formula 1, in which R3 represents a group of formula Ib and R is unsubstituted or in the benzene moiety one or more, for example two or three, hydroxy, lower alkoxy , lower alkanoyloxy, and/or a benzocyclobuten-1-yl residue substituted with halogen and/or substituted with lower alkyl in the l-position, R1 represents carboxy, lower alkoxycarbonyl or carbamoyl, R2 represents hydrogen, hydroxy, lower alkoxy, lower alkanoyloxy or amine,
a l kl is 1 or 2 to 3 or less C-
lower alkylene or lower alkylidene connecting both ring systems via an atom), and their tautomers and/or salts.

The present invention particularly relates to the formula 1 (wherein R3 represents a group Ia or Ib and R is unsubstituted or in the benzene moiety lower alkoxy having up to 4 carbon atoms, e.g. methoxy; lower alkyl having up to 4 carbon atoms, e.g. monosubstituted with methyl or with halogen of atomic number up to 35, e.g. chlorine, or with lower alkyl having up to 4 carbon atoms, e.g.
benzocyclobuten-1-yl radicals, indan- 1-yl residue or secondly indan-2-yl residue or 1,2,3.4
-tetrahydronaphth-1-yl residue, R represents lower alkoxycarbonyl, in particular lower alkoxycarbonyl having from 2 to 5 C-atoms, such as ethoxycarbonyl, or carbamoyl, and R2 represents hydrogen or hydroxy , alk, is 3 or less C-
Lower alkylene bridging the ring system via an atom, especially 3
compounds of lower alkylene with up to 3 C atoms, for example methylene, the dotted line means that there may be single or especially double bonds, and their tautomers and/or salts Regarding.

The invention particularly relates to benzocyclos of the formula 1, in which R3 represents a group Ib and R is unsubstituted or substituted with lower alkoxy having up to 4 C-atoms in the benzene moiety, such as methoxy. represents a buten-1-yl-residue, R1 is lower alkoxycarbonyl, especially 2-5
C-atoms, for example ethoxycarponyl or carbamoyl, R2 is hydrogen or hydroxy, and alk is a lower ring bridging the ring system via up to 1 to 3 C-atoms. represents alkylene, especially with up to 3 C-atoms, such as methylene;
The dotted line refers to the compounds (meaning that there may be single or especially double bonds) and to tautomers and/or salts.

The present invention is based first of all on formula 1 (wherein R3 represents a group of formula Ib and R is unsubstituted or in the benzene moiety, in particular 5-
represents a benzocyclobuten-1-yl residue monosubstituted by lower alkoxy with up to 4 C-atoms, for example methoxy, in the position R, with up to 4 C-atoms;
represents lower alkoxycarbonyl having an atom, for example, ethoxycarbonyl, R2 represents hydroxy, a
l kl stands for methylene or ethylene and the dotted line means that there may be single bonds or especially double bonds), as well as their tautomers and/or salts.

The present invention preferably relates to novel compounds and processes for their preparation as mentioned in the Examples.

The subject of the invention is likewise for example a) a compound of the formula IT a : R3-Xr (IT a) in which xl represents hydroxy or a reactive esterified hydroxyl or a salt thereof of the formula 1%: b) 弐m: 剋 (in the formula, xl represents a residue that can be converted into R1), a tautomer or salt thereof, or or C) preparation of compounds of the formula I, in which R2 represents hydroxy and R represents in particular lower alkoxycarbonyl, their tautomers and/or salts. for,
2■・ (wherein, Y is the formula -CH=R2', C(Y2)-R2
' or cyano, R2' represents oxo or imino, and Y2 represents a removable residue), or a salt thereof; hydroxy or amine and the dotted line indicates the presence of a double bond, and R1 in particular represents lower alkoxycarbonyl), their tautomers and/or salts, A compound of formula Va: or a tautomer or salt thereof is reacted with a compound of formula %() (in which X3 represents a halogen or lower alkokene), or its li4, or e) a compound of formula For the preparation of compounds of the formula (in which R2 is different from hydrogen), their tautomers and/or compounds of the formula ■: Blue.

(in the formula, x4 represents a residue that can be converted into R2) or a salt thereof, or f) especially a compound of formula 1 (in the formula, R2 represents hydrogen), For the preparation of their tautomers and/or salts, the formula ■: (wherein Aθ represents an acid anion and R2″ is hydrogen, furthermore etherified esterified or protected hydroxy or acylated or a protected amine), the excess double bonds are reduced to single bonds and any protective groups present are removed and, if desired, the compounds obtained by this or other methods can be converted to formula converting it into other compounds of I, separating the isomer mixture obtained by this method into each component, separating the enantiomeric mixture or diastereomeric mixture obtained by this method into individual enantiomers or diastereomers, The compounds of formula 1, their tautomers and their / or a method for producing salt.

The reactions mentioned above and below are carried out in a manner known per se, for example in the absence or usually in the presence of suitable solvents or diluents or mixtures thereof, optionally with cooling, at room temperature or under heating, e.g. from about -10°C to the boiling point of the reaction medium, preferably from about 20°C to about 150°C.
°C, and if desired in a closed container,
It is carried out under pressure, in an inert gas atmosphere and/or under water-free conditions.

Starting materials with a basic core may be present, for example, in the form of acid addition salts, for example with the aforementioned acids, whereas starting compounds with acid groups can be present with bases, e.g. Salts can be formed with bases of the types mentioned above. Furthermore, the starting compounds may exist in tautomeric form, in particular in the case of the 2nb compound where R2 represents hydroxy and the dotted line means that there is a double bond. It's okay.

Reactive esterified hydroxyxl with a dihydrogen is especially a hydroxyl esterified with a strong inorganic acid or an organic sulfonic acid, e.g.
Halogens, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halogensulfonyloxy, such as fluorosulfonyloxy, optionally, such as halogens, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxy Sulfonyloxy, halogensulfonyloxy, e.g. fluorosulfonyloxy, lower alkanesulfonyloxy optionally substituted, e.g. with halogen, e.g. methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or Optionally, for example, it means benzosulfonyloxy substituted with lower alkyl or halogen, such as p-bromophenyl- or P-1 luenesulfonyloxy.

The reaction is carried out in particular in the presence of a condensing agent, such as a suitable base. Examples of the base include alkali metal hydroxide,
-hydride, -amide, -alkal-to, -carbonate, -triphenylmethylide, -di-lower alkylamide, -amino-lower alkylamide or -lower alkylsilylamide, naphthalinamide (naphthamide), lower alkylamine, base Mention may be made of heterocyclic, ammonium hydroxide as well as carbocyclic amines. Specifically, sodium hydroxide, sodium hydride, sodium amide,
Sodium ethylate, tert-butylade, sodium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3-(
aminopropyl)-amide, potassium-bis-(trimethylsilyl)-amide, dimethylaminenaphthalene, di- or triethylamine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diaza-bicyclo(4,3,0)non -5-dyne (DBN) as well as 1,8-diazarbisiglo(s,4,0)unde-7-ene (DBU).

The starting materials of formula IIa are partially known. The novel compounds IIa, in which R3 represents the group Ib, can be prepared, for example, from the corresponding ω-R-alkanecarboxylic acid using diporan or from the ω-R-alkanecarboxylic acid ester with lithium aluminum hydride. to the respective corresponding alkanol (ITa;

The starting materials of the formulas IIa and IIb are known or can be obtained in a manner known per se.

Residues x2, which can be converted into a unique R, are, for example, functionally modified carboxy groups different from R7, such as cyano, anhydride carboxy groups, optionally substituted amines/, optionally esters, etc. esterified or amidated carboxy, tri-lower alkoxy- or trihalogenmethyl different from esterified or amidated carboxy R1.

Carboxy anhydride is, for example, a mineral acid, e.g. 7% C7
with hydrogenic acid, or with carboxylic acids, such as optionally substituted lower alkanoic acids or benzoic acid, or with halogenformic acid-lower alkyl half ester carboxy anhydrides.

Examples include halogencarbonyl, e.g. chlorocarbonyl, lower alkanoyloxycarbonyl, e.g.
Examples include acetyloxycarbonyl or lower alkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Substituted amidinos are, for example, amidinos substituted with aliphatic residues, eg lower alkyl, eg lower alkylamidino, eg ethyl amidino.

Esterified or anhydrous carboxyimidoyl means, for example, alkoxy- or halogen-poimidolyl, such as lower alkoxy-1, such as ethoxy- or chloropoimidolyl.

Tri-lower alkoxy or trihalogenmethyl is, for example, trimethoxymethyl or trichloromethyl.

x2 can be converted to R1, for example, by solvolysis. Solventants are, for example, water, lower alkanols corresponding to the desired esterified carboxy, ammonia or amines corresponding to the desired amidated carboxy groups R1. Treatment with the corresponding solvent is optionally carried out in the presence of acids or bases. Acids include, for example, inorganic or organic protic acids, such as mineral acids, such as sulfuric acid or hydrohalic acids, such as hydrochloric acid; or, for example,
Sulfonic acids, such as lower alkane- or optionally substituted benzenesulfonic acids, such as methane- or P
-) luenesulfonic acid; or, for example, carboxylic acids, such as lower alkanecarboxylic acids, such as acetic acid, while bases include, for example, those mentioned in variant a), in particular sodium hydroxide or water. Potassium oxide can be used.

During solvation, anhydrous carboxy, for example substituted amidino, optionally esterified or anhydrous carboxyimidoyl, esterified or amidated carboxy R, different from esterified or amidated carboxy , trilower alkoxy or trihalogenmethyl is hydrolyzed to carboxy, and cyano is hydrolyzed to carbamoyl or carboxy. In this case, the lower alkanoyloxy residue and/or the etherified or acylated hydroxy group or the acylated amino group R2, which are optionally located on the ring R, can be hydrolyzed to hydroxy or amino, respectively, during the hydrolysis process.

Esterified or amidated carboxyls different from cyano, anhydride carboxy or esterified or amidated carboxy R1 can, for example, be subjected to alcoholysis with a suitable lower alkanol to give the esterified carboxy, and cyanide and anhydride carboxy can be , for example, carrying out ammonolysis or amitolysis using ammonia or an amine corresponding to the amidated carboxy R1.

Starting materials of formula (1) are obtained by preparing a compound of formula: It can be produced by reacting in the presence of one.

Tributary stream 1- Cyclization is, for example, Dietz? 7 (Dieckman
n) In analogy to the reaction, it is carried out in particular in the presence of a base as mentioned under variant a) and by subsequent hydrolysis treatment.

In a preferred embodiment, for example, a compound of the formula: in which R2' represents oxo or imino is used with said base, in particular with an alkali metal lower alkanolade, such as sodium methanolade or sodium ethanolade. can be subjected to treatment. Compound IVa is thereby cyclized to a compound of formula 1, in which the dotted line indicates the absence of a double bond and R2 represents hydroxy or an amine. The starting material rVa is e.g. : A reactive benzocycloalkenyl(imino)alkanol ester of (where Xl is a reactive esterified hydroxy) with the formula: H2N CH2-CH2-R□ (
■b) is reacted with the β-amino acid compound of formula ■C: The resulting 3-aminopropion #visitor of formula: is reacted with acrolein or formula:
Reactive esterified hydroxy; R2' = oxo or imino) is obtained by reacting with an optionally functionally modified aldehyde.

In another preferred embodiment of variant C), 2) (wherein Yl and R1 represent lower alkoxycarbonyl)
cyclization of the compound of formula 1 (wherein the dotted line indicates the presence of a double bond and R2 represents hydroxy) or the corresponding compound of formula 1 (wherein R2' is oxo) The tautomer of

For the preparation of said starting materials of the formula (1), for example, by reduction of the corresponding nitriles, the resulting formula: Rs
Starting from compounds of -NR2(IVe) or their salts, these are added to at least 2 mol of 2CR2=CHR1
(IV f ).

The compound IVci (wherein R3 is a group Ib) can be prepared, for example, by reacting a compound of the formula: RCH2X1 (■e a : X1: reactive esterified hydroxy) with an alkali metal azide to form the corresponding formula: R- CH2Ns (r7
eb) or with an alkali metal cyanide to give a compound of the corresponding formula: R-CH2CH2-CH (■ec), and then the dilated product is converted into an amine (■e; R3'=
R-CH2- or R-CH2CH2-), for example,
By lithium aluminum hydride or by intermediate IV
In the case of ec, it is obtained by reduction with hydrogen in the presence of Raney nickel or with poran/dimethyl sulfide.

The compound ffe (wherein R3 is a group 1a) can be prepared, for example, by using the corresponding formula R-COOH(IVe d) 0) using a carbon atom with thionyl chloride followed by an alkali metal azide with the corresponding formula: R-COH2 (TVee)
and then decomposing it to the corresponding amine TVeCRs =R), for example by treatment with trifluoroacetic acid followed by an alkali metal hydroxide.

The C-acylation by the variant ILL2 methods can be carried out in particular in the presence of the bases mentioned in variant a)i.

Reaction of a compound of the formula R3X+ (Tla) with a compound of the formula VC: in the presence of one of the bases mentioned above, analogous to the N-substitution according to variant a), gives the starting material of the formula Va.

Residue x4 that can be converted into R2 is, for example, a residue that can be converted into group R2 by solvolysis, that is, reaction with a compound of the formula R2H (VIa) or a salt thereof, for example, a reactive Esterified hydroxy groups, for example halogen atoms, such as chlorine, bromine or iodine. The residue x4 which can be converted into hydroxy can also be a diazonium group, for example a diazonium group of the formula N2ΦAe, where the anion Ae represents a strong acid, e.g. a mineral acid, e.g. a chloride or sulphate ion. , or an etherified or acylated hydroxy group R2 or an optionally acylated amino group R2.

Solvolysis is carried out in conventional manner, for example with bases, such as alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide or potassium hydroxide, or tertiary nitrogen bases, such as tri-lower alkyl amines, For example, triethylamine, or a heterocyclic nitrogen base, such as pyridine, or a quaternary ammonium hydroxide, such as
In the presence of benzyl-trimethyl-ammonium hydroxide or a metal salt, for example formula: R2'9M'' (■b
) in the form of a metal salt of (M) represents an alkali metal kanone, for example sodium ion, by adding the compound VTa. in the presence of a solvent or diluent, e.g., an excess of the reactants and/or an inert solvent miscible therewith, if desired with cooling or warming, e.g. It is advantageous to carry out at a temperature range and/or under an inert gas, for example nitrogen.

For the preparation of starting materials of the formula ■ and their salts, it is possible, for example, to start from compounds of the formula: Rs react in the presence of

Variant f): The anion Ae can be, for example, an anion of a strong protic acid, such as a halide ion, such as chloride, bromide or iodide, or a sulfonate ion, such as an optionally substituted lower a/l / cuff or benzenesulfonate ion, such as methanesulfonate, ethanesulfonate or p-bromobenzenesulfonate or P-1 luenesulfonate ion.

R2'' is especially an etherified hydroxy R2 or a protected hydroxy. A protected hydroxy can be, for example,
Silyloxy, for example tri-lower alkylsilyloxy, for example trimethylsilyloxy, and may also be triphenyl-lower alkoxy, for example trityloxy. Protected aminos are, for example, silylamines, such as tri-lower alkylsilylamino, such as trimethylsilylamino, and also phenyl-, diphenyl- or triphenyl-lower alkylamino, such as benzylamino, diphenylamino or tritylamino. Good too.

Reduction of excess double bonds can be achieved by treatment with a suitable reducing agent, e.g. hydrogenation in the presence of a hydrogenation catalyst, to form a hydride-
This is carried out by reduction with a conversion reagent or by reduction with a metallic reduction system consisting of a metal and a proton-eliminating agent.

Examples of hydrogenation catalysts include elements of subgroup I of the periodic table of elements or derivatives thereof, such as palladium, platinum,
Platinum oxide, ruthenium, rhodium, tris(triphenylphosphine)-rhodium-nihalide, such as -chloride, or optionally supported on a support such as activated carbon, alkali metal carbonate or monosulfate or silica gel An example of this is Ranney 0 Nickel. Hydride conversion reagents include, for example, suitable light metal hydrides, in particular alkali metal aluminum hydrides or boron hydrides, such as lithium aluminum hydride,
Lithium triethylborohydride, sodium borohydride, sodium cyanoborohydride or tin hydride,
For example, triethyl or tributyltin hydride,
Or Ziporan can be mentioned. Metal constituents of the metallic reducing system are, for example, base metals, such as alkali or alkaline earth metals, such as lithium, sodium, potassium,
magnesium or calcium, or transition metals, such as zinc, tin, iron or titanium, while proton-eliminating agents include protic acids of the type mentioned above, such as hydrochloric acid or acetic acid, lower alkanols, Examples include ethanol and/or amines or ammonia. Such systems are, for example, sodium/ammonia, zinc/hydrochloric acid, zinc/acetic acid or zinc/ethanol.

For example, the starting material of formula (II) can be prepared using the formula:
The reaction is carried out by reacting a compound of formula (1) a: with a compound of formula (1) or a salt thereof of I a ; X1=A).

In the starting materials of formulas II b, ▪ and IIIa, the hydroxy Ti R2 may be present in etherified form and the hydroxy or amino group R2 may also be present in intermediate protected form; Protected hydroxy as well as hydroxy or amino groups in the starting materials are, for example, silyloxy, such as tri-lower alkylsilyloxy, such as trimethylsilyloxy, and also triphenyl-lower alkoxy, such as trityloxy. Good too. Protected amino/1 is, for example, silylamino, such as tri-lower alkylsilylamino, such as trimethylsilylamino, and also phenyl-, diphenyl- or triphenyl-lower alkylamino, such as benzylamino, diphenylmethylamino or tritylamino. It may be.

The reduction of intermediately protected residues, i.e. the removal of the intermediate protecting group, can be carried out in a conventional manner, e.g. by solvolysis, e.g. by mild hydrolysis, e.g. under neutral or weakly acidic conditions. Water treatment, for example by the action of dilute aqueous mineral acids or carbonic acids, such as dilute hydrochloric acid or acetic acid.

The compounds of the present invention obtained by each method or other methods are:
It can be converted into other compounds according to the invention in a conventional manner.

Thus, for example, an esterified or amidated carboxy group R1 can be added in a customary manner, for example with a basic or acidic hydrolyzing agent, such as an alkali metal hydroxide or a primary acid salt, such as sulfur hydroxide or potassium carbonate. ,
Alternatively, it can be hydrolyzed to carboxy in the presence of a mineral acid, such as hydrochloric acid or sulfuric acid. The esterified carboxy can be further oxidized in the presence of acidic or basic solvolytic agents, such as mineral acids such as sulfuric acid, or the corresponding alkali metal alcoholades or hydroxides.
It can be converted into other esterified carboxy groups R1 by reaction with or treatment with alcohol, and into amidated carboxy groups by reaction with ammonia or the corresponding amines.

The free heel carboxy R1 can be converted to 1 in a conventional manner, e.g., a mineral acid, e.g.
By treatment with the corresponding alcohol in the presence of sulfuric acid,
or conversion to a halide, followed by reaction with the corresponding alcohol, e.g. in the presence of pyridine or triethylamine, or conversion to an alkali metal salt, followed by a reactive ester of the corresponding alcohol, e.g.
It can be converted to an esterified carboxy by reaction with the corresponding halide. Similarly, carboxy compounds can be esterified with the corresponding alcohols using a dehydrating agent such as N,N-dicyclohexylcarbodiimide. Free or esterified carboxy can also be prepared by reaction with ammonia or an amine having at least one hydrogen atom and dehydration of the ammonium salt formed during the intermediate treatment, e.g. by heating or with a dehydrating agent, e.g. - Can be converted to amidated carboxy by dicyclohexylcarbodiimide or by conversion to the halide followed by reaction with ammonia or an amine having at least one hydrogen atom.

Furthermore, hydroxy optionally present on the residues R or R' can be esterified, for example by treatment with lower alkanecarboxylic acid anhydrides or halides, to convert them into lower anchoranoyloxy, or into lower alkamers. It can be converted into the corresponding etherified hydroxy by reaction with reactive esters, especially brominated or hydrochloric acid esters. In a similar manner, optionally present hydroxy groups or amino groups R2 can also be acylated, for example by treatment with lower alkanecarboxylic acid anhydrides or monohalides or lower alkanesulfonic acid chlorides, such that lower alkanoyloxy or lower alkene Convert to sulfonyloxy, and similarly hydroxy R2
can be etherified. Conversely, in esterified or etherified hydroxy groups, such as lower alkanoyloxy or lower alkoxy, the hydroxy group can be liberated by solvolysis, preferably under acidic conditions. In a similar manner, etherified or acylated hydroxy R2 can also be hydrolyzed to hydroxy, and acylated amino can also be hydrolyzed to amino. Furthermore, a hydroxy group etherified with a phenyl lower alkanol or esterified with a carbonic acid half ester can be liberated by hydrogenolysis.

If in the compounds of the invention the dotted line means that there is a double bond, then that bond can be removed, for example, in a manner known per se with the aid of a reducing agent, for example of the type mentioned in variant f). Especially using sodium borohydride,
Alternatively, it can be hydrogenated to a single bond by catalytic hydrogenation.

Furthermore, the compounds according to the invention (in which the dotted line represents a double bond and R2 represents hydrogen) can be prepared, for example, in a manner known per se by the compound R2-H, in which R2 is optionally etherified or (representing an acylated hydroxy group or amino group) can be converted into the corresponding piperidine compound of the present invention. The addition is in particular carried out in the presence of a suitable base, for example a base of the type mentioned in process variant a).

Compounds of the invention (in which the dotted line represents a single bond) are, for example, compounds R2H (in which R2 represents an optionally etherified or acylated hydroxy group or an optionally acylated ami7 group). ) to give the corresponding tetrahydro-pyridine compounds of the invention in a manner known per se, in which R
2 represents hydrogen). For removal of an unsuitable starting group R2, for example hydroxy, it may be converted in situ to a more suitable starting group R2, for example lower alkanesulfonyloxy, or to a halogen, for example chlorine, bromine or iodine. be able to. In that case, the removal is carried out in particular in the presence of a suitable base, for example a base of the type mentioned in variant a).

Salts of compounds of formula 1 or their tautomers can be produced by methods known per se. Thus, for example, acid addition salts of compounds of 2 are obtained by treatment with acids or suitable ion-converting reagents. Salt is prepared using the usual method.
Acid addition salts can be converted into aS compounds, for example, by treatment with a suitable basic agent.

Depending on the reaction method or reaction conditions, the salt-forming, in particular basic, compounds of the invention can be obtained in free form or in salt form.

Since there is a close relationship between the free form and the salt form of the new compound, in the above and below, the free compound or its salt will be referred to as the corresponding salt or free compound as the case may be, as having the same meaning and purpose. It shall also mean a compound.

The novel compounds are also obtained in the form of their hydrates, including their salts of salt-forming compounds, and others, including the solvents used for crystallization.

Depending on the nature of the starting materials and processing methods, new compounds can be
In the form of possible isomers or as mixtures thereof, e.g. depending on the number of asymmetric carbon atoms, pure optical isomers, e.g. antiisomers, or isomeric mixtures 5 e.g. racemates, diastereoisomers They can exist as mixtures or racemic mixtures.

The resulting diastereomeric mixtures and racemic mixtures can be separated into pure isomers, diastereomers or racemates in known manner on the basis of the physicochemical differences of the components, for example by fractional crystallization.

The resulting enantiomeric mixture is separated by known methods, for example by recrystallization from optically active solvents, by chromatography on chiral adsorbents, with the aid of suitable microorganisms, by separation with specifically immobilizing enzymes, By forming inclusion compounds, e.g. using chiral or raw ethers (in which case only the enantiomers form a complex) or by converting into diastereomeric salts, e.g. , an optically active acid, such as a carboxylic acid, such as tartaric acid or malic acid, or a sulfonic acid, for example, by reaction with a sulfonic acid, and diastereoisomers obtained by these methods. The mer mixture can, for example, be separated into diastereomers on the basis of their solubility differences, and the desired enantiomer then liberated by the action of a suitable medium. It is advantageous to isolate the useful enantiomer.

Starting from compounds obtained as intermediates in any step of the process, the remaining steps are carried out or starting materials are used in the form of derivatives or salts and/or their racemates or opposites. or specifically formed under reaction conditions! It also concerns Mr. E.

In the process of the invention it is preferred to use starting materials which give rise to the compounds mentioned at the outset as particularly useful. In particular, the new starting materials developed for the preparation of the compounds according to the invention, their use and the processes for their preparation are likewise subject to the invention, in which case the variables (substituents)
R, R'.

RL, R2, R3, alkl and alk2 and the substituents R or R' each have the meaning given to them for the preferred group of compounds of formula 1.

Particular mention may be made in this connection of the compounds of the formula c: and their salts. These likewise exhibit self-consciousness properties with a potency comparable to that of the corresponding compounds of formula 1 or T' and can likewise be used in medicine as active substances for self-consciousness agents, e.g. 3-[(5-,Methoxybenzocyclobuten-1-yl)methylamine]-propionic acid ethyl ester-hydrochloride showed a
An intravenous dose of 0 mg/kg showed a significant anti-amnestic effect, and an oral dose of 3 mg/k3 showed a significant anti-amnestic effect in the step-down-passive avoidance test.

The invention therefore also applies to formula IVc (wherein R1 is carboxy, lower alkoxycarbonyl, carbamoyl, N-
represents lower alkyl-carbamoyl or N,N-di-lower alkylcarbamoyl, R3 is of formula R-(Ia), Ral
kx - (rb) or R'=alk2 (Ic), where R is unsubstituted or in the benzene moiety one or more of hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and /
or a benzocycloalkenyl residue substituted with trifluoromethyl and/or substituted with lower alkyl in the α-position and having a total number of ring C-atoms of 8 to 12 and bonded via a saturated C-atom; , R' is unsubstituted or substituted in the benzene moiety by one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl, the total number of ring C-atoms is from 8 to 12 represents a benzocycloalkylidene residue, alkl represents lower alkylene or lower alkylidene, and alk2 represents lower alkyl-
represents an ω-ylidene residue of the formula IVc (wherein R3 is a group I
In the compound represented by a), when R represents lower alkoxycarbonyl or carbamyl, R is unsubstituted or monosubstituted at the 5-position with halogen, lower alkyl or lower alkoxy, unlike indan-2-yl. , R represents carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl, R is different from unsubstituted 1,2,3,4-tetrahydronaphth-2-yl The present invention relates to compounds of formula IVc and their salts, uses of those compounds, processes for their preparation, and pharmaceutical formulations containing compounds of formula IVc or pharmaceutically usable salts.

One variable symbol (substituent) of formula 'IVc, in which case, for example,
has the meaning given as preferred in Equation 1.

The present invention therefore particularly relates to the formula c (wherein R or R' is unsubstituted) in the benzene moiety one or more, for example two or three, hydroxy, lower alkoxy,
benzocyclobuten-l-yl residue, benzocyclobuten-1-ylidene residue, indan-1-yl residue or indan substituted with lower alkanoyloxy and/or halogen and/or with lower alkyl in the α-position -2-yl residue or 1,2,3.4-tetrahydronaphth-1-yl or 1,2,3.4-tetrahydronaphth-2-yl residue, R1 is carboxy, lower alkoxycarbonyl or carbamoyl represents a 1
k is lower alkylene or lower alkylidene, respectively, and both ring systems are bonded with 1 to 2 to 3 or less C-atoms, alk2 is lower alkyl-ω-ylidene, and both C- with 2 or 3 ring systems
) and their salts.

The invention therefore particularly relates to the formula (i)c (wherein R3 is a group Ia)
or Ib and R is unsubstituted or lower alkoxy having up to 4 C-atoms in the benzene moiety, e.g.
methoxy; lower alkyl having up to 4 C-atoms;
For example, methyl; or halogen with an atomic number of 35 or less,
For example with lower alkyl monosubstituted with chlorine or having up to 4 C-atoms, such as methyl, or with lower alkoxy having up to 4 C-atoms, such as methoxy, likewise up to 4 lower alkyl having a C-atom of, for example, a benzocyclobuten-1-yl residue, an indan-1-yl residue or a secondly indan-2-yl residue or a 1,2, 3. represents a 4-tetrahydronaphth-1-yl residue, R1 represents lower alkoxycarbonyl, especially one having from 2 to 5 C-atoms, such as ethoxycarbonyl, or carbamoyl, and alk represents a ring system with 1 to 3 C-atoms, in particular those with 3 or less C-atoms (e.g. methylene), and their salts.

The invention therefore first of all relates to a group of the formula IVc, in which R3 represents a radical of the formula Ib and R is unsubstituted or lower alkoxy in the benzene moiety, in particular in the 5-position, having up to 4 C-atoms. , for example, represents a benzocyclobuten-1-yl residue monosubstituted with methoxy, and R1 is from 2 to 5
lower alkoxycarbonyl having up to 3 C-atoms,
For example, it relates to compounds in which ethoxycarbonyl is represented and alkl represents methylene or ethylene, and salts thereof.

The present invention preferably relates to novel compounds of the formula lVc mentioned in the Examples and processes for their preparation.

For example, g) Formula ■a and vmb R3-Zl (VIIIa)Z2-C
H2-CH(Z3)-R1(VIIIb), where one of the residues zI and Z2 represents a reactive esterified hydroxy, the other represents an amine and z3 represents hydrogen, or Zl is an amine and Z2 and 23 jointly represents a further bond) with each other and then, if necessary, converting the compounds obtained by the above method or other methods into other compounds of formula IVc, which are obtained by the above method. The isomer mixture obtained by the above method is separated into its respective components, the enantiomeric or diastereomeric mixture obtained by the above method is separated into each enantiomer or each diastereomer, the free compound obtained by the above method is converted into a salt, and/ Also a subject of the present invention is a process for producing compounds of formula IVc, their tautomers and their salts, characterized in that the salt obtained by the above method is converted into the free compound or other salts. be.

Reactive esterified hydroxys are particularly hydroxys esterified with strong inorganic or organic sulfonic acids, such as halogens, such as chlorine, bromine or iodine, sulfonyloxys, such as hydroxysulfonyloxy, halogensulfonyloxys, such as fluorosulfonyl. oxy, optionally substituted, e.g. with halogen, lower alkanesulfonyloxy, e.g. methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or optionally substituted, e.g. with lower alkyl or halogen. represents benzenesulfonyloxy, such as p-bromophenyl- or p-toluenesulfonyloxy.

In this case, the reaction is carried out in particular in the presence of a condensing agent, for example a suitable base. Examples of the base include alkali metal hydroxide, -hydride, -amide, -furcarrad, -carbonate, -triphenylmethylide, -di-lower alkylamide, -amino-lower alkylamide or mono-lower alkylsilylamide, Examples include naphthalene amines, lower alkyl amines, basic heterocycles, ammonium hydroxide and carbocyclic amines.
Sodium hydride, sodium amide, sodium ethylate, potassium tert-butylade, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium-3-(aminopropyl)amide, -bis-(trimethylsilyl)amide, dimethyl Aminonaphthalene, di- or triethylamine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diazo-bicyclo[4,3°0]non-
5-ene (DBN) and 1,8-diazabisiglo(5,4,0)undec-7-ene (DBU). The reaction of amine (Z1=amino) with acrylic acid compound XXI (Z2+23=bond) is carried out, for example, at about 60 to 120° C. under heating.

The starting material VfIia is identical to the compounds TIa or IVe, the preparation of which is indicated in process variants a) to C).

For the compound IVc obtained by the above process, the post-operations to be carried out, if desired, are in particular the conversion reactions of R or R' and R, enantiomers and diastereomers analogous to those indicated for the compounds of formula (1). Separation and interconversion of salt and free compound, which are carried out similarly.

The present invention likewise describes the activity of the compounds of formula 1 or IVc or their tautomers, or of the pharmaceutically usable salts of such salt-forming compounds, useful as pharmacological, primarily self-aware agents. Concerning use as a substance. They are therefore preferably used in the form of pharmaceutically usable preparations in methods of preventive and/or therapeutic treatment of the animal or human body, in particular as self-conscious agents, for example for the therapeutic treatment of memory disorders. I can do it.

The invention likewise relates to medicaments containing the compounds of the invention or their pharmaceutically usable salts as active substances, as well as processes for their production.

In the case of medicaments of the invention containing compounds of the invention or pharmaceutically usable salts thereof, mention may be made of those for enteral, e.g. oral or rectal, and parenteral administration to warm-blooded animals. In this case, the pharmacologically active substance is included alone or together with a pharmaceutically usable carrier agent. The daily dosage of the active substance depends on the age and individual symptoms, as well as on the method of administration.

The new drug contains, for example, about 10% to about 80% of the active substance.
%, preferably about 20% to about 60%. The medicaments according to the invention for intrarectal or rectal administration are, for example, in dosage unit form, such as dragees, tablets, capsules or suppositories, as well as ampoules. These can be prepared by methods known per se, for example, conventional mixing-1 granules-1 sugar-coating-1 dissolving-
Or manufactured by freeze-drying method. That is, the active substance is combined with the solid phase substance, the mixture obtained is optionally granulated, and then, if desired or desired, the mixture or granulation is converted into tablets or dragees after addition of suitable auxiliary substances. - By processing into nuclei, drugs for oral use can be obtained.

Suitable carrier substances are in particular filler substances, such as sugars, such as lactose, sucrose, mancot or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as e.g. , starch paste (e.g. using corn-1-wheat-1-rice or potato starch), gelatin, tragaganth, methylcellulose and/or polyvinylpyrrolidone,
If desired, disintegrants are used, such as the starches mentioned above, but also carpoxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or its salts, such as sodium alginate. Auxiliaries are first of all kinetic modifiers and lubricants, such as silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate, and/or polyethylene glycol. The dragee cores are optionally provided with a suitable coating resistant to gastric juices, in particular a concentrated sugar solution optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or a suitable organic coating. Lacquer solutions in solvents or solvent mixtures or solutions of suitable cellulose formulation liquids, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used to produce gastric juice-resistant coatings. For example, dyes or pigments may be added to the tablets or dragee coatings to identify or characterize the various active ingredients.

Further pharmaceutical preparations which can be used orally are nested (hard) capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a softener 1, such as glycerin or turpinto. Nested (hard) capsules contain the active ingredient in a mixture with filler substances such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and optionally stabilizers. It may be contained in the form of granules. In soft capsules, the active ingredients are preferably dissolved or suspended in suitable liquids, for example fatty oils, paraffin oils or liquid polyethylene glycols, optionally with the addition of stabilizers. .

Medicaments that can be used rectally include, for example, suppositories, which may consist of any combination of active substance and suppository base material. Suppository base materials include, for example:
Natural or synthetic triglycerides, paraffinic hydrocarbons,
Polyethylene glycols or higher alkanols are suitable.

Additionally, gelatin rectal capsules can also be used, which contain a combination of the active ingredient and a base material. Such base materials include, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

For parenteral administration, the active ingredient is first of all in water-soluble form,
For example, aqueous solutions of water-soluble salts, as well as suspensions of the active substances, such as the corresponding oily injection suspensions, are suitable, for example in suitable lipophilic solvents or vehicles.
Fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, are used or contain thickeners, such as sodium-carboxymethylcellulose, sorbitol and/or dextran, and optionally stabilizers. There are aqueous injectable suspensions.

The amount of active substance administered depends on the species, age and individual condition of the phlebotomy animal, as well as on the method of administration. In general, for warm-blooded animals weighing 75 to 8, the approximate daily dose is about 20 to about 500 mg orally, especially about 25 to 2.
Calculated at 50 mg, it is advantageous to administer the same amount in several doses.

The following examples illustrate the invention described above but are not intended to limit the scope of the invention. Temperatures are given in degrees Celsius.

Example I Diethyl N-[5-methoxybenzocyclobuten-1-yl)methyl]-iminodi(3-propionic acid) 1
8 g (49 mmol) in 100 d of toluene and the resulting solution was dissolved in sodium hydride (50% dispersion in mineral oil).
A suspension of 3 g (63 mmol) in toluene was added dropwise. The resulting reaction mixture was stirred to an internal temperature of 1
10'C! The resulting ethanol was distilled off.

The reaction mixture was then allowed to cool, diluted with ethyl acetate,
While stirring, 100 ml of water was added. The organic phase was separated, dried over magnesium sulfate and concentrated by distillation. The resulting crude material was purified by chromatography and converted to the hydrochloride salt with a solution of hydrochloric acid in ethanol. Crystallization from ethanol gives 4-hydroxy-1-[(
5-methoxybenzocyclobuten-1-yl)methyl]
-1.2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-carvone Acid ethyl ester hydrochloride was obtained.

The starting material is, for example, 245 J (2,28 mol) of 5-methoxyhendicyclobuten-1-ylmethylamine, which can be prepared as follows.
3g (752 mmol) of ethanol (1100m7)
It was added dropwise to the solution with stirring and heated under reflux for 20 hours.

The resulting reaction mixture was concentrated under water pump vacuum and then purified by chromatography. The substance thus purified is converted into the hydrochloride salt with a solution of hydrochloric acid in ethanol and crystallized from ethanol/diethyl ether, with a melting point of 97-98.5°C. ) Methyl coimino
Di(3-propionic acid) diethyl ester hydrochloride was obtained.

Example 2 In the same manner as in Example 1, 3.6 g (7
4 mmol) (50% dispersion in w4 oil) and N-[[5
-Methoxybenzocyclobuten-1-yl)methyl]iminodi(3-propionic acid) dimethyl ester from a toluene (300-) solution, melting point 114.2-116.4
4-Hydroxy-1-((5-methoxybenzocyclobuten-1-yl)methyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride, also known as 1-[' (5-methoxybenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-
Carboxylic acid methyl ester hydrochloride was obtained.

Starting material N-[(5
-Methoxybenzocyclobuten-1-yl)methylcoimino-di(3-7'ropionic acid) dimethyl ester hydrochloride was prepared from 5-methoxybenzocyclobuten-1-ylmethylamine in the same manner as described in Example 1. 4.2g
(25 mmol) and methyl acrylate 6.8. It can be produced from a solution of J (fromimole) in methanol (50,/).

Example 3 11.7 g (33 4X105 while adding a solution of 1.2 g of platinum oxide in ethanol (300d) to
Hydrogenation was carried out at Pa and room temperature. The catalyst was removed and the reaction solution was concentrated. Cis-4-human ax-1-[(5-methoxybenzocyclobuten-1-yl)methylcopiperidine-3-carboxylic acid ethyl ester hydrochloride having a melting point of 156-160°C when crystallized from ethanol/diethyl ether. was gotten.

Example 4 10.6 g (3
3.4 mmol) was dissolved in 40° of ethanol and added to a solution of 0.7 g (17 mmol) of sodium borohydride in 160° of ethanol/water (1:1). The reaction mixture was stirred at room temperature for 3 hours, then diluted with 200 g of water,
Extracted with dichloromethane. The extracts were combined, dried over sodium sulfate, and concentrated by distillation under reduced pressure. In addition to the cis derivative described in Example 3 by silica gel chromatography purification, trans-4-hydroxy-1-
Ethyl [(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylate was also obtained as a viscous oil.

Rf=0.44, hexane/ethanol=4:1 Example 5 Methanesulfonic acid chloride 1.1. /(14 mmol) to cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride 4 g (12.5 mmol)
The mixture was added to a dichloromethane (100,/) solution of 1.7 g (14 mmol) of 4-dimethylaminopyridine and 3.5,/(25 mmol) of triethylamine while stirring at room temperature. Stirring was continued at room temperature until the reaction was complete. The reaction mixture was concentrated, and a solution of 4 g of potassium hydroxide in ethanol (50, J) was added, and the whole was stirred for 30 minutes. The mixture was diluted with dichloromethane and washed with water. The organic phase was separated, dried over magnesium sulfate, and evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography, converted to the hydrochloride salt with a solution of hydrochloric acid in ethanol, and crystallized from ethanol/diethyl ether to give 1-[(5-methoxy) with a melting point of 204.5-205.5°C. benzocyclobuten-1-yl)methyl] -1,2,5,
6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride was obtained.

Example 6 N-[2-(5-methoxybenzocyclobuten-1-yl)ethyl]iminodi(
26.5 g (70 mmol) of diethyl 3-propionate and 4.4 g (9-1 mmol) of sodium hydride (
4-Hydroxy-1-[2
-(5-methoxybenzocyclobuten-1-yl)ethyl]-1,2,5,6-tetrahydro-pyridine-3-
Carboxylic acid ethyl ester hydrochloride and 1-[2-(5-
methoxybenzocyclobuten-1-yl)ethyl]-4
-Oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride was prepared.

The starting material can be prepared, for example, as follows: Borane dimethyl sulfide trimole) (10M in tetrahydrofuran) is dissolved in 2-(5-
5 g (29 mmol) of methoxybenzocyclobuten-1-yl)acetonitrile in tetrahydrofuran (50,
+J) Add 30% of 6N hydrochloric acid to the solution gradually at room temperature and then heat under reflux for 30 minutes.
．． 7 was added and the mixture was then heated under reflux for a further 30 minutes. The reaction mixture was cooled, adjusted to pH 10 with 4N sodium hydroxide solution, and extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure to yield 2-(5-methoxybenzodiglobuten-1-yl).
Ethylamine was obtained as a viscous oil.

Rf = 0, 1, toluene/ethanol/concentrated ammonia water = 90:20:1 2- (5-methoxybenzocyclobuten-1-yl)
12 g (68 mmol) of ethylamine and 22 g of ethyl acrylate. a/(200 mmol) to N-[2-(5
Diethyl-methoxybenzocyclobuten-1-yl)ethylaminodi(3-propionate) was obtained as a viscous oil.

Rf=0.24, hexane/ethyl acetate=8:2 Example 7 By the same operation as in Example 3, 4-hydroxy-1-[
2-(5-Methoxybenzocyclobuten-1-yl)ethyl]-1.2,5,6-tetrahydro-pyridine-3
- When 3.7 g (10 mmol) of ethyl carboxylate hydrochloride was hydrogenated under 4×10'Pa hydrogen overpressure and room temperature, and a solution of platinum oxide 400B in ethanol (100,7) was added, cis-4-hydroxyl with a melting point of 144°C −1, −[2
-(5-Methoxybenzocyclobuten-1-yl)ethylcopiperidine-3-carboxylic acid ethyl ester hydrochloride was prepared.

Example 8 By the same operation as in Example 4, 4-hydroxy-1-[
2-(5-Methoxybenzocyclobuten-1-yl)ethyl]-1.2,5,6-tetrahydro-pyridine-3
- From a 50% aqueous solution of ethanol (80, J) containing 3.3 g (10 mmol) of ethyl carboxylate and 0.2 g (5 mmol) of sodium borohydride, Butene
Ethyl (1-yl)ethyl]-piperidine-3-ethyluponate was obtained as a viscous oil.

Rf = 0, 4, hexane/ethanol = 8:2 Example 9 By the same operation as in Example 5, cis-4-hydroxy-
8 g of ethyl 1-[2-(5-methoxybenzocyclobuten-1-yl)ethyl]-piperidine-3-carboxylate
(24 mmol), 4-dimethylaminopyridine 3.2
g (26 mmol), triethylamine 6.65, J (
48 mmol) and methanesulfonic acid chloride 2 m/(
1-(2-(5-
methoxybenzocyclobuten-1-yl)ethyl]-
1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride was obtained.

Example 10 In a similar manner to the procedure described in Example 1, N-[2-(
5-methoxybenzocyclobuten-1-yl)ethyl]
-Iminodi(3-propionic acid) dimethyl ester 18.6 g (53 mmol) and sodium hydride 3.
3 g (69 mmol) (50% dispersion in mineral oil) from a solution in toluene (35°-) with a melting point of 157-158.5°C.
-Hydroxy-1-[2-(5-methoxybenzocyclobuten-1-yl)ethyl]-1.2,5,6-titrahydrobiridine-3-carboxylic acid methyl ester hydrochloride, also known as 1-['2 -(5-methoxybenzocyclobuten-1-yl)ethyl]'-4-oxo-piperidine-3
-Carboxylic acid methyl ester hydrochloride was prepared.

The starting material N[2-(5-methoxybenzodiclobuten-1-yl)ethyl]-iminodi(3-propionic acid) dimethyl ester (Rf = 0.64, hexane/ethyl acetate = 7; 3) is, for example, By the procedure described in Example 1, 14 g (77 mmol) of 2-(5-methoxybenzocyclopten-1-yl)ethylamine and 21 WJ (230 mmol) of methyl acrylate can be obtained from a solution of 21 WJ (230 mmol) in methanol (150). can.

Example 11 4-hydroxyloxy 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,25,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride 3.5 g (ICM: Limol) was dissolved in 50% dioxane and 50% 25% aqueous ammonia, and the resulting solution was placed in a pressure tube and heated to 80°C for 48 hours with stirring.
The reaction mixture was then extracted with trichloromethane, and the extract was washed with water, dried over sodium sulfate, and condensed under reduced pressure. The crude product was purified by chromatography, converted to the hydrochloride salt with hydrochloric acid and crystallized from methanol/diethyl ether to give 4-amino-1, mp 184-184-5°C.
-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3
-Carboxylic acid ethyl ester hydrochloride, also known as 1-[(5-
Methoxybenzocyclobuten-1-yl) methiseco-4
-Imino-piperidine-3-carboxylic acid ethyl ester hydrochloride was obtained.

Example 1z Methanesulfone # (5-methoxybenzocyclobutene-
2.42 g (10 mmol)
, 4-piperidone-3-carboxylic acid ethyl ester 1.
7 g (10 mmol) and potassium carbonate 1.38 g (1
0 mmol) was heated under reflux in 5oIIJ of ethanol for 24 hours.The mixture was then filtered, concentrated under water jet vacuum and purified by silica gel chromatography. When the resulting substance is converted to the hydrochloride salt with a solution of hydrochloric acid in ethanol and crystallized from ethanol, it has a melting point of 18
4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1.2 at 1 to 1.82°C,
5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-[2-('5-methoxybenzocyclobuten-1-yl)methyl]-4-oxo-
Piperidine-3-carboxylic acid ethyl ester hydrochloride was obtained.

The starting material can be prepared, for example, as follows: Pyridine 6.1. n! (furomimol) and methanesulfonic acid chloride 3.6-(46 mmol) in (5-methoxybenzocyclobuten-1-yl)methanol 5.0 g
(30.5 mmol) in dichloromethane (50.7) was added O'O with stirring and without removing water. The mixture was then stirred at room temperature for a further 18 hours to complete the reaction. 50% of ice water was added and the whole was stirred for 30 minutes.

The organic phase was separated and washed once each with 2N sodium hydroxide solution, 2N hydrochloric acid and water. Drying with sodium sulfate and concentrating under reduced pressure yields methanesulfone! (5-Medoxybenzocyglobuten-1-ylmethyl)ester was obtained as a viscous oil.

Rf = 0, 4, toluene/ethyl acetate = 9:1 Example 13 By the same operation as in Example 1, 3.6 g (22 mmol) of 5-methoxybenzosifgobuten-1-yl-methylamine and acrylic Ethyl acid 2.4. From a solution of J (22 mmol) in toluene (70 rnl), melting point 129-13
3-(5-Methoxybenzocyclobuten-1-ylmethylamino)pucopionic acid ethyl ester sulfate salt at 0°C was obtained at room temperature.

Example 14 1-bromo-2-(indan-1-yl)-ethane4.
5 g (20 mmol) was dissolved in 2° of toluene, 4.9 g (20 mmol) of gubacoline hydrogen bromide S and N,
N-diisopropyl-N-ethylamine 5.7 g (44
mmol) in dimethylformamide (15,7) at room temperature. The mixture was heated under a nitrogen atmosphere for 45 minutes.
The mixture was stirred at .degree. C. for 12 hours, then most of the solvent was removed under reduced pressure, the residue was acidified with 2N hydrochloric acid, and the aqueous solution was extracted with diethyl ether. The acidic aqueous phase was made basic with a mild aqueous sodium bicarbonate solution and extracted by shaking with diethyl ether. The organic phase is separated, washed with saturated sodium chloride solution and dried over magnesium sulfate to give 1-[2-(indan-1-yl)ethyl]-1°2.5,'6-tetrahydro-pyridine-3 -Carboxylic acid methyl ester was obtained.

An ethereal solution of hydrogen chloride is added to the resulting crude base, and the resulting hydrochloride is recrystallized from isopropanol/diethyl ether to give 1-(2
-(indan-1-yl)ethyl] -1,2,5,6
-Tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride was obtained.

Example 15 A solution obtained by dissolving 5.13 g (20 mmol) of methanesulfonic acid (6-methoxyindan-1-ylmethyl) ester in 20 mmol of toluene was added to 4.9 g (22 mmol) of gubacoline hydrobromide. Dimethylformamide (1
5, rJ) solution and N.

N-diisopropyl-N-ethylamine 5,65 g (4
The reaction mixture was stirred at 50'C under nitrogen atmosphere for 24 hours. The solvent was then removed under reduced pressure, the residue was dissolved in 2N hydrochloric acid, the resulting acidic solution was extracted by shaking with diethyl ether, and the ether phase was separated. The acidic aqueous solution was made basic with saturated sodium bicarbonate solution and extracted with diethyl ether. The ether solution was thoroughly washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to solidity by distillation under reduced pressure. The resulting residue was purified by silica gel chromatography using dichloromethane/methanol (19:1), and the resulting eluate was distilled to solidify. Obtained 1-
[(6-Methoxyindan-1-yl)methyl]-1.2.5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester was dissolved in diethyl ether, and oxalic acid was added to the resulting solution. Recrystallization of the precipitated oxalate from inpropamel/water and diethyl ether yields 1-[(6-methoxyindan-1-yl)methyl]-1.2,5, with a melting point of 184-186°C. 6-Tetrahydro-pyridine-3-carboxylic acid methyl ester oxalate was obtained.

The necessary starting materials can be produced, for example, as follows.

30.9 g (0.15 mol) of 6-methoxyindan-1-carboxylic acid methyl ester was dissolved in 60 g of diethyl ether.
8.5 g of lithium aluminum hydride (
0.0,'22 mol) in diethyl ether (300 mJ) over a period of 1 hour, during which time the mixture was brought to reflux. The mixture was continued to reflux for 15 hours,
It was cooled in a water bath and treated with water in the following order: 8.5-115% sodium hydroxide solution and 25% water.

The resulting suspension of white aggregates was filtered off, and the residue was triturated twice with diethyl ether and filtered again. The organic phase was dried over magnesium sulfate and concentrated by distillation under reduced pressure. The resulting residue was a colorless viscous oil containing crude 6-methoxyindan-1-methanol.

Crude 6-methoxyindan-1-methanol 5.7 g (3
2 mmol] was dissolved in dichloromethane (50), and the resulting solution was added to a solution of 4.3 g (38 mmol) of chlorinated methanesulfonic acid in dichloromethane (to,y). The resulting mixture was cooled to 5° C. in a water bath and added dropwise over 20 minutes to a solution of 73.9 g (38 mmol) of triethylamine in dichloromethane (10, J). The resulting mixture was stirred at room temperature for 3 hours, and then the precipitated triethylammonium chloride was removed and the mixture was extracted by shaking with ice water. The organic phase was dried over magnesium sulfate and concentrated to solidity by distillation under reduced pressure. The obtained oil was crude methanesulfonic acid (6-methoxyindan-1-
ylmethyl) ester, and this material was immediately reacted further.

Example 16 N-[(6-methoxyindan-1-yl)methyl]iminodi(3-propionic acid) dimethyl ester 5,2
The reaction mixture was heated at 80 °C for 3 h. , a mixture of methanol and toluene was distilled off at an internal temperature of 110°C.

The resulting residue was poured into ice/hydrochloric acid, and the organic phase was separated. Make the acidic aqueous solution basic with sodium bicarbonate solution,
Extracted by shaking with diethyl ether/ether acetate. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to solidity by distillation under reduced pressure.

The resulting residue contained crude 4-hydroxy-1-[(6-methoxyindan-1-yl)methyl]-1゜2.5,6-tetrahydropyridine- and 1-[(6-methoxyindan-1-yl) -yl)] ] methyl-4-oxopyridine-3carboxylic acid methyl ester. The crude product obtained was purified by chromatography on 6 g of silica gel using cyclohexane as eluent and converted to the hydrochloride with an ethereal solution of the hydrochloride. The hydrochloride salt was recrystallized from Impropatol/diethyl ether. The pure 4-hydroxy-1-[(6-
methoxyindan-1-yl)methyl]-1.2,5,
6-titrahydroviridine, also known as 1-((6-methoxyindan-1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride, has a melting point of 1
The temperature was 75-178°C.

The starting material can be prepared, for example, as follows: 12.8 g (50 mmol) of methanesulfonic acid (6-methoxyindan-1=ylmethyl) ester and 5.2 g (80 mmol) of sodium azide are dissolved in dimethyl Sulfoxide 130- was dissolved and the resulting solution was stirred at 80°C for 1 hour. The resulting reaction mixture was poured into ice water and extracted by shaking with diethyl ether. The organic phase was washed twice with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to solidity by distillation under reduced pressure. As a residue, 9.7 g of 6-methoxyindan-l-ylmethyl azide was obtained as a crude oil.

20 g of 6-methoxyindan-1-ylmethyl azide (
0.1 mole) was dissolved in 400 d of diethyl ether, and the resulting solution was dissolved in 5.0 g of lithium aluminum hydride (0.1 mole) in 400 d of diethyl ether.
, 13 mol) of diethyl ether 200+Jaffi solution at 25-30°C. After the addition, the mixture was kept under reflux for 6 hours, and then, under water cooling, 5-15% sodium hydroxide solution (5-5%) of water and 15-15% of water were added in this order. The white precipitate formed was removed for 72 hours and diluted with dichloromethane for 3 hours.
Boiled twice. The organic liquids were combined, dried over magnesium sulfate, and concentrated to solidity by distillation under reduced pressure. N-(6-methoxyindan-1-
ylmethyl)amine was converted to the hydrochloride salt using an ethereal solution of hydrochloric acid and recrystallized from Impropatol/diethyl ether. The melting point of the pure 6-methoxyindan-1-ylmethyl ammonium chloride obtained is 12
The temperature was 9-131°C.

5.1 g (28.7 mmol) of 6-methoxyindan-1-ylmethylamine produced from the latter was mixed with 7.4 g (86 mmol) of methyl acrylate in 60-methanol.
The whole solution was heated under reflux for 12 hours, the reaction mixture was concentrated by distillation, and the residue was purified by chromatography on 10 g of silica gel using cyclohexane. The crude N-[(6-methoxyindan-1-yl)methylcoiminodi(3-propionic acid) dimethyl ester obtained was further used in crude form.

Example 17 9.9 g (26 mmol) of N-((6-methoxyindan-1-yl)methyl]iminodi(3-propionic acid) diethyl ester and sodium hydride suspension 1 were prepared in the same manner as in Example 16. .63 g (34 mmol) to 4-hydroxy-1-[(6-methoxyindan-1
-yl)methyl]-1,2,5,6-tetrahydro-pyridine-, also known as 1-[(6-methoxyindan-1-yl)methyl2-4-oxo-piperidine-3-carboxylic acid ethyl ester .

The hydrochloride salt was precipitated from the crude base using an ethereal solution of hydrochloric acid and the hydrochloride salt was recrystallized from Impropatol/diethyl ether. The pure 4-hydroxy-1-[(6-methoxyindan-1-yl)methyl] obtained
-1,2,5,6-tetrahydro-pyridine- and 1-
[(6-methoxyindan-1-yl)methyl]-4-
The melting point of oxo-piperidine-3-carboxylic acid ethyl ester was 155-156°C.

The starting material can be prepared, for example, as follows: 6-Methoxyindan-1-ylmethylamine 10.2
g (56 mmol) and ethyl acrylate 17.2 g (1
72 mmol) was dissolved in 120 mmol of ethanol and kept under reflux for 24 hours. The obtained reaction product was concentrated and solidified by distillation under reduced pressure, and the obtained oily N-[(6-
Methoxyindan-1-yl) methylcoiminology (
3-Propionic acid) diethyl ester was purified by chromatography on 20 g of silica gel using cyclohexane.

Example 18 11.6 g (30 mmol) of N-[2-(6-methoxyindan-1-yl)ethyl coiminodi(3-propionic acid) diethyl ester was dissolved in 100 mmol of toluene, and the resulting solution was diluted with 50 mmol of toluene. % Sodium hydride 1.85g
(39 mmol) was added to a suspension of 50% of toluene at room temperature. The resulting reaction mixture was heated to 80°C for 3 hours. Thereafter, the external temperature was raised to 110-120°C and the mixture of ethanol and toluene was distilled off.

Cool the residue and add 100% ice-cold N-hydrochloric acid. Injected into J. The aqueous phase was separated, the organic phases were each extracted twice by shaking with 30-N-hydrochloric acid, the acidic aqueous portions were combined and made alkaline with saturated sodium bicarbonate solution. After extraction by shaking with diethyl ether/ethyl acetate, the organic phase was washed with phased sodium chloride solution and dried over magnesium sulphate. After removing the solvent, the oily residue obtained was filtered by chromatography on 10 g of silica gel using cyclohexane. 9.8 g of the purified base were converted to the hydrochloride salt with an ethereal solution of hydrochloric acid and the latter was recrystallized from Impropatol/diethyl ether. The obtained 4-hydroxy-1-[2-(6-methoxyindan-1-yl)ethyl]-1゜2.5,6-tetrahydraviridine, also known as 1-[2-(6-methoxyindan-1-yl)ethyl]-1゜2.5,6-tetrahydraviridine- The melting point of 1-yl)ethyl]-4-year-old xopiperidine-3-carboxylic acid ethyl ester hydrochloride was 140-145°C.

The starting materials can be prepared, for example, as follows: 12.8 g (50 mmol) of methanesulfonic acid (6-methoxyindan-1-ylmethyl) ester and 3.7 g (75 mmol) of sodium cyanide are dissolved in dimethyl Dissolved in sulfoxide 70- and the resulting solution was heated at 80° C. for 6 hours. The resulting reaction mixture was poured into 200 ml of ice water and extracted three times by shaking each time with 100 ml of toluene. The organic phases were combined, washed successively with saturated sodium chloride solution and dried over magnesium sulphate. Removal of the solvent under reduced pressure gave crude 2-(6-methoxyindan-1-yl)acetonitrile.

9.3 g (49 mmol) of crude 2-(6-methoxyindan-1-yl)acetonitrile were dissolved in 100 methanol and then after adding 1 g of Raney nickel and 20 g of liquid ammonia at 70-80 °C and 120 Parr pressure. Hydrogenated. After 3 hours, the catalyst was removed from the methanol solution and subsequently washed with methanol. The methanol solutions were combined and acidified with hydrochloric acid. This acidic solution was concentrated and solidified by distillation under reduced pressure, and the residue was dissolved in 100% water.
The mixture was dissolved in water, made alkaline using concentrated sodium hydroxide solution, and extracted by shaking with diethyl ether. The ether phase was washed with saturated sodium chloride solution and dried over magnesium sulphate. When the solvent is removed,
Crude 2-(6-medoxyingun-1-yl)ethylamine was obtained in the form of a yellow oil.

6.1 g (31.8 mmol) of 2-(6-medoxyingun-1-yl)ethylamide and 10 g (100 mmol) of ethyl acrylate were dissolved in ethanol 60-, and the resulting solution was dissolved. Refluxing was continued for 12 hours. Subsequently, the solvent was removed under reduced pressure and the residue was purified with 20 g of Florisil using cyclohexane to give the crude N-[2-(6
-Methoxyindan-1-yl)ethylcoimino-di(3-propionic acid) diethyl ester was obtained in the form of a yellow fluid oil.

Example 19 11.8 g of N-(6-methoxyindan-1-yl)-imino-di(3-propionic acid) diethyl ester
(32.4 mmol) was dissolved in 100 ml of toluene,
The obtained solution was added to 2.1 g of 50% sodium hydride dispersion.
(42 mmol) in toluene 50.7 suspension at room temperature. The resulting reaction mixture was heated at 80°C for 3 hours. Thereafter, the external temperature was raised to 110-120°C, and the ethanol and toluene mixture was distilled off. Subsequently, the reaction mixture obtained was cooled, poured into a mixture of 100°C of 2N hydrochloric acid and ice, extracted by shaking with diethyl ether, and the acidic aqueous phase was made basic with sodium bicarbonate solution.

The resulting mixture was diluted with diethyl ether/ethyl acetate (2:
Extracted by shaking with L), the organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using cyclohexane to give 4-
Hydroxy-1-(6-methoxyindan-l-yl)
-1゜2.5,6-tetrahydropyridine-1 Alternative name 1
-(6-methoxyindan-1-yl)-4-oxo-
Piperidine-3-carboxylic acid ethyl ester was obtained in the form of an oil. The latter was converted to the hydrochloride salt with an ethereal solution of hydrochloric acid and recrystallized from ethanol/diethyl ether. The obtained 4-hydroxy-1-(6-methoxyindan-1-yl)-1,2,5,6-tetrahydrobiridine and 1-(6-methoxyindan-1-yl)
yl)-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride had a melting point of 170-173°C.

The starting material can be prepared, for example, as follows: 9.5 g (50 g) of 6-methoxyindan-l-carboxylic acid
8.9 g (75 mmol) of thionyl chloride and 3 drops of diethylformamide were added to the solution obtained by dissolving 100 mmol of trichloromethane, and the whole mixture was kept under reflux for 1.5 hours.

The resulting reaction mixture was concentrated and solidified by distillation under reduced pressure, and then 50 rIJ of toluene was added. The mixture was again concentrated by distillation and the operation was repeated by adding another 50 d of toluene.

The obtained residue (10.8 g) was dissolved in dichloromethane 200-
0.32 g (1 mmol) of tetrabutylammonium bromide was added to the resulting solution, and a solution of 5.0 g (77 mmol) of sodium acetate in 70°C of water was added at 0°C. , the whole mixture was stirred at 0°C for 2 hours.

Thereafter, the organic phase was separated, the aqueous phase was subsequently washed with dichloromethane, the dichloromethane phases were combined and dried over magnesium sulfate at 0°C. 11.4 g (Zoo mmol) of trifluoroacetic acid was added to the combined dichloromethane solution. The entire mixture was boiled under reflux for 18 hours.

When the reaction mixture had cooled, ice was added and the resulting mixture was extracted by shaking with 1001 nl of saturated sodium bicarbonate solution and dried over magnesium sulfate. The solvent is removed and the resulting crystalline residue is crystallized from acetone/cyclohexane/petroleum ether, melting point 1.
Pure N-(6-methoxyindan-1-yl)-trifluoroacetamide was obtained at 28-136°C.

19 g (73 mmol) of N-(6-methoxyindan-1-yl)trifluoroacetamide was added to 30 g of methanol.
0J, and 100% of N-potassium hydroxide solution was added to the resulting solution at 40°C. The resulting strongly alkaline solution was stirred at room temperature for 12 hours, filtered through diatomaceous earth 7 times, washed successively with water and acidified with concentrated hydrochloric acid. The resulting solution was concentrated under reduced pressure, and the residue was made alkaline with concentrated sodium hydroxide solution and extracted by shaking with diethyl ether. The ethereal solution was washed with potable sodium chloride solution, dried over solid potassium hydroxide and concentrated under reduced pressure. An ethereal solution of hydrochloric acid was added to the resulting oily residue, and the precipitated hydrochloride salt was recrystallized from ethanol/diethyl ether. Obtained N chloride
-(6-Methoxyindan-1-yl)ammonium had a melting point of 253-254°C.

The base was liberated from 6.0 g (30 mmol) of N-(6-methoxyindan-1-yl)ammonium chloride using diethyl ether and 2N sodium hydroxide solution.

5.3 g (30 mmol) of the obtained base was added to 5.3 g (30 mmol) of ethanol.
9.0- of ethyl acrylate in the resulting solution.
g (90 mmol) was added thereto, and the mixture was boiled under reflux for 24 hours.

Thereafter, the mixture was allowed to stand at room temperature for 8 days. The solvent was removed under reduced pressure and the residue was purified on silica gel using cyclohexane. The resulting eluate was concentrated by distillation to give N-(5,-methoxyindan-1-yl)imino-di(3-propionic acid) diethyl ester in the form of an oily residue, which was further purified. I was able to use it without having to do anything.

Example 2O N-[(7-medoxy 1,2,3.4-tetrahydro-tit-1-yl)methylcoiminodi(3-propionic acid) diethyl ester 29.32 g (75 mmol) in dimethylformamide (200 J) 4.35 g of sodium hydride dispersion (50% in oil) in a solution of (9
0 mmol) was added little by little at room temperature with stirring. The resulting mixture was then stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated by distillation under high vacuum, cold 2N hydrochloric acid was added to the residue, and extraction was performed with diethyl ether. The hydrochloric acid extracts were combined and extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated again by distillation. Hot dissolution of the oily residue in acetone and subsequent cooling yields 4-hydroxy-1 with a melting point of 132-134°C.
-((7-medoxy1.2,3.4-tetrahydro-
1-[(7-Medoxy 1,
2,3.4-Tetrahydro-naphth-1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride crystallized.

The starting material can be prepared, for example, as follows: 19.1 g (100 mmol) of 1.2,3.4-tetrahydro-7-methoxy-naphth-1-ylmethylamine
22 g of ethyl acrylate (
220 mmol) was added, and the entire mixture was heated to 65°C.
The mixture was stirred for 48 hours. After cooling, the solvent was distilled under reduced pressure to yield N-[(7-medoxy-1,2,3.4-tetrahydro-naphth-1-yl)methyl]iminodi(propionic acid) diethyl ester as a reddish oil. obtained in the form.

Example 21 2.28 g (60 mmol) of sodium borohydride was stirred at 0 to 5°C, and then 4-hydroxy-1,2,5,
6-tetrahydro 1-[(7-medoxy 1.2,3
．． 4-tetrahydro-naphth-1-yl)methylcopyridine-3-carboxylic acid ethyl ester hydrochloride IL,
'45 g (3'0 mmol) of ethanol 150-
Added to the solution in small portions. The resulting mixture was stirred at 0-5°C for 1 hour, and the reaction mixture was concentrated under reduced pressure. Water was added to the residue and extracted with dichloromethane. The organic phases were combined, washed with water, dried over sodium sulfate and completely concentrated by distillation. 8.0 g of the obtained crude product, yellow oil, was purified using silica gel (0,040-0,063) 32 using a mixture of toluene and ethyl acetate (1:1).
Purified by 0g chromatography. In this way cis- and trans-4-hydroxy-1-[(-
7-Medoxy 1.2,3.4-tetrahydro-naphth-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester was obtained as a colorless oil.

Example 22 A toluene 20 solution of 2.06 g (18 mmol) of methanesulfonic acid chloride was stirred at 0 to 5°C, and then 4-hydroxy-1-[(7-medoxy-1.2,3.4-tetrahydro -naphth-1-yl)methylcopiperidine-3-
Cis/trans m4 of carboxylic acid ethyl ester 5
, 2 g (15 mmol) and 1,8-diazabicyclo[
5, 4.

0]-undes-7-nin 11.4 g (75 mmol)
was added to a 100% toluene solution. The reaction mixture was then allowed to warm to room temperature and stirred for a further 18 hours at room temperature. Ice water was added to the resulting reaction mixture, and the organic phase was extracted with 2N hydrochloric acid. The hydrochloric acid extracts were combined, made alkaline with concentrated sodium hydroxide solution, and extracted with dichloromethane. The organic phases were combined, washed with water, dried over sodium sulfate,
It was concentrated by distillation. 4.85 g of an oily residue is purified by chromatography on 240 g of silica gel (0.040-0.063) using toluene/ethyl acetate (9:1) to give 1-[(7-medoxy 1.2,
3.4-tetrahydro-naphth-1-yl)methyl]-
1.2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester was obtained in the form of a pale yellow oil.

The hydrochloride salt formed using hydrochloric acid in diethyl ether crystallizes from ethanol/diethyl ether and has a melting point of 177
~179°C (decomposition).

Example 23 5.45 g (15 mmol) of N-[(7-medoxy 1,2,3.4-tetrahydronaphth-2-yl)methyl]-iminodi(3-propionic acid) dimethyl ester
0.86 g (18 mmol) of a sodium hydride dispersion (50% in oil) was added in two portions to the dimethylformamide 55-solution at room temperature with stirring. After stirring the mixture for 2 hours, the resulting reaction mixture was completely concentrated by distillation under high vacuum. The resulting residue is cooled for 2
N-hydrochloric acid was added, and the mixture was extracted with diethyl ether. The aqueous hydrochloric acid extracts were combined and extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated by distillation. Dissolve the oily residue in hot acetone, add diethyl ether until the mixture becomes cloudy, and cool. Melting point 167~
4-hydroxy-1-[(7-medoxy-1) at 169°C
．． 2,3.4-tetrahydro-naphth-2-yl)methyl]-4.2,5,6-tetrahydro-pyridine-3-
Carboxylic acid methyl ester hydrochloride, also known as 1-[(7-medoxy 1,2,3゜4-tetrahydro-naphtho-2-
yl)methyl]-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride crystallized.

The starting material is 23.43 g of nearmethoxy 1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester, which can be prepared, for example, as follows.
A solution of 100 mmol) of anhydrous tetrahydrofuran 160 was added to a suspension of 3.79 g (100 mmol) of lithium aluminum hydride in anhydrous diethyl ether 160 over 30 minutes while stirring at room temperature. After the resulting mixture was stirred at room temperature for 1 hour, 3.8 parts of water, 3.8 parts of sodium hydroxide solution (15%) and 11.4 parts of water were added to the reaction mixture. The obtained precipitate was removed by suction, and the solution was concentrated and solidified by distillation under reduced pressure. The oily residue is dissolved in diethyl ether, washed with water, dried over sodium sulfate and concentrated by distillation to solidity to give 7-medoxy 1,2,3,4-tetrahydro-naphthalene-
2=methanol was obtained in the form of a yellow oil.

7-Medoxy 1.2,
3.4-tetrahydronaphthalene-2-methanol 19
．． Added to a solution of 2 g (100 mmol) of anhydrous pyridine 80-. The slightly exothermic reaction was continued at room temperature using a water bath. The reaction mixture was stirred at room temperature for 1 hour to complete the reaction, then diluted with ice water and extracted with diethyl ether. The organic phase was washed with 2N hydrochloric acid and water with ice cooling, dried over sodium sulfate, filtered and concentrated to solidity by distillation under reduced pressure. The resulting oil is crystallized from diethyl ether/pentane to give P-)luenesulfonic acid (7-medoxy 1.2,3.
4-tetrahydro-naphth-2-ylmethyl) ester was obtained.

A 10-solution of 3.9 g of sodium azide in water was mixed with 13.86 g of p-toluenesulfonic acid (7-medoxy 1,2°3.4-tetrahydro-naphth-2-ylmethyl) ester.
g (40 mmol) in ethanol 200-solution,
The mixture was boiled under reflux for 18 hours. After cooling, the alcohol was evaporated under reduced pressure, water was added to the residue, and extraction was performed with dichloromethane. The organic phase is washed with water, dried over sodium sulfate and concentrated by distillation to give (7-medoxy-1,2,3.4-tetrahydro-naphth-2-yl) in the form of a yellow oil.
Methyl azide was obtained.

A solution of 6.51 g (30 mmol) of (7-medoxy-1,2,3.4-tetrahydro-naphth-2-yl)methyl azide in 100% anhydrous tetrahydrofuran was dissolved in 1.14 g (30 mmol) of lithium aluminum hydride in anhydrous diethyl ether. 100 ml of the suspension was stirred and added to it over 30 minutes at room temperature. After stirring the resulting mixture at room temperature for 2 hours, the resulting reaction mixture was diluted with 1 part water and 1 part water.
4+aZ, sodium hydroxide solution (15%) 1.14-
and 3.4-hydrolyzed with water. The obtained precipitate was removed by suction 72, and the solution was concentrated by distillation under reduced pressure. The resulting oil was dissolved in diethyl ether and then in 2N hydrochloric acid. The hydrochloric acid extracts were combined, made alkaline using concentrated sodium hydroxide solution under cooling with water, and extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated by distillation under reduced pressure to give 7-medoxy 1.2,3.4-tetrahydro-naphth-2-ylmethylamine in the form of a yellow oil. . The melting point of the hydrochloride was 205-206°C.

3.78 g of methyl acrylate in a solution of 3.82 g (20 mmol) of 7-medoxy 1,2,3.4-tetrahydro-naphth-2-ylmethylamine in 60 WJ of methanol.
was added and the whole mixture was stirred at 65°C for 18 hours. After cooling, the reaction mixture was concentrated by distillation under reduced pressure to yield N-[(7-medoxy-1,2,3.4-tetrahydro-naphth-2-yl)methylcoimino-di(3-propionic acid) dimethyl ester. Obtained in the form of a reddish oil.

Example 24 P-) Luenesulfonic acid (7-medoxy 1°2.3.
4-tetrahydro-naphth-2-ylmethyl) ester 5.19 g (15 mmol) of dimethylformamide 7
5-To the solution was first added 3.66 g (16.5 mmol) of 1,2°5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester salt (guvacoline hydrobromide), then N 6.78 g (52.5 mmol) of -ethyl-N,N-diisopropylamine were added. The resulting mixture was stirred for 18 hours at so"c and then concentrated by distillation under high vacuum. Water was added to the residue and extraction was carried out with diethyl ether. The organic phase was washed with water and 2N
Extracted with hydrochloric acid. The hydrochloric acid extract was made alkaline with sodium hydroxide solution (30%) at low temperature and extracted with dichloromethane.

The organic phases were then combined, dried over sodium sulfate, and concentrated by distillation under reduced pressure to give 1-[(7-medoxy-1,2,3.4-tetrapyronaphth-2-yl)methyl]-1.2 ,5,6-titrahydrobiridine-3-
The carboxylic acid methyl ester was obtained in the form of a pale yellow oil.

The hydrochloride salt, formed using hydrochloric acid in diethyl ether, crystallizes from acetone/diethyl ether and has a melting point of 161
The temperature was ~163°C.

Example 25 A hexane solution of 17.44 n-butyllithium was mixed with 2.81 g of diisopropylamine and 3.0 g of anhydrous tetrahydrofuran.
- Added to solution at 0-5°C. The whole mixture was heated at room temperature for 30 minutes.
Stir for 1 minute, cool again to -15°C, 1-[(5-
A solution of 6.13 g (25 mmol) of methoxybenzocyclobuten-1-yl)methylcopiperidin-4-one in 30% of tetrahydrofuran was added. After 15 minutes, a solution of 3.05 g (28 mmol) of trimethylchlorosilane in tetrahydrofuran 15- was added dropwise to the resulting mixture.

The entire mixture obtained was stirred overnight at room temperature, filtered, and concentrated to solidity by distillation under reduced pressure to give 1-[(5
-methoxybenzocyclobuten-1-yl)methyl]-
4-1 Limethylsilyloxy-1,2,5,6-tetrahydrobiridine was obtained in the form of a pale yellow oil.

1-[(5-methoxybenzocyclobuten-1-yl)
methyl]-4-)limethylsilyloxy-1,2,5,
6.39 g (20 mmol) of 6-tetrahydroviridine was dissolved in 50 mmol of dichloromethane, and the resulting solution was mixed with 2.3 g (24 mmol) of chloroformic acid ethyl ester and 60 mg (2.4 mmol) of anhydrous zinc bromide. 50°C of dichloromethane was added dropwise to a solution cooled to 0°C. After heating the resulting mixture to room temperature and stirring for 1 hour, the mixture was poured with 150 ml of saturated sodium bicarbonate solution and
Extracted with dichloromethane.

The organic phases were combined, dried over sodium sulfate and concentrated by distillation. The residue was dissolved in 70% of ethanol and acidified with an ethanolic solution of hydrochloric acid.

Next, diethyl ether is added and when cooled, the melting point is 181 ~
4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1.2,5,6 at 182°C
-Tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-4-oxopiveridine-3-carboxylic acid ethyl ester hydrochloride crystallized.

The starting material can be prepared, for example, as follows: Methanesulfonic acid (5-methoxybenzocyclobutene-
To a solution of 12.11 g (50 mmol) of 1-ylmethyl) ester in 100 d of dimethylformamide was added first 8.45 g (55 mmol) of piperidone hydrochloride-hydrate and then N
-Ethyl-N,N-diisopropylamine 22.62g
(175 mmol) was added.

The resulting mixture was stirred at 80°C for 18 hours, then cooled and concentrated to solidity by distillation under reduced pressure. The residue was dissolved in diethyl ether and washed with water. The organic phase was separated and extracted with 2N hydrochloric acid. - The hydrochloric acid extracts were combined, made alkaline at low temperature using sodium hydroxide solution, and extracted with dichloromethane. The extracts were combined, dried over sodium sulfate, and concentrated and solidified by distillation under reduced pressure.

A dark brown resin was obtained, which was mixed with toluene/ethyl acetate (1:
1) using silica gel (0,040-0,063 m
m) Purification by chromatography using 350 g and 1-[(5-methoxybenzocyclobutene-
1-yl)methylcopyheridin-4-one was obtained in the form of a pale yellow oil.

The hydrochloride salt, prepared using hydrochloric acid in diethyl ether, crystallized from acetone/diethyl ether and had a melting point of -162-163°C.

Example 26 N-(7-methoxy 1,2,
10.48 g of 3.4-tetrahydro-naphth-2-yl)iminodi(3-propionic acid) dimethyl ester (
30 mmol) in anhydrous dimethylformamide 100-solution. The resulting reaction mixture was stirred at room temperature for 2 hours to complete the reaction, and concentrated and solidified by distillation under reduced pressure. Cold 2N hydrochloric acid was added to the residual liquid, and extraction was performed with diethyl ether. The combined aqueous hydrochloric acid extracts were extracted with dichloromethane, then the combined dichloromethane extracts were dried over sodium sulfate and concentrated by distillation. The oily residue was dissolved hot in acetonitrile and diethyl ether was added until the mixture became cloudy, at which time it cooled to give a melting point of 18°8-1.
4-Hydroxy-1-(7-medoxy-1.2,3.4-tetrahydro-naphth-2-yl) at 90°C (decomposition)
-1,2,5,6-tetrahydropyridine-, also known as 1
-(7-Medoxy 1.2,3.4-tetrahydro-naphth-2-yl)-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride crystallized.

The starting material can be produced, for example, as follows: 4.73 g (55 mmol) of methyl niaacrylate in 1.2
,3.4-tetrahydro-7-methoxy-naphtho-2-
4.43 g (25 mmol) of methanol 1
50 - added to the solution and the entire mixture obtained was heated under reflux for 24 hours.
heated for an hour. After that, 4.73g more methyl acrylate
(55 mmol) was added and further heated under reflux for 48 hours. After cooling, the reaction mixture is concentrated by distillation to give N-(7-medoxy 1,2,3.4-tetrahydro-naphth-2-yl)imino-di(3-propionic acid) dimethyl ester with a reddish color. It was obtained in the form of an oil.

Example 27 3-(7- 3-(7
-Medoxy 1,2,3.4-tetrahydro-naphtho-
2-ylamino)propionic acid ethyl ester could be prepared in each case.

Example 28 1.14 g (30 mmol) of sodium borohydride was mixed with 4-hydroxy-ni(7-medoxy-1.2,3.4-tetrahydro-naphth-2-yl)-1 while stirring at 0 to 5°C. , 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride was added in portions to a suspension of 5.3 g (15 mmol) of methanol 75. The resulting reaction mixture was stirred at 0-5°C for 1 hour to complete the reaction, and concentrated under reduced pressure. Water was added to this reaction mixture, and extraction was performed with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulfate and concentrated by distillation to give cis- and trans-4-hydroxy-1-(7-
Medoxy 1゜2.3.4-tetrahydro-naphtho-2
-yl)-piperidine-3-carboxylic acid methyl ester was obtained in the form of a yellow oil.

Example 29 A solution of 1.78 g (15.5 mmol) of methanelsulfonic acid chloride in 15-toluene was stirred at 0 to 5°C, and then cis- and trans-4-hydroxy-1-(7-medoxy-1)
．． 4.15 g (2,3.4-tetrahydro-naphth-2-yl)piperidine-3-carboxylic acid methyl ester (1
3 mmol) and 1,8-diazabicyclo[5,4,Ol
A solution of 9.89 g (65 mmol) of undes-7-nin in toluene 90 was added. The resulting reaction mixture was then warmed to room temperature and stirred for an additional 18 hours.
Ice water was added to the reaction mixture and the organic phase was extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts were made alkaline with concentrated sodium hydroxide solution, and the extraction was repeated with dichloromethane. The extracts were combined, washed with water, dried over sodium sulfate, and concentrated by distillation. The obtained crude product was purified with silica gel (0,0
40-0.06i3) 190 g of chromatographic purification yields 1-(7-medoxy-1.2,3.4-tetrahydro-naphth-2-yl)-1,2,5,6-tetrahydro-pyridine-3 The -carboxylic acid methyl ester was obtained as a yellow oil, which was crystallized from diethyl ether/pentane and had a melting point of 65-66°C.

The hydrochloride salt produced using hydrochloric acid in diethyl ether crystallizes from acetone/diethyl ether and has a melting point of 210-
The temperature was 212°C (decomposition).

Example 30 Methanesulfonic acid [2-(6-methoxyindan-1-
7.7 g (26 mmol) of N-ethyl ester were dissolved in 20 mmol of toluene, and the resulting mixture was dissolved in 6.3 g (28.6 mmol) of gubacoline hydrobromide and N-ethyl ester.
A solution of 12.7 g (57 mmol) of N,N-diisopropylamine in dimethylformamide 15- was added at room temperature. The resulting mixture was left at room temperature for 3 days, then the solvent was removed under reduced pressure at 40-50°C.

The obtained residue was dissolved in 2N hydrochloric acid, extracted by shaking with diethyl ether, and the acidic aqueous solution was made basic using water-cooled sodium hydrogen oxide.

The resulting mixture was extracted by shaking with diethyl ether, the ether phase was washed with saturated sodium chloride solution and dried over magnesium sulphate. Obtained 1-[
2-(6-methoxyindan-1-yl)ethyl]-1
．． The 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester was purified by chromatography on 6 g of silica gel using cyclohexane to give a yellow oil.

The crude base was converted to the hydrochloride salt using an ethereal solution of hydrochloric acid, and this was recrystallized from Impropatool/diethyl ether to give 1-[2-(6-methoxyindan-1
-yl)ethyl]-1,2°5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride was obtained, with a melting point of 145-148°C.

The starting material can be prepared as follows: 15.7 g (fromimole) of 6-methoxyindan-1-yl acetic acid are dissolved in 150 ml of tetrahydrofuran.

Thereafter, the resulting solution was added to a suspension of 4.3 g (114 mmol) of sodium borohydride in diethylene glycol 60 while stirring at 40 to 50°C, and boron trifluoride etherate 21 was added to the solution while stirring at 40 to 60°C. .6g (1
52 mmol) was introduced dropwise under a nitrogen stream. Upon completion of diporane formation (approximately 1 hour), the reaction solution was kept under reflux for 8 hours, cooled in a water bath, and 140 d of 1 molar sodium hydrogen phosphate solution were added slowly.

The resulting mixture was concentrated under reduced pressure, made alkaline with 2N sodium hydroxide solution, and extracted by shaking with diethyl ether. The ethereal solution was washed with saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave crude 2-(6-methoxyindan-1-yl)ethanol in the form of a yellowish viscous oil.

5.0 g (26.0 mmol) of crude 2-(6-methoxyindan-1-yl)ethanol was dissolved in 50 W of dichloromethane.
J and the resulting solution was dissolved in chlorinated methanesulfonic acid 3.
6 g (31 mmol) and triethylamine 3.6 g (
31 mmol) was added dropwise while cooling with ice. The resulting mixture was stirred at room temperature for 3 hours and extracted from the precipitated triethyl anchini chloride. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and heated at 40°C under reduced pressure.
When concentrated by distillation, methanesulfonic acid 2
-(6-methoxyindan-1-yl)ethyl ester was obtained, which could be used without further purification.

Example 31 1.5 NJ of concentrated hydrochloric acid was added to 4-hydroxy-1-[(5-methoxybenzocyclobuten-l-yl)methyl]-1.2
, 5,6-tetrahydro-pyridine-3-carboxylic acid nitrile salt 4.05 g (15 mmol) in 100 wJ of 95% ethanol and the entire mixture obtained was
Heated under reflux for an hour. After cooling, the entire mixture was heated under reduced pressure for approx.
This solution was mixed with 5 N-hydrochloric acid and toluene 20
- and then stirred and cooled, the melting point was 1.
4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1.2 at 81-182°C,
5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester salt, also known as 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester salt Crystallized.

The starting material is, for example, 10.5 g (0.1 mol) of nitriethylamine and 5.84 g (0.11 mol) of acrylonitrile, which can be prepared as follows: 3-(5-methoxybenzocyclobutene-1- 30.16 g (0.1 mol) of ethyl methylaminopropionic acid ester
was added to a 250-mL solution of ethanol, and the entire mixture was stirred at room temperature for 15 hours. The resulting reaction mixture was then concentrated under reduced pressure using a water pump, and the residue was dissolved in diethyl ether and washed with ice water until neutral. The ether solution was dried over potassium carbonate, filtered, and concentrated by distillation to yield 3-(N-(2-cyanoethyl)-N-(
(5-Methoxybenzocyclobuten-1-yl)methyl]amine)-propionic acid ethyl ester was obtained in the form of a yellow oil.

Sodium hydride (approximately 55% in mineral oil) 5', 3- (N-
A solution of 13.07 g (41.3 mmol) of (2-cyanoethyl) -N-[(5-methoxybenzocyclobuten-1-yl)methylcoamino)propionic acid in 200% tetrahydrofuran was added under a nitrogen atmosphere to form a mixture. The whole was stirred at room temperature for 16 hours. 2N sulfuric acid 70- was added to the resulting mixture to obtain a yellow solution. When diethyl ether 300- and water 1O- were mixed with this solution, two layers were formed. The aqueous layer was each extracted three times with 100-diethyl ether. The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure to approximately 100°C, and diluted with 5N hydrochloric acid 8.
0- and toluene 20-. After that, it was stirred and cooled, and 4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1°2.5
, 6-tetrahydro-pyridine-3-carboxylic acid nitrile salt and 1-[(5-methoxybenzocyclobutene-1
-yl)methyl]-4-oxo-piperidine-3-carboxylic acid nitrile-hydrochloride crystallized.

Example 32 Concentrated sulfuric acid 4- to 10.2 g (0,
04 mol) in 96% ethanol 200-solution and the entire mixture obtained was heated under reflux for 16 hours. After cooling,
The reaction mixture was concentrated under reduced pressure to 50°C. Residue 2004
of dichloromethane and 100-mL of water and neutralized with saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was re-extracted once more by shaking with 100 ml of dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered and concentrated by distillation. The crude product obtained was purified by chromatography on 250 g of silica gel and converted to the hydrochloride salt with an ethereal solution of hydrochloric acid.
Crystallized from ethanol/diethyl ether. Melting point 2
1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,2,5,6- at 04.5-205.5°C
Tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride was obtained.

The starting material can be prepared, for example, as follows: - methanesulfonic acid (5-methoxybenzocyclobutene-
1-ylmethyl) ester 42.2 g (0.1 mol),
11.9 g (0.11 mol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid nitrile and 15 [of N-ethyl-N,N-diisopropyl-amine] were dissolved in 250 g of dimethylformamide under a nitrogen atmosphere. , the entire mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to about 100°C, and 300°C of water was added to it, and 300°C of water was added to it, each by shaking with 150°C of dichloromethane.
Extraction was performed twice. The organic phases were combined, dried over sodium sulfate, filtered and concentrated by distillation. The residue was purified by chromatography on 500 g of silica gel using toluene/ethyl acetate (19:1) as eluent to obtain 1-
[(5-Methoxybenzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-
The carboxylic acid nitrile was obtained in the form of a yellow oil.

Example 33 Cis- and trans-4-bromo-1-((5-methoxybenzocyclobuten-1-yl)methylcobiperidine-3-carboxylic acid ethyl ester Jl/19, 1 g
(50 mmol) and anhydrous sodium acetate 8.2 g (0
, 1 mol) in 100 aj of glacial acetic acid was heated under reflux for 16 hours. After cooling, the reaction mixture obtained was concentrated and partitioned between dichloromethane and aqueous sodium carbonate solution, the organic phases were combined, dried over sodium sulfate and concentrated by distillation. The obtained cis- and trans-4-acetoxy-1-
[An oily mixture of (5-methoxybenzocyclobuten-1-yl)methylcobiperidine-3-carboxylic acid ethyl ester was chromatographed on 600 g of silica gel (
60, Merck) using trichloromethane/methanol (98:2) as eluent.

The trans isomer was isolated first, followed by the cis isomer. The hydrochloride salt was prepared from the latter using an ethereal solution of hydrochloric acid. The melting point was 202-203°C. The starting material can be prepared, for example, as follows: 1-[(5-methoxybenzocyclobuten-1-yl)
Methyl]-1,2,5,6-tetrahydro-pyridine-
4 g (0.1 mol) of 3-carboxylic acid ethyl ester 30, L were introduced in portions under stirring into 150 g of a 33% hydrogen bromide solution in glacial acetic acid. After stirring the resulting mixture at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane and aqueous sodium carbonate. The organic phase was dried over sodium sulfate and the solvent was distilled off under reduced pressure to give ethyl cis- and trans-4-bromo-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylate. A mixture of esters was obtained in the form of a yellow oil.

Example 34 A solution of 1 g (0.1 mol) of benzyl alcohol in 100% of tetrahydrofuran was dissolved in sodium hydride (50% in mineral oil).
% dispersion) 4.8 g of anhydrous tetrahydrofuran 100-
When the gas reaction was complete, the reaction mixture was heated under reflux for 6 hours, after cooling, 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1.2,5,6-
Tetrahydrofuran 2 of 30.14 g (0.1 mol) of tetrahydro-pyridine-3-carboxylic acid ethyl ester
The 00-solution was added and the whole mixture was again heated under reflux for 5 hours. After cooling, the solvent is concentrated by distillation to give cis- and trans-4-benzyloxy-1-[(5
-methoxybenzocyclobuten-1-yl)methyl]-
A mixture of piperidine-3-carboxylic acid ethyl ester was obtained in the form of an oil.

Example 35 Cis- and trans-4-benzyloxy-1-[(5
-Methoxybenzocyclobuten-1-yl)methylgobiperidine-3-carboxylic acid ethyl ester mixture to
, z4g (25mmol) in 95% ethanol 1501
2 g of 10% palladium loading capacity was added to the resulting solution, and the mixture was heated with a Parr apparatus at room temperature for 1 hour.
Hydrogenation was carried out for 2 hours. The resulting reaction mixture was filtered through diatomaceous earth and concentrated to solidity by distillation. The distillation residue is purified by chromatography on 400 g of silica gel using toluene/ethyl acetate (19:1) as eluent, initially trans-4-hydroxy-1-[(
5-methoxybenzocyclobuten-1-yl)methyl]
-piperidine-3-°carboxylic acid ethyl ester is isolated, followed by cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester. isolated. (Melting point of hydrochloride: 156-160°C) Example 36 1-[(5-methoxybenzocyclobuten-l-yl)
To a solution of 25.68 g (50 mmol) of methyl]-4-ethoxy-3-ethoxycarbonyl-pyridinium tosylate in 96% ethanol, 3.3 g of sodium borohydride was introduced over 30 minutes at 0° C. under a nitrogen atmosphere. did. The resulting mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours, and the resulting solution was concentrated by distillation under reduced pressure. 70% of water was added to the residue, and each extraction was performed three times with 100% of dichloromethane. The organic phases were combined, dried over magnesium sulphate and concentrated by distillation. 5N to the residue
Addition of a mixture of 80 wJ of salt solution and 20 wJ of toluene, followed by stirring and cooling, yields 4-hydroxy-1-[(5-methoxybenzocyclobutene-1) with a melting point of 181-182°C.
-yl)methyl]-1,2,4,5-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1
-((5-methoxybenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride crystallized.

The starting materials can be prepared, for example, as follows! 31.84 g (0,1
19.52 g of 4-ethoxynicotinic acid ethyl ester was added to a 150-mol solution of 95% ethanol, and the whole mixture was stirred at room temperature for 3 days. When the solvent was distilled off under reduced pressure, 1-[(5-methoxybenzocyclobuten-1-yl)
Methyl]-3-ethoxycarbonyl-4-ethoxy-pyridinium-tosylate was obtained in the form of a pale yellow foam.

Example 37 3-[N-(5-methoxybenzocyclobuten-1-ylmethyl)-N-(3
A solution of 12.78 g (40 mmol) of ethyl ester (-oxopropyl)-aminocopropionate in 100% dimethylformamide was added, and the entire mixture was stirred at 40°C.
The mixture was stirred for 3 hours. Thereafter, the solvent was distilled off under reduced pressure and the residue was chromatographed into components on 400 g of silica gel using dichloromethane/methanol (95:5) as eluent. First trans-4-hydroxy-
1-((5-methoxybenzocyclobuten-1-yl)
methyl]-piperidine-3-carboxylic acid ethyl ester was isolated, followed by cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester. isolated. The melting point of the latter hydrochloride was 156-160''0.

The starting material can be produced, for example, as follows.

3-(5-methoxybenzocyclobuten-1-ylmethylamino)propion ugly ethyl ester hydrochloride 30.1
6 g (0.1 mol) in dioxane 250° C. with 10.5 g (0.1 mol) of triethylamine and 20 g (0.11 mol) of 2-(2-bromoethyl)-1,3-dioxolane at 80°C. Stir for a while. After cooling, the solvent was distilled off under reduced pressure, and the residue was poured into diethyl ether and washed with ice water until neutral. The ether solution is dried over potassium carbonate and distilled to 5 liters to give 3-[N
-(1,3-dioxolan-2-yl)-N-(5-methoxybenzocyclobuten-1-ylmethyl)-aminocopropionic acid ethyl ester was isolated in the form of a yellow oil.

200 g of silica gel permeated with a 10% aqueous oxalic acid solution was mixed with 21.8 g of the obtained compound (
60 mmol) in dichloromethane 30() and the resulting suspension was stirred at room temperature for 3 hours. After filtration, 5
% aqueous sodium bicarbonate solution, and the organic phase was dried over sodium sulfate and concentrated by distillation under reduced pressure. For purification, the distillation residue was purified by chromatography on 600 g of silica gel using toluene/ethyl acetate (19:1) as eluent to give 3-[N-(5-methoxybenzocyclobuten-1-ylmethyl)-N-(3 -xoprovir)-
Aminocopropionic acid ethyl ester was obtained in the form of yellow sleeves.

Example 38 4-Hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,2°5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride 2 g (5,7 mmol) was introduced into 80° C. of dichloromethane at −80° C. under an argon atmosphere. While stirring, 1.08 i (11.3 mmol) of boron tribromide were metered in.

It was kept at -80°C for 30 minutes and then the resulting reaction mixture was gradually heated to 5°C over 2 hours with stirring. Thereafter, 40% of ethanol was carefully added and the entire mixture was then concentrated under reduced pressure with a water pump. The residue was diluted with ethanol 150. It was dissolved in aZ and again concentrated by distillation under reduced pressure using a water jet pump. This operation was repeated two more times. The resulting residue was then crystallized from ethanol/diethyl ether to give 4-hydroxy-1-[(5-hydroxybenzocyclobuten-1-yl)methyl]-1,2°5,6- Tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride and l-[(5-hydroxybenzocyclobutene-1
-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride was obtained.

Example 39 N-(benzocyclobuten-1-ylmethyl)imino-di(3-propionic acid) was prepared in the same manner as in Example 1.
24 g (72 mmol) of diethyl ester and 4.7 g (94 mmol) of sodium hydride (50% dispersion in mineral oil) were dissolved in 650 mmol of toluene to give a melting point of 182-1
4=Hydroxy-1-[(benzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride and 1-[(benzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride at 83°C. -1-yl)methyl]-
4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride was obtained.

The starting material N-[(benzocyclobuten-1-yl)methylcoiminodi(3-propionic acid) diethyl ester (the hydrochloride has a melting point of 87-89°C) was prepared from Example 1.
It could be produced from a solution of 15 g (114 mmol) of benzocyclobuten-1-ylmethylamine and 37-(340 mmol) of ethyl acrylate in 200 ml of ethanol in the same manner as described in .

Example 40 1.9 g (39 mmol) of sodium hydride (50% dispersion in mineral oil) and N-(5
-methoxy-1-methyl-ben-dicyclobutene-1-
4-Hydroxy-
(5-methoxy-1-methyl-benzocyclobutene-1
-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride and 1-
[(5-Methoxy-1-methyl-benzocyclobutene-
1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride could be prepared.

5-Methoxy-1-
Methyl-benzocyclobuten-1-ylmethylamine l
og (56 mmol) and ethyl acrylate 18. Z(
Melting point 1 from a 100-solution of ethanol (169 mmol)
N-(5-methoxy-1-methyl-benzocyclobuten-1-ylmethyl)imino-di(3
-propionic acid) diethyl ester hydrochloride was obtained.

The starting material can be prepared, for example, as follows: 5-methoxy-1-methyl-benzocyclobutene-1-
5 g (29 mmol) of carboxylic acid nitrile was dissolved in 50 mmol of ethanol, and 5 g (29 mmol) of liquid ammonia was added to the resulting solution.
290 mmol) and 1 g of Raney nickel were added. The reaction mixture was then hydrogenated for 1 hour at 90° C. and io'Pa. The cooled reaction mixture was filtered over diatoms and concentrated to solidity by distillation. The residue was dissolved in ethamer, converted to hydrochloride using mica acid, and crystallized by adding diethyl ether, giving a melting point of 159-160°C.
5-methoxy-1-methyl-benzocyclobuten-1-ylmethylammonium chloride was obtained.

Example 41 By the same operation as in Example 3, 4-hydroxy-1-[
(benzocyclobuten-1-yl)methyl] -1,2
, 3.2 g (10 mmol) of 5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride was added with a solution of 400 mg of platinum oxide in 100% ethanol,
When hydrogenated at 0'Pa, cis-4-hydroxy-1-[(benzocyclobutene-1-
Example 42 In the same manner as in Example 1, N-(benzocyclobuten-1-yl)imino-di(3- From 1 g of a toluene suspension of 5.9 g (16 mmol) of diethyl propionic acid and 50% sodium hydride, melting point 208-2
4-Hydroxy-1-(benzocyclobutene-
1-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-(benzocyclobuten-1-yl)-4-ogisobiperidine-3-carboxylic acid Ethyl ester hydrochloride could be produced.

Starting material N-(benzocyclobuten-1-yl)
Iminodi(3-propionic acid) diethyl ester was prepared using 3.5 g (29 mmol) of benzocyclobuten-1-yl-amine and 9.6 J (88 mmol) of ethyl acrylate in the same manner as described in Example 1. Ethanol 1
00.7 solution. Rf=0
, 3, hexani//ethyl acetate (4:1) Example 43 cis-4-hydroxy-1-, [(5-methoxybenzodiglobuten-1-yl)methyl]-piperidine-3-
2 g (5.6 mmol) of ethyl carboxylate salt and 20 d of anhydrous vinegar were mixed in 100 ml of toluene for 18 min.
Heated under reflux for an hour. Thereafter, 200 g of ice water was added to the cooled reaction mixture, and the entire mixture was stirred for 30 minutes. The resulting reaction mixture was made alkaline to pH 10 with 2N sodium hydroxide solution, and then the toluene phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated by distillation. The crude product thus obtained was purified by chromatography on a 10-fold volume of silica gel using diethyl ether as eluent.

The purified product was converted to hydrochloride and ethanol/
When crystallized from diethyl ether, melting point is 202-203
cis-4-acel-xy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-
3-carboxylic acid ethyl ester hydrochloride was obtained.

Example 44 By the same operation as in Example 5, cis-4-hydroxy-
1-[(benzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester 9.2 g
2 mmol), 9 m/(64 mmol) of triethylamine, 4.3 g (35 mmol) of 4-dimethylaminopyridine, and 2.7 d (35 mmol) of methanesulfonic acid chloride in a 100-dichloromethane solution as starting materials and 10 g of potassium hydroxide. Melting point 157-158°C by subsequent treatment at room temperature with an ethanol 140-solution of
1-[(benzocyclobuten-1-yl)methyl]
1.2,5,6-tetrahydro-pyridine-3-carboxylic acid ester hydrochloride could be produced.

Example 45 Trans-4-hydroxy-1-[(benzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester 3.8 g (J, 3 mmol), triethylamine 3,6-(26 mmol) ) and 1.8 g (14 mmol) of 4-dimethylaminopyridine were introduced into dichloromethane lO-. Chlorinated methanesulfonic acid 1.1- was added to the resulting mixture at room temperature. Afterwards, it was stirred for 30 hours, and the resulting reaction mixture was diluted with dichloromethane, washed three times with water, and dried over sodium sulfate. The obtained crude product was purified by silica gel chromatography, and the purified product was converted to the hydrochloride salt with an ethanolic solution of hydrochloric acid, and crystallized by adding diethyl ether to give trans-1-piperidine- at 145-146°C. 3-carboxylic acid ethyl ester hydrochloride was obtained.

The starting material was prepared in the same manner as in Example 4 to obtain 4-hydroxy-1-[(benzocyclobuten-1-yl)methyl].
- prepared from a solution of 8 g (28 mmol) of 1.2,5,6-titrahydrobiridine-3-carboxylic acid ethyl ester and 0.55 [(14 mmol) of sodium borohydride in 160% aqueous ethanol] Can be done.

Example 46 Cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester salt Ugly salt Ig (2.8 mmol)
and 20-25% ammonia water were stirred together with 5- ethanol at 60° C. for 8 hours in a pressure tube. The reaction mixture was then diluted with water and extracted twice with trichloromethane. The extract was dried over sodium sulfate and concentrated by distillation.

The obtained product is dissolved in methanol, methanesulfonic acid is added to adjust the pH to 3, and diethyl ether is added to crystallize it, resulting in 4-hydroxy- with a melting point of 167-177℃.
1-((5-methoxybenzocyclobuten-1-yl)
Methyl]-piperidine-3-carboxylic acid amide methanesulfonate was obtained.

Example 47 By the same procedure as in Example 1, sodium hydride (50% dispersion in mineral oil) Ig (20 mmol) and N-((5
-Chlorobenzocyclobuten-1-yl)methyl]-imino-di(3-propionic acid) diethyl ester from a solution of 4-hydroxy-1-[(5-10lobenzocyclobuten-1-yl)methyl]-imino-di(3-propionic acid) diethyl ester in toluene with a melting point of 161-163°C. Butene-1
-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as L
-[(5-chlorobenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride could be produced.

The starting material, N-[(5-glolopenzocyclobuten-1-yl)methylcoimino-di(3-propionic acid) diethyl ester hydrochloride with a melting point of 97-99°C, was prepared by the procedure described in Example 1. Similarly, 4 g (24 mmol) of 5-chlorobenzocyclobuten-1-ylmethylamine and 7.8 g of ethyl acrylate. /(72 mmol) from an ethanol 80-solution.

The melting point of the hydrochloride is 240-241°C, the necessary 5
-Talolopenzocyclobuten-1-ylmethylamine was prepared by the same procedure as in Example 6, including 5 g (31 mmol) of 5-chlorobenzocyclobutene-1-carboxylic acid nitrile and poran/dimethyl sulfide (10 g of 5-chlorobenzocyclobutene-1-carboxylic acid nitrile in tetrahydrofuran). mol) 4.6+J (46 mmol) of tetrahydrofuran 100-solution.

Example 48 1.7 g (36 mmol) of sodium hydride (50% dispersion in mineral oil) and N-[(
4-Methoxybenzocyclobuten-1-yl)methylcoiminodi(3-propionic acid) diethyl ester 1
0 g (27 mmol) of toluene 220. 4-hydroxy-1-[(4
-methoxybenzocyclobuten-1-yl)methyl]-
1.2,5,6-titrahydraviridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-[(4-methoxybenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-carvone Acid ethyl ester hydrochloride could be produced.

The starting material can be prepared in a similar manner to Example 1 as follows: 6.2 g (38 mmol) of 4-methoxybenzocyclobuten-1-ylmethylamine and 12 ethyl acrylate.
．． n! (112 mmol) to N-4(4-methoxybenzodiglobuten-1-yl)methylcoimino-di(
3-propionic acid) diethyl ester was obtained in the form of a viscous oil.

Rf=0.3. The required 4-methoxybenzocyclobuten-niylmethylamine, in which the melting point of hexane/ethyl acetate (4:1) hydrochloride is 208-210°C, was prepared in a manner similar to that described in Example 6. 13 g (80 mmol) of methoxybenzocyclobutene-1-carboxylic acid nitrile and poran/dimethylsulfide (10 mol in tetrahydrofuran) 12. It could be prepared from a solution of aZ (12 mmol) in 70% tetrahydrofuran.

Example 49 By the same procedure as in Example 1, 1.1 g (23 mmol) of sodium hydride (50% dispersion in mineral oil) and N-[
(5-methoxy-3-methyl-benzocyclobutene-1
From a solution of 6.6 g (17.5 mmol) of 4-hydroxy-1-[(5-methoxy-3-methyl)methylcoimino-di(3-propionic acid) diethyl ester in toluene, melting point 160-162°C, 1-[(5-methoxy-3,-methyl-benzocyclobutene) -1-yl)methyl]-4-oxo-
Piperidine-3-carboxylic acid ethyl ester hydrochloride could be produced.

The starting material can be prepared by the same procedure as in Example 1 as follows: 5-Methoxy-3-methyl-benzocyclobutene-1-
4.1 g (23 mmol) of ylmethylamine and 7,! of ethyl acrylate! M (69.5 mmol) to N-[(
5-Methoxy-3-methyl-benzocyclobutene-1-
yl)-methylcoimino-di(3-propionic acid) diethyl ester was obtained in the form of a viscous oil.

Rf=0.32, hexane/ethyl acetate (4: starting material is 5-methoxy-3-methyl-benzocyclobutene-1
- 4.4 g (25 mmol) of carboxylic acid nitrile in 5 g of ethanol with 0.5 g of Raney nickel and 5 g of ammonia.
It can be produced in the same manner as in Example 6 by hydrogenating the solution. The melting point of the hydrochloride is 228-229°C.

Example 50 Sodium hydride (50% dispersion in mineral oil) 110+wg (2.3 mmol) and N
-[2-(5-Methoxybenzocyclo-buten-1-ylidene)ethyl coiminodi(3-propionic acid) diethyl ester from a solution of 580 mg (1.5 mmol) in toluene in 60°C with a melting point of 167-169°C. Hydroxy-1-[2-(5-methoxybenzocyclobutene-1)
-ylidene)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-[2-(5-methoxybenzocyclobutene-1)
-ylidene)ethyl]-4-oxo-piperidine-3-
Carboxylic acid ethyl ester hydrochloride could be produced.

The starting material can be prepared as follows: 10 g (63 mmol) of 5-methoxybenzocyclobutene-1-carboxylic acid nitrile are heated under an argon atmosphere to -60
75,7' (75 mmol) of a 1 molar solution of diisobutylaluminum hydride in hexane was introduced slowly into 200 i of tetrahydrofuran at <RTIgt;° C.</RTI> under stirring.

The resulting reaction mixture was gradually warmed to room temperature and stirred for an additional 4 hours. Thereafter, 500 g of saturated ammonium chloride solution were added at room temperature and the whole mixture was subsequently stirred for 40 minutes. 220 d of 5% sulfuric acid was added and extraction was performed twice with diethyl ether. The organic phases were combined, dried and concentrated. The obtained crude product was purified by chromatography using 10 times the amount of silica gel to obtain 5-methoxybenzocyclobutene-1-lupoxaldehyde. Rf=0
．． 23. Hexane/ethyl acetate (9:1) 5-methoxybenzodiglobutene-1-lupoxaaldehyde 5,5
g (34 mmol) and 13.8 g (42 mmol) of cesium carbonate.
mmol) in dioxane 55, . Introduced to Z. Under stirring, phosphonoacetic acid triethyl ester 8
．． 7 g (39 mmol) were added and the entire mixture was heated on the go'c for 2 hours. The reaction mixture was then concentrated, dissolved in dichloromethane and washed with water. The organic phase was dried over sodium sulfate and concentrated by distillation. The obtained crude product was purified by silica gel chromatography to obtain 3-('5-methoxybenzocyclobuten-1-yl)acrylic acid ethyl ester.

Rf=0.5, hexane/diethyl ether (4:1) 3-(5-methoxybenzocyclobuten-1-yl)
7.3 g (31.5 mmol) of acrylic acid ethyl ester were stirred with 7 g (125 mmol) of potassium hydroxide in 50% aqueous ethanol 140°C at 50'0 for 5 hours. The resulting reaction mixture was adjusted to pH 1 with hydrochloric acid and extracted three times with dichloromethane. The organic extracts were combined, dried over sodium sulfate, and concentrated by distillation. The crude product was purified by silica gel chromatography,
When crystallized from diethyl ether/hexane, melting point 1
3-(5-Methoxybenzodiglobuten-1-ylidene)propionic acid at 34-137°C was obtained.

2.1 g (10 mmol) of 3-(5-methoxybenzocyclobuten-1-ylidene)propionic acid and 1.4 g (10 mmol) of triethylamine were introduced into 20 mmol of toluene under an argon atmosphere. Diphenylphosphoryl azide 2.2aZ (IO mmol) was added to the resulting mixture and the entire mixture was heated at 80° C. for 30 minutes with stirring. The resulting mixture was allowed to cool to room temperature, 2.9.7 (20 mmol) of 2-trimethyl-silylethanol was added and the entire mixture was heated to 80° C. for 7 hours. The reaction mixture was then concentrated to solidity on a rotary evaporator. The oily residue was taken up in diethyl ether, washed with water and 2N sodium hydroxide solution, dried over sodium sulfate and concentrated by distillation. The crude product was purified by silica gel column chromatography using a 1 molar solution of tetraammonium chloride in tetrahydrofuran.
7 (10 mmol) at 50° C. for 2 hours, and then concentrated to solidity by distillation. The residue was stirred vigorously with n-pentane/water (1:1) and the n-pentane phase was separated and discarded.

The aqueous phase was adjusted to pH 8 with ammonium chloride and a crystalline product precipitated. The resulting precipitate was filtered with suction. More product crystallized when the mother liquor was saturated with sodium chloride.

The crystalline products are combined, dissolved in trichloromethane/methanol (i:1), dried over sodium sulfate and concentrated by distillation to give a 0M crystalline residue, which is stirred with diethyl ether and then filtered, mp 238-240. ℃
2-(5-methoxybenzocyclobuten-1-ylidene)ethylamine was obtained.

2-(5-
580 ag (3.3 mmol) of methoxybenzocyclobuten-1-ylidene)ethylamine was dissolved in 20-
in which ethyl acrylate 1.1, J (9,9 mmol)
When reacted with N-[2-(5-methoxybenzocyclobuten-1-ylidene)ethyl
3-propionic acid) diethyl ester was formed. R
f=0.14. Hexane/ethyl acetate (4:1) Example 51 N-(6-
methoxyindan-2-yl)methyl]iminosis (
3-propionic acid) diethyl ester to 4-hydroxy-1-[(6-methoxyindan-2-yl)methyl]-1,2,5,6-tetrahydro-pyridine-, also known as 1-[(6-methoxyindan-2-yl)methyl] -2-yl)methyl]-
4-Oquine-piperidine-3ethylboxylic acid ethyl ester and their hydrochloride salts were obtained.

The starting material is, for example, 6-methoxyindan-1-one α
- metallization and reaction with chloroformic acid methyl ester to form 6-medoxy 1-oxo-indan-2-carboxylic acid methyl ester, which is hydrogenated with 6-methoxyindan-2-carboxylic acid methyl ester, hydrogenating Reduction with lithium aluminum hydride gave 6-methoxyindan-2-methanol, which was converted with methanesulfonic acid chloride/sodium azide and reduced again with lithium aluminum hydride to give 6-methoxyindan-2-ylmethyl. It can be obtained by reacting an amine with twice the molar amount of ethyl acrylate.

Example 52 Methanesulfonic acid (6-methoxyindan-2-methanol) obtained from 6-methoxyindan-2-methanol (see Example 51) analogously to the procedure described in Example 30.
1-[(6-methoxyindan-2-yl)methyl]-1.2,5 , 6-tetrahydro-pyridine-3-carboxylic acid methyl ester and its hydrochloride (melting point: 160-162°C) were obtained.

Example 53 6-Methoxyindan-2-carboxylic acid methyl ester is obtained via Tarthus decomposition via 6-methoxyindan-2-carboxylic acid azide in a similar manner to the procedure described in Example 1, and then From the obtained 6-methoxyindan-2-ylamine and methyl acrylate, 4-hydroxy-1-(6-methoxyindan-2
-yl)-1,2,5,6-tetrahydropyridine-, also known as t-(6-methoxyindan-1-yl)-4-
Oxo-piperidine-3-carboxylic acid methyl ester and its hydrochloride (melting point: 166-168°C) were obtained.

From the latter, 1-(6-methoxyindan-2-yl)-1,
2,5°6-tetrahydro-pyridine-3-carboxylic acid methyl ester and hydrochloride were obtained.

Example 54 1-[(5-methoxybenzocyclobuten-1-yl)
methyl]-1,2,5,6-tetrahydro-pyridine-
Catalytic hydrogenation of 3-carboxylic acid ethyl ester gives 1-
[(5-Methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester is obtained, which is hydrolyzed to give 1-[(5-methoxybenzocyclobuten-1-yl) Methyl]-piperidine-3-carboxylic acid and the respective hydrochloride salts were also obtained.

Example 55 Methanesulfonic acid (5-methoxybenzocyclobutene-
1-yl) methyl ester 7.27 g (30 mmol)
First, 5.66 g (36 mmol) of piperidine-3-carboxylic acid ethyl ester was added to a 60-solution of dimethylformamide, and then 9.70 g (75 mmol) of N-ethyl-N,N-diisopropylamine was added. . The mixture was heated at 60° C. for 18 hours and after cooling concentrated by distillation under high vacuum. The residue was dissolved in diethyl ether, washed with water, and the organic phase was extracted with 2N hydrochloric acid. The hydrochloric acid extracts were combined, made alkaline with sodium hydride solution at low temperature, and extracted with dichloromethane.The combined organic phases were dried over sodium sulfate and solidified by distillation under reduced pressure, yielding 1-((5- Methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester was obtained in the form of a yellow oil.

The hydrochloride salt produced using hydrochloric acid in diethyl ether crystallizes from ethanol/diethyl ether and has a melting point of 1
The temperature was 93-195°C (decomposed).

Example 56 1N sodium hydroxide solution 31,5,t(31,5
10 g (1.5 mmol) of 1-[(5-methoxybenzocyclobuten-1-yl)methylcopiperidine-3-carboxylic acid ethyl ester hydrochloride (1.5 mmol) was added to a 60-mL solution of ethanol. The resulting mixture was heated at room temperature for 5 minutes.
After stirring for a minute, 40°C of water is added and the mixture is heated to 50-60°C.
℃ and maintained at that temperature for 30 minutes. After cooling,
15 gJ of concentrated acid was added to the resulting solution, and the entire mixture was evaporated by distillation under reduced pressure. Heat the residue with acetone
50- and insoluble sodium chloride was separated. After concentrating the acetone solution to 50-, the melting point is 195-198
1-[(5-Methoxybenzocyclobuten-1-yl)methylcopiperidine-3-carboxylic hydrochloride at 10°C crystallized.

Example 57 2-(5
-methoxybenzocyclobuten-1-yl)ethylamine, 6-methoxyindan-1-ylmethylamine 2-(6-
medoxyindan-1-yl) ethylamine, 6-methoxyindan-1-ylamine, 7-medoxy1.2,3.4-tetrahydro-naphth-1-ylmethylamine, 5-hydroxybenzocyclobuten-1-yl Methylamine, benzocyclobuten-1-ylmethylamine, 5-chloro-benzocyclobuten-1-ylmethylamine, 4-methoxybenzocyclobuten-1-ylmethylamine, 5-methoxy-3-methyl-benzocyclo Butene-1-
ylmethylamine, 5-methoxy-1-methyl-benzocyclobutene-1.
-ylmethylamine, 2-(5-methoxybenzocyclobuten-1-ylidene)ethylamine and 6-methoxyindan-2-ylmethylamine, respectively, by reacting with equimolar amounts of ethyl acrylate in an ethanol solution. [2-(5-methoxybenzocyclobutene-1-
yl)ethylaminocopropionic acid ester, 3-(6-methoxyindan-1-ylmethylamino)
propionic acid ethyl ester, 3-[2-(6-methoxyindan-1-yl)ethylaminocopropionic acid ethyl ester, 3-(6-methoxyindan-1-ylamino)propionic acid ethyl ester, 3-(7- Medoxy 1,2,3,4-tetrahydro-
naphth-1-ylmethylamino)-propionic acid ethyl ester, 3-(5-hydroxybenzocyclobuten-1-ylmethylamino)propionic acid ethyl ester, 3-(benzocyclobuten-1-ylmethylaminopropionate ethyl ester) ester, 3-(5-chlorobenzocyclobuten-1-ylmethylamino)propionic acid ethyl ester, 3-(4-methoxybenzocyclobuten-1-ylmethylamino)propionic acid ethyl ester, 3-(5-methoxy -3-Methyl-benzocyclobuten-1-ylmethylamino)propionic acid ethyl ester, 3-(5-methoxy-1-methyl-benzocyclobuten-1-ylmethylamino/)propionic acid ethyl ester, 3- [2- (5-methoxybenzodiglobutene-1-
ylidene) ethylaminocopropionic acid ethyl ester and 3-(6-methoxyindan-2-ylmethylamine)
Propionic acid ethyl ester was obtained and 3-(6 -Medoxybenzocyclobuten-1-ylmethylamino)propionic acids and the respective acid addition salts, such as their hydrochlorides, were obtained.

Example 58 In a similar manner to the procedures described in Examples 13 and 26, 5-methoxybenzodiglobuten-1-ylmethylamine, 2-(5-methoxybenzocyclobuten-1-yl)
Ethylamine, 2-(indan-1-yl)ethylamine, 6-methoxyindan-1-ylmethylamine, 2-(6-methoxyindan-1-yl)ethylamine, 7-medoxy 1,2,3.4-tetrahydro 3-(5-methoxybenzocyclobuten-1-ylmethylamino)propion by reacting with equimolar amounts of acrylic methyl -naphth-2-ylmethylamine and 6-methoxyindan-2-ylmethylamine, respectively. acid methyl ester, 3-[2-(5-methoxybenzodiglobuten-1-yl)ethylaminocopropionic acid methyl ester, 3-(2-indan-1-ylethylamino)propionic acid methyl ester, 3-( 6-methoxyindan-1-ylmethylamine)
propionic acid methyl ester, 3-[2-(6-methoxyindan-1-yl)ethylaminocopropionic acid methyl ester, 3-(7-medoxindan-1-ylmethylaminocopropionic acid methyl ester and 3-(6- methoxyindan-2-ylmethylamino)
Propionic acid methyl esters were obtained and acid addition salts such as their hydrochlorides were obtained.

Example 59 As an active ingredient, for example, 4-hydroxy-1-[(5-
methoxybenzocyclobuten-1-yl)methyl]-1
, 2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-((5-methoxybenzocyclobuten-1-yl)methyl]-4-oxo-
Piperidine-3-carboxylic acid ethyl ester hydrochloride 1
Tablets containing 25B per tablet can be manufactured as follows.

Composition (per 1000 tablets) Active ingredient 25.0g lactose
100.7g wheat starch
7.5g polyethylene glycol 6000 5.0g talc
5.Og Magnesium stearate
1.8g deionized water suitable
All solid components are first passed through a sieve with a mesh width of 0.6 mm. Then, mix the active ingredients, lactose, talc, magnesium stearate and half the amount of starch. The remaining half of the starch is suspended in 40° of water and the resulting suspension is added to a circulating solution of polyethylene glycol in 100° of water. The resulting starch paste is added to the main raw material mixture and the resulting mixture is granulated, with water optionally added. The obtained granules were dried at 35° C. overnight, passed through a sieve with a mesh width of 1.2 mm, and compressed into tablets with a diameter of about 6 mm with depressions on both sides.

Example 60 Active ingredients include 1, for example, 4-hydroxy-1-[(
5-methoxybenzocyclobuten-1-yl)methyl]
-1.2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-r(5-7L toxybenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3- Tablets containing 50 rng per tablet of carboxylic acid ethyl ester hydrochloride can be manufactured as follows: Composition (per 10,000 tablets) Active ingredient 500.00 g Lactose
140.80g potato starch 274.70g stearic acid
10.00g talc
50.00g Magnesium stearate
2.50g=coidal silica 3
2.00 g of ethanol (appropriate amount) The active ingredient, lactose, and 194.70 g of potato starch were moistened with an ethanolic solution of stearic acid, and the whole was sieved to form granules. After drying, the remaining potato starch, talc, magnesium stearate and colloidal silica were added and mixed, and the resulting mixture was compressed into tablets weighing O and Ig, respectively. The tablet may, if desired, be provided with m-slits for dosing smaller doses.

It is also possible to mix 100 mg of the active ingredient per tablet by a similar operation.

Example 61 As an active ingredient, for example, 4-hydroxy-1-[(5-
methoxybenzocyclobuten-1-yl)methyl]-1
．． 2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride, also known as 1-[(5-methoxybenzocyclobuten-1-yl)methyl-4-oisopiperidine-3-carboxylic acid ethyl ester salt ## Capsules containing 0.025g of salt per capsule can be manufactured as follows: Red Crust (per 1,000 capsules) Active ingredient 25,00g lactose
249.00g gelatin
2.00g corn starch to, oog talc
15,00g water
An appropriate amount of the active ingredient is mixed with lactose, the resulting mixture is uniformly moistened with an aqueous gelatin solution, the whole is passed through a sieve with a mesh width of 1.2 to 1.5 am, and the resulting granules are mixed with dried cornstarch and talc. Mix,
Place the resulting mixture in 3 hard gelatin capsules (size 1).
00 mg each.

In a similar manner to the operations described in Examples 59-61,
Different compounds of general formula 1, such as those according to Examples 1 to 56, or compounds 1 of general formula rVc, such as Example 5
It is also possible to produce medicaments containing those according to 7.

Claims (1)

[Claims] 1. Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula, R_1 is carboxy, lower alkoxycarbonyl, carbamoyl (carbamyl), N-lower alkylcarbamoyl, or N,N- represents di-lower alkylcarbamoyl, R_2 represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, R_3 represents the formula R-(I a), R-al
k_1-(Ib) or R'=alk_2-(Ic), where R is unsubstituted or 1 in the benzene moiety
substituted with one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl, and/or substituted with lower alkyl in the alpha position and bonded via a saturated carbon atom represents benzocycloalkenyl having a total number of ring carbon atoms of 8 to 12, and R' is unsubstituted or in the benzene moiety is one or more hydroxy, lower alkoxy,
represents a benzocycloalkylidene residue having a total number of ring carbon atoms of 8 to 12 substituted with lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl,
alk_1 represents lower alkylene or lower alkylidene, alk_2 represents lower alkyl-ω-ylidene,
Novel hydropyridine-derivative compounds, and tautomers and/or salts thereof, in the above formula (I), in which the dotted line represents that there may be a single bond or especially a double bond. 2, R or R' is unsubstituted or one or more, for example two or three, in the benzene moiety;
Benzocyclobutene substituted with hydroxy, lower alkoxy, lower alkanoyloxy and/or with halogen and/or substituted with lower alkyl in the α-position
1-yl residue, benzocyclobuten-1-ylidene residue, indan-1-yl- or indan-2-yl residue or 1,2,3,4-tetrahydronaphth-1-yl or 1,2, Represents a 3,4-tetrahydronaphth-2-yl residue, R_1 represents carboxy, lower alkoxycarbonyl or carbamoyl, R_2 represents hydrogen, hydroxy, lower alkoxy, lower alkanoyloxy, lower alkanesulfonyloxy, optionally in the phenyl moiety represents lower alkyl, lower alkoxy-substituted and/or halogen-substituted phenyl-lower alkoxy or amino, alk_1 connecting both ring systems via 1 or 2 or no more than 3 C-atoms, respectively; Compounds according to claim 1, which represent a lower alkylene or lower alkylidene linking and alk_2 represents a lower alkyl-ω-ylidene linking both ring systems via 2 or 3 C-atoms, and tautomers and/or salts thereof. 3. R_3 represents a group Ia or Ib, and R is unsubstituted or in the benzene moiety lower alkoxy having up to 4 carbon atoms, such as methoxy; lower alkyl having up to 4 carbon atoms, such as methyl, or an atom 35 or less monosubstituted with halogen, for example chlorine, or lower alkyl having up to 4 carbon atoms in the benzene moiety, such as methyl, or lower alkoxy having up to 4 carbon atoms, such as methoxy, as well lower alkyl having up to 4 carbon atoms, for example benzocyclobuten-1-yl, indan-1-yl or secondly indan-2-yl or 1,2, 3,4
-tetrahydronaphth-1-yl residue, R_1 is lower alkoxycarbonyl, especially 2 to 5 C-
lower alkoxycarbonyl having atoms, for example ethoxycarbonyl, or carbamoyl, R_2 represents hydrogen or hydroxy and alk_1 bridges the ring system via up to 1 to 3 C-atoms, lower alkylene;
2. Compounds according to claim 1 representing lower alkylene, in particular having up to 3 C-atoms, such as methylene, and tautomers and/or salts thereof. 4, R_3 represents a group of formula Ib, R represents a benzocyclobuten-1-yl residue unsubstituted or substituted in the benzene moiety by lower alkoxy having up to 4 carbon atoms, for example methoxy; R_1 represents lower alkoxycarbonyl, especially one having from 2 to 5 carbon atoms, such as ethoxycarbonyl or carbamoyl, R_2 represents hydrogen or hydroxy, alk_1
Compounds according to claim 1, in which represents lower alkylene bridging the ring system via 1 to 3 carbon atoms, in particular those having 3 or less carbon atoms, such as methylene, and also their Tautomers and/or salts. 5. The compound is 4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)-methyl]-1,2,5
, 6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥1-[(5-methoxybenzocyclobuten-1-yl)-methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester; 4 -Hydroxy-
[(5-methoxybenzocyclobuten-1-yl)-methyl]-1,2,5,6-tetrahydro-pyridine-3
-Carboxylic acid methyl ester, ¥1-[(5-methoxybenzocyclobuten-1-yl)-methyl]-4
-Oxo-piperidine-3-carboxylic acid methyl ester; cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)-methyl]-piperidine-3
-carboxylic acid ethyl ester; trans-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)-methyl]-piperidine-3-carboxylic acid ethyl ester; 1-[(5-methoxybenzocyclobuten-1-yl)-methyl]-carboxylic acid ethyl ester; -1
-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester; 4-hydroxy-1-[2-(5-methoxybenzocyclobutene-1
-yl)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥-1
-[2-(5-methoxybenzocyclobuten-1-yl)-ethyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester; cis-4-hydroxy-1-[2-
(5-methoxybenzocyclobuten-1-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester; trans-4-hydroxy-1-[2-(5-methoxybenzocyclobuten-1-yl)ethyl]- piperidine-3
-Carboxylic acid ethyl ester; 1-[2-(5-methoxybenzocyclobuten-1-yl)ethyl]-1,2,
5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester; 4-hydroxy-1-[2-(5-methoxybenzocyclobuten-1-yl)-ethyl]-1,2
,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, ¥-1-[2-(5-methoxybenzocyclobuten-1-yl)-ethyl]-4-oxo-piperidine-3-carvone acid methyl ester; 4-amino-1-[(5-methoxybenzocyclobutene-1-
yl)-methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester and 1-[(5
-methoxybenzocyclobuten-1-yl)-methyl]
-4-imino-piperidine-3-carboxylic acid ethyl ester; 1-[2-(indan-1-yl)ethyl]-1
, 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester; 1-[(6-methoxyindan-1
-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester; 4-hydroxy-1-[(6-methoxyindan-1-yl)methyl]-1,2,5 , 6-tetrahydro-pyridine-3-carboxylic acid methyl ester also known as 1-[(6-methoxyindan-1-yl)methyl]-4-oxo-piperidine-
3-carboxylic acid methyl ester; 4-hydroxy-1-
[(6-methoxyindan-1-yl)methyl]-1,
2,5,6-Tetrahydro-pyridine-3-carboxylic acid ethyl ester￥Alternative name￥1-[(6-methoxyindan-1-yl)methyl]-4-oxo-piperidine-3-
Carboxylic acid ethyl ester; 4-hydroxy-1-[2
-(6-methoxyindan-1-yl)ethyl]-1,
2,5,6-Tetrahydro-pyridine-3-carboxylic acid ethyl ester￥Alternative name￥1-[2-(6-methoxyindan-1-yl)ethyl]-4-oxo-piperidine-
3-carboxylic acid ethyl ester; 4-hydroxy-1-
(6-methoxyindan-1-yl)-1,2,5,6
-Tetrahydro-pyridine-3-carboxylic acid ethyl ester￥Alternative name￥1-(6-methoxyindan-1-yl)
-4-oxo-piperidine-3-carboxylic acid ethyl ester; 4-hydroxy-1-[(7-methoxy-1,2
,3,4-tetrahydro-naphth-1-yl)methyl]
-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester￥Alternative name￥1-[(7-methoxy-
1,2,3,4-tetrahydro-naphth-1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester; 3,4-Tetrahydro-naphth-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester; trans-4-hydroxy-1-[(7-methoxy-1,2,3,4-tetrahydro-naphtho- 1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester; 1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-1-yl)-methyl]-1,2,5, 6
-tetrahydro-pyridine-3-carboxylic acid ethyl ester; 4-hydroxy-1-[(7-methoxy-1,2
,3,4-tetrahydro-naphth-2-yl)methyl]
-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl)
methyl]-4-oxo-piperidine-3-carboxylic acid methyl ester; 1-[(7-methoxy-1,2,3,4
-tetrahydro-naphth-2-yl)methyl]-1,2
,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester; 4-hydroxy-1-(7-methoxy-
1,2,3,4-tetrahydro-naphth-2-yl)-
1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, ¥1-(7-methoxy-1
,2,3,4-tetrahydronaphth-2-yl)-4-
Oxo-piperidine-3-carboxylic acid methyl ester;
cis-4-hydroxy-1-(7-methoxy-1,2,
3,4-Tetrahydro-naphth-2-yl)-piperidine-3-carboxylic acid methyl ester; trans-4-hydroxy-1-(7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl) )-piperidine-3-carboxylic acid methyl ester; 1-(7-methoxy-1,2,
3,4-tetrahydro-naphth-2-yl)-1,2,
5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester; 1-[2-(6-'methoxyindan-1
-yl)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester; cis-4-acetoxy-1-[(5-methoxybenzocyclobutene-
1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester; trans-4-acetoxy-1-[(5-
Methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester lysis-4-
Penzyloxy-1-[(5-methoxy-benzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester; trans-4-benzyloxy-
1-[(5-methoxybenzocyclobuten-1-yl)
methyl]-piperidine-3-carboxylic acid ethyl ester; 4-hydroxy-1-[(5-hydroxybenzocyclobuten-1-yl)-methyl]-1,2,5,6-tetrahydro-pyridine-3-carvone Acid ethyl ester, ¥1-[(5-hydroxybenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-
Carboxylic acid ethyl ester; 4-hydroxy-1-[(
benzocyclobuten-1-yl)methyl]-1,2,5
, 6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥1-[benzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester; 4-hydroxy-[( 5-methoxy-1-methyl-benzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥1-[(5-methoxy-1 cis-4-hydroxy-1-[(benzocyclobuten-1-yl)methyl]-piperidine- 3-Carboxylic acid ethyl ester; 4-hydroxy-1-(benzocyclobuten-1-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥1-(benzocyclobuten-1-yl) buten-1-yl)-4-oxo-piperidine-3-carboxylic acid ethyl ester; cis-4-acetoxy-1[(5-methoxy-benzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid Ethyl ester; 1-[(benzocyclobutene-1
-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester; trans-1
-[(benzocyclobuten-1-yl)methyl]-4-
Methane-sulfonyloxy-piperidine-3-carboxylic acid ethyl ester; 4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid amide; 4-hydroxy-1[ (
5-chlorobenzocyclobuten-1-yl)-methyl]
-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥1-[(5-chlorobenzocyclobuten-1-yl)methyl]-4-oxo-
Piperidine-3-carboxylic acid ethyl ester; 4-hydroxy-1-[(4-methoxybenzocyclobutene-1
-yl)-methyl]-1,2,5,6-tetrahydro-
Pyridine-3-carboxylic acid ethyl ester, ¥1
-[(4-methoxybenzocyclobuten-1-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester; 4-hydroxy-1-[5-methoxy-3
-methyl-benzocyclobuten-1-yl)methyl]-
1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥1-[(5-methoxy-
3-Methyl-benzocyclobuten-1-yl)]-4-
Oxo-piperidine-3-carboxylic acid ethyl ester;
4-Hydroxy-1-[2-(5-methoxybenzocyclobuten-1-ylidene)ethyl]-1,2,5,6-
Tetrahydro-pyridine-3-carboxylic acid ethyl ester, ¥1-[2-(5-methoxybenzocyclobuten-1-ylidene)ethyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester; 4-hydroxy −
1-[(6-methoxyindan-2-yl)methyl]-
1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester; 1-[(6-methoxyindan-
2-yl)methyl]-4-oxo-piperidine-3-carboxylic acid ethyl ester; 1-[(6-methoxyindan-2-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3- Carboxylic acid methyl ester; 1-(
6-methoxyindan-2-yl)-1,2,5,6-
Tetrahydro-pyridine-3-carboxylic acid methyl ester; 1-(6-methoxyindan-2-yl)-1,2
,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester; 1-[(5-methoxybenzocyclobuten-1-yl)methyl]piperidine-3-carboxylic acid ethyl ester or 1-[(5-methoxybenzobenzo The compound according to claim 1, which is cyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid, and salts thereof. 8. Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula, R_1 represents carboxy, lower alkoxycarbonyl, carbamoyl (carbamyl), N-lower alkylcarbamoyl, or N,N-dilower alkylcarbamoyl. , R_2 represents hydrogen, an optionally etherified or acylated hydroxy group, or an optionally acylated amino group; R_3 represents the formula R-(I a), R-alk_1-(
I b) or R' = alk_2-( I c), where R is unsubstituted or in the benzene moiety one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or tri- represents a benzocycloalkenyl residue substituted with fluoromethyl and/or substituted with lower alkyl in the alpha position and having a total number of ring carbon atoms of 8 to 12 bonded via saturated carbon atoms, R' The total number of ring carbon atoms substituted with one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl in the substituted or benzene moiety is from 8 to
12 benzocycloalkylidene residues, alk_
1 represents lower alkylene or lower alkylidene, al
k_2 represents lower alkyl-ω-ylidene, and the above formula (
I), in which the dotted line represents that there may be a single bond or especially a double bond, and a method for producing novel hydropyridine derivative compounds, as well as tautomers and/or salts thereof, , a) Formula IIa: R_3-X_1(IIa) (In the formula, X_1 represents hydroxy or reactive esterified hydroxy) or its salt as Formula IIb: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IIb) b) Formula III: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) {In the formula, X_2 represents a residue that can be converted to R_1} or c) compounds of formula I {wherein R_2 represents hydroxy or amino and R_1 especially represents lower alkoxycarbonyl}, in the compound or its tautomer or salt, X_2 is converted to R_1, or For the production of tautomers and/or salts of formula IV: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) {where Y_1 is the formula -CH=R_2', C(Y_2)-
R_2′ or a cyano group, R_2′ represents oxo or imino, and Y_2 represents a removable residue}, or a salt thereof is cyclized; For the production of compounds, their tautomers and/or salts (R_2 represents hydroxy or amino and the dotted line represents the presence of a double bond, and R_1 particularly represents lower alkoxycarbonyl) Formula Va: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Va) The compound of formula Vb: X_3-R_1(Vb) {where X_3 represents halogen or lower alkoxy }
or e) a compound of formula I {wherein R_2 is different from hydrogen}
For the preparation of compounds, their tautomers and/or salts, the formula VI: ▲Mathematical formulas, chemical formulas, tables, etc.▼(VI) {In the formula, X_4 represents a residue that can be converted into R_2 } or salts thereof; ,formula
VII: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VII) {In the formula, A＾■ represents an acid anion, R_2″ is hydrogen, and further etherified esterified or protected hydroxy or acylated or protected represents the amino acid}
In the compound, the excess double bonds are reduced to single bonds and any protective groups present are removed and, if desired, the compounds obtained by this or other methods are converted to formula I
The isomer mixture obtained by this method is separated into each component, the enantiomeric mixture or diastereomeric mixture obtained by this method is separated into individual enantiomers or diastereomers, and the isomer mixture obtained by this method is separated into individual enantiomers or diastereomers. A production process characterized in that the free compound obtained by the process is converted into a salt and/or the salt obtained by the process is converted into a free compound or another salt. 7. Formula IVc: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IVc) In the formula, R_1 is carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, or N
, N-di-lower alkylcarbamoyl, and R_3 has the formula R-(I a), R-alk_1-(I b) or R'=
alk_2-(Ic), where R is unsubstituted or substituted in the benzene moiety with one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl and/or substituted with lower alkyl in the α-position and having a total number of ring carbon atoms of 8 to 12 and bonded via saturated carbon atoms,
R' is unsubstituted or substituted in the benzene moiety by one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl, having a total number of ring carbon atoms of 8 to 12;
represents a benzocycloalkylidene residue, alk_1 represents lower alkylene or lower alkylidene, and alk_1 represents a lower alkylene or lower alkylidene residue;
2 represents a lower alkyl-ω-ylidene residue; when R_1 represents lower alkoxycarbonyl or carbamoyl, R_3 represents the group Ia, R represents indan-2-yl and lower alkyl, lower is different from indan-2-yl substituted with alkoxy or halogen, and when R_1 represents carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R is 1,2, Novel 3-aminopropionic acid derivatives, which are different from 3,4-tetrahydronaphth-2-yl, and salts thereof. 8, g) Formulas VIIIa and VIIIb R_3-Z_1(VIIIa) Z_2-CH_2-CH(Z_3)-R_1(VIIIb)
{wherein one of the residues Z_1 and Z_2 represents a reactive esterified hydroxy, the other represents an amino and Z_3 represents hydrogen, or Z_1 is an amino and Z_2 and Z_3 jointly represent a further bond } with each other, and then, if necessary, converting the compound obtained by this or other methods into other compounds of formula IVc and separating the isomeric mixture obtained by this method into its components. , separating the enantiomeric or diastereomeric mixture obtained by this method into each enantiomer or each diastereomer, converting the free compound obtained by this method into a salt, and/or
Or, the method for producing a novel 3-aminopropionic acid derivative according to claim 7, characterized in that the salt obtained by this method is converted into a free compound or other salt. 9. Claims 1 to 5 as active ingredients
Compound or formula IVc described in any one of the following paragraphs: ▲Mathematical formula, chemical formula, table, etc.▼(IVc) In the formula, R_1 is carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, or N
, N-di-lower alkylcarbamoyl, and R_3 has the formula R-(I a), R-alk_1-(I b) or R'=
alk_2-(Ic), where R is unsubstituted or substituted in the benzene moiety with one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl and/or substituted with lower alkyl in the α-position and having a total number of ring carbon atoms of 8 to 12 and bonded via saturated carbon atoms,
R' is unsubstituted or substituted in the benzene moiety by one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl, having a total number of ring carbon atoms of 8 to 12;
represents a benzocycloalkylidene residue, alk_1 represents lower alkylene or lower alkylidene, and alk_1 represents a lower alkylene or lower alkylidene residue;
2 represents a lower alkyl-ω-ylidene residue; when R_1 represents lower alkoxycarbonyl or carbamoyl, R_3 represents the group Ia, R represents indan-2-yl and lower alkyl, lower 3-aminopropionic acid derivatives, which are different from alkoxy- or halogen-substituted indan-2-yl, or their pharmaceutically acceptable salts, together with customary pharmaceutical adjuvants, are added to the active ingredients as described above. A drug containing by mixing with commonly used pharmaceutical adjuvants. 10. As an active ingredient, formula IVc: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IVc) In the formula, R_1 is carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, or N
, N-di-lower alkylcarbamoyl, and R_3 has the formula R-(I a), R-alk_1-(I b) or R'=
alk_2-(Ic), where R is unsubstituted or substituted in the benzene moiety with one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl represents a benzocycloalkenyl residue having a total number of 8 to 12 ring carbon atoms and substituted with lower alkyl in the α-position and/or in the α-position and bonded via saturated carbon atoms; R′ is unsubstituted or in the benzene moiety; Total number of ring carbon atoms substituted with one or more hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl from 8 to 1
2 represents a benzocycloalkylidene residue, alk_1
represents lower alkylene or lower alkylidene, alk
A stimulant containing a 3-aminopropionic acid derivative, wherein _2 represents a lower alkyl-ω-ylidene residue.