JPH01104054A - Imidazolinyl derivative of dihydronaphthalene and tetrahydronaphthalene - Google Patents

Abstract

NEW MATERIAL: A compd. of formula I (wherein A is formula II, -CH= or -CH₂-, etc.; R is H, a 1-6C alkyl or phenyl; R₁ is H, a 1-6C alkyl, phenyl, 1-4C alkyl; each of X₁ to X₄ is H, hydroxy, a halogen, 1-6C alkyl or 1-6C alkoxy, etc.), and its salts.

EXAMPLE: 3,4,-Dihydro-2-(2-imidazolin-2-yl)-1(2H)-naphthalenone.

USE: The compd. exhibits an action for regulating noraldorenarin or serotonin balance. It is useful for migraine, thrombosis, diabetes, obesity, senile dementia and alcoholism as well as useful as an antihypertensive agent andantidepressant.

PROCESS: A compd. of formula III (wherein R₂ is a 1-4C alkyl; Y is a halogen) is allowed to react with a compd. of formula IV in a solvent such as ethanol at the room temp. to 100°C to obtain the compd. of the formula I (the case that A being the formula II).

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1,2-dihydronaphthalene and 1,2,3
゜2-imidazoline of 4-tetrahydronaphthalene...
The present invention relates to 2-yl derivatives, processes for their preparation, and pharmaceutical compositions containing them.

The present invention is based on the following general formula (■); In formula 1, A is -C-, -CH-, -CH= or -CH2-; R is hydrogen, C1-C6 alkyl or phenyl; R is Hydrogen, 01-C6 alkyl or phenyl-C1-C
4 alkyl; Xl, X2. Each of X3 and x4 may be the same or different, hydrogen, hydroxy, halogen.

01-C6 alkyl, 01-C6 alkoxy or tri-C-C4 alkyl: or x1, X32. ×3
and one of x4 is hydroxy, halogen, C1 to C4
phenyl, phenylthio, substituted or unsubstituted on each phenyl ring with 1, 2 or 3 substituents independently selected from alkyl and 01-C4 alkoxy;
a W1 substituent selected from phenoxy and benzyl;
and pharmaceutically acceptable salts thereof.

The present invention encompasses all possible isomers of formula (I) and mixtures thereof as well as metabolites and H 2 metabolic precursors of compounds of formula (I). Compounds of formula (I) in which A is 10H- may be in the cis or trans configuration. Cis and trans isomers, alone and mixtures thereof, are included within the scope of this invention.

Compounds of formula (I) wherein A is -C-, i.e. formula (Ia
) has two other tautomeric structures, namely the formula (
A vine represented by the enol structure of Ib) and the enone-imidazolidine 4 structure of formula (Ic).

(Engineer
(In the Ic21 formula, Xl, X2.X3.X4.R
and R1 are as defined above. In fact, when such compounds exist in the free base form, they can exist and be isolated in the (Ib) or (IC) structures as evidenced by spectroscopic data. However, in the Suimon i11 book, such a compound has the formula (I
It is expressed as the compound of a). The above formula where A is -C- (
When the compounds of I) are isolated in salt form, for example the hydrochloride, they are only present in the keto form of formula (Ia), as evidenced by spectroscopic data.

Commercially acceptable salts of compounds of formula (I) include free acids such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, Contains acid addition salts with oxalic acid, malonic acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid and salicylic acid.

Alkyl and alkoxy groups can be branched or straight chain groups.

The halogen atom is preferably fluorine, chlorine or bromine, especially fluorine or chlorine.

The C-C6 alkyl group is preferably a C-C alkyl group, especially the 01-C4 alkyl group is methyl or ethyl.

The C-C alkoxy group is preferably a 01-C alkoxy group, especially the C-04 alkoxy group is methoxy, ethoxy or isobroboxino.

The phenyl-01-C4 alkyl group is preferably benzyl or )I-nylethyl. .

Trihalo01-C4 alkyl is, for example, trichloro-0
1-C4 alkyl, especially trifluoromethyl.

When one of X , X , X and or substituted with a substituent selected from halogen and hydroxy.

As noted above, this invention has within its scope pharmaceutically acceptable biobreakers and prodrugs of compounds of formula (I), i.e., having a different formula than formula (I) above;
Nevertheless, it also includes compounds that are converted directly or indirectly into the compound of formula (I) in vivo when administered to humans.

Preferred compounds of the invention are those in which A is as defined above; R is hydrogen or 01-C4 alkyl; R1 is hydrogen;
01-C4 alkyl or benzyl: Xl, X2. Each of X3 and x4 may be the same or different, but hydrogen, halogen, hydroxy or C1-C4
alkoxy; or one of x1, The above is an acceptable salt.

More preferred compounds of the invention are those in which A is as defined above; R and R1 are hydrogen; each of X , X , X and x4 is independently hydrogen.

Compounds of formula (I) that are hydroxy or C1-C4 alkoxy and pharmaceutically acceptable salts thereof.

Examples of preferred compounds of the invention are as follows: (1)
3.4-dihydro-2-(2-imidazoline-2-
yl)-1(2H)-naphthalenone; ■ 3,4-dihydro-2-(2-imidazoly, C2
-yl)-8-methoxy-1(2H)-naphthalenone;
■ 3.4-dihydro-2-(2-imidazoline-2-
yl)-7-methoxy1(2H)-naphthalenone; (
4) 3.4-dihydro-2-(2-imidazoline-
2-yl)-6-methoxyH2H)-naphthalenone;
■ 3,4-dihydro-2-(2-imidazoline-2-
yl)-5-methoxy-1(2H)-naphthalenone: (
ω 1,2,3.4-tetrahydro-2-(2-imidazolin-2-yl)-1-naphthalenol (particularly trans-isomer): ω 1,2,3.4-tetrahydro-2- (2-imidazolin-2-yl)-8-methoxy-1-naphthalenol (especially the trans-isomer); ■ 1,2,3.4-tetrahydro-2-(2-imidazolin-2-yl)-7 -methoxy-1-naphthalenol (especially the trans-isomer); ■ 1,2,3.4-tetrahydro-2-(2-imidazolin-2-yl)-6-methoxy-1-naphthalenol (especially the trans-isomer); 1,2,3.4-tetrahydro-2-(2-imidazolin-2-yl)-5-methoxy-1-naphthalenol (especially trans-isomer) -dihydro-naphthalen-2-yl)-2-imidazoline: (!2) 2-(3,4-dihydro-8-methoxy-
(132-(3,4-dihydro, rho-7-methoxy-naphthalen-2-yl)-2-imidazoline)-2-imidazoline: (1412-(3,4-dihydro-6-methoxy- Naphthalen-2-yl)-2-imidazoline: ■ 2-(3,4-dihydro-5-methoxy-naphthalen-2-yl)-2-imidazoline: 061 5.6-dihydro-7-(2-imidazoline-
(2-yl)-1-naphthalenol; #2-(3,4-dihydro-7,8- Dimethoxy
Naphthalen-2-yl)-2-imidazoline: (21)
2-(3,4-dihydro-6,7-dimethoxy-naphthalen-2-yl)-2-imidazoline; (22)
2-(3,4-dihydro-5,6-simethoxynaphthalen-2-yl)-2-imidazoline: (23)
5.6-dihydro-7-(2-imidazolin-2-yl)-1,2-naphthalenediol: (24) 5.6-dihydro-7-(2-imidazolin-2-yl)-2,3- Naphthalene diol; (25) 7,8-dihydro-6-(2-imidazolin-2-yl)-1,2-naphthalene diol; (26) 2-(1,2,3,4-tetrahydro-naphthalene-2 -yl)-2-imidazoline; (27) 2-(1,2,3,4-tetrahydro-8
-methoxynaphthalen-2-yl)-2-imidazoline; (28) 2-(1,2,3,4-tetrahydro-7-methoxy-naphthalen-2-yl)-2-imidazoline: (29) 2- (1,2,3,4-tetrahydro-6-methoxy-naphthalen-2-yl)-2-imidazoline: (30) 2-(1,2,3,4-tetrahydro-5-methoxy-naphthalene-2- il)-2
-Imidazoline: (31) 5,0,7.8-tetrahydro-7-(2-imidazolin-2-yl)-1-naphthalenol: (32) 5,6,7.8-tetrahydro-7-(2
-imidazolin-2-yl)-2-naphthalenol; (33) 5,6,7.8-tetrahydro-6-(2
-imidazolin-2-yl)-2-naphthalenol; (34) 5,6,7.8-tetrahydro-6-(2
-imidazolin-2-yl)-1-naphthalenol: (35) 2-(1,2,3,4-tetrahydro-7
,8-dimethoxy-naphthalen-2-yl)-2-imidazoline: (36) 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-naphthalen-2-yl)
-2-imidazoline = (37) 2-(1,2,3,
4-tetrahydro75,6-dimethoxy-naphthalene-
2-yl)-2-imidazoline: (38) 5,6,
7.8-tetrahydro-7-(2-imidazoline-2-
(39) 5
,6,7.8-tetrahydro-6-12-imidazolin-2-yl)-2,3-naphthalenediol; (40)
5,6,7.8-tetrahydro-6-(2-imidazolin-2-yl)-1,2-naphthalenediol: and pharmaceutically acceptable salts thereof.

The structural formulas of the compounds with the above numbers are shown in the table below.

11 HHHHHH-OH trout 12 0CH3HHHHH-CH- 13H0CH3HHHH-CH- 14HH0CH3HHH-CH- 15HHH0CH3HH-CH- 160HHHHHH-CH- 17HOHHHHH-CH- 18HHOHHHH-CH- 19HHHOHHH-CHH 2O20CH30CH3HHHH-CH-21H0CH
30CH3HHH-CH-22HHQC)130C)I
3HH-CH-230HOHHHHH-CH= 24 HOHOHHHH-CH-25HHOHO
HHH-CH= 26 HHHHHH-CH2- 270CH3HHHHH-CH,, - 28H0CH8, HHHH-CH,, -29HH0CH
3H) (H-CH2- 30HHH0CH3HH-CH2- 310HHHHH)l -CH2-32HOHHH
HH-CH2- 33HHOHHH-CH2- 34HHHOHHH-CH2- 350CH30CH3HHHH-CH2-36H0CH
30CH3HHH-CH,, -37HH0CH30CH
3HH-CH2-380HOHHHHHH-C)12- 39 HOHOHHHH-C)l, -40HHO
HOHHH-CH2- The compound of the present invention and its salt have the following formula (a) Formula (It) [where xl, x2. x3. x4 and R are as defined above, R2 is 01-C4 alkyl, and Y is halogen] to a compound of formula (III) HN-, CH-C
(b) Formula (IV) In formula 1, Xl, X2. X3. X4. R and HiR1G, t-
to obtain a compound of formula (I) in which CH=: or (C)
A compound of the formula (Ia>1, in which X, X2. or (d) obtain a compound of formula (V) [wherein X , X2.X3.X4.R711FR1G
! As defined above] is reduced so that A is -C
A compound of formula (I) of H2- is obtained, and if desired further of formula (
converting the compound of formula (I) into another compound of formula (I); and/or
or, if desired, converting the compound of formula (I) into its pharmaceutically acceptable salt, and/or obtaining the it compound of formula (I), if desired, from that salt; If so, it can be produced by a process consisting of separating an isomer mixture into single isomers.

When Y in the compound of formula (If) is halogen, it is for example chlorine or bromine, preferably chlorine.

The formula (n
) can be reacted with a compound of formula (III).

When M in the compound of formula (1v) is the residue of an active derivative of an acid, it is in particular an acyl residue, such as a 02-C4 alkanoyl group, preferably acetyl, or a sulfonyl group, such as mesyl or At a temperature in the range of 150°C, a catalytic amount of a strong acid such as 11H2SO4
It may be carried out in a suitable solvent such as glacial acetic acid, dimethylformamide or pyridine in the presence of .

In particular, when M in the compound of formula (IV) is hydrogen, the compound of formula (TV) can be prepared by refluxing the compound of formula (TV) in a concentrated hydrogen-free acid, such as hydrohalic acid, preferably hydrochloric acid or hydrobromic acid, or in a suitable amount of The same reaction can be carried out by refluxing in pyridine in the presence of 5OCp2.

When M in the compound of formula (IV) is an acyl group, such as acetyl, the reaction may be carried out by thermal decomposition at a temperature in the range of about 200°C to about 300°C.

Reduction of a compound of formula (Ia) or a salt thereof to obtain a compound of formula (I) in which A is -CHOH- can be carried out from room temperature to about 1
of a suitable catalyst such as Pd, Pt or PtO□ in a suitable solvent such as a lower aliphatic alcohol, particularly methanol or ethanol or acetic acid, at a temperature in the range of 00°C and under a pressure in the range from atmospheric pressure to about 30 atmospheres. Preferably, this can be carried out by catalytic hydrogenation of a salt of the compound of formula (Ia), such as a halide, especially a chloride or bromide, in the presence of a compound of formula (Ia).

Reduction of a compound of formula (V) to obtain a compound of formula (I) in which A is -CH2- can be carried out, for example, from room temperature to about 100°C.
in a suitable solvent, preferably an alkanol such as methanol or ethanol, acetic acid, cyclohexane, n-hexane, ethyl acetate, at a temperature in the range of , and a pressure in the range of from atmospheric pressure to about 30 atmospheres.

This can be carried out by carrying out the catalytic addition in benzene or toluene in the presence of a suitable catalyst such as palladium, platinum, ptO, ruthenium or Raney nickel.

If desired, compounds of formula (I) can be converted to other compounds of formula (I).

These arbitrary conversions can be carried out in a manner known per se.

Thus, compounds of formula (I), for example in which one or more of X, X, X3 and By reaction with chlorine or bromine, it is converted into a compound of formula (I) in which one or more of x1, X3, X2 and x4 is a halogen atom, such as chlorine or bromine.

For example: a) 01-C6 alkyl halide preferably chloride;
b) reaction with bromide or iodide, or b) C in a suitable solvent such as nitrobenzene or CH2Cl2 or C82.
Alkylation via a Friedel-Krach reaction by reaction with a 1-C6 alcohol results in x1. X2. ×3“
and a compound of formula (I) in which one or more of x4 is hydrogen,
One or more of X , X , X and x is 01 to C
6 alkyl to compounds of formula (I).

In both (a) and (b), at a temperature ranging from room temperature to 100° C., in the presence of a suitable amount of a Friedel-Krach catalyst such as Ai) C1l, Zn C1l or BF3: and a C-C6 aliphatic alcohol. When used, the reaction is carried out in the presence of a strong acid such as HF, HClO4, or if desired in IHSo4 or concentrated H3PO4 or without the addition of other solvents.

By conventional methods well known in organic chemistry, x, x
2. A compound of formula (I) in which one or more of x3 and x4 is a C1-C6 alkoxy group, It can also be converted into a compound of formula (I) in which one or more of X3 and x4 is a hydroxy group. For example, from 30°C to reflux temperature, preferably at reflux temperature, strong inorganic acids, i.e. HCj, H
Br.

Lewis acids such as AI
This conversion can be accomplished by processing using C+e or BF3.

The conversion of the compounds of formula (I) into their salts, the conversion of the salts into the free compounds and the separation of isomer mixtures into single isomers may be carried out in conventional manner. For example, mixtures of geometrical isomers, such as cis and trans isomers, may be separated by fractional crystallization in a suitable solvent, or by column chromatography or high pressure liquid chromatography.

in the presence of a gaseous hydrohalic acid such as FA acid or hydrochloric acid, preferably hydrochloric acid, in a suitable solvent such as a lower dialkyl ether, preferably diethyl ether, at a temperature ranging from about 0°C to about 50°C. In formula E, xl, x2.
x3. x4 and R2G; as defined above] can be reacted with a suitable C1-C4 alkanol to obtain a compound of formula (II).

The compound of formula (II) thus obtained can be reacted as a crude product without isolation from the reaction medium with the compound of formula (1) according to step (a).

If necessary, the obtained compound of formula (II) can be purified from by-products and purified according to step (a).
It is also possible to react with the compound III).

Compounds of formula (III) are known and can be obtained by known methods.

A compound of formula (IV) in which M is hydrogen is a compound of formula (I) and is obtained by reducing a compound of formula (V) or a salt thereof according to step (C) above.

Formula (I) wherein M is the residue of an active derivative of an acid as defined above
The compound of V) can be prepared by known methods, for example, from air temperature to about aO
of the formula (IV
) with a suitable acyl or sulfonyl halide, preferably a chloride, such as acetyl chloride or tosyl chloride or mesyl chloride.

The compound of formula (Ia) is a compound of formula (I) in which A is -CO-, and can be obtained by reacting a compound of formula (Ill) and a compound of formula (II) according to step (a) above. .

Further, the compound of formula (V) is a compound of formula (I> in which A is 10H=, and can be obtained from the compound of formula (IV) according to the above step (b').

The cyano derivative of formula (W) is a known compound, and/
Or literature such as J, ^, C, S, Rainbow, 1745 (1
945) according to the well-known method.

Due to its affinity for C2-adrenergic receptors, e.g. the yohimbine binding test (T, H, Lavin, B, 8°t+otrnan and R, J, LefkOWitZ,
Molecular Pharllacology,
Also, clonidine-induced hypotamia (hyp
tests positive for enhancement or inhibition of (Von Voigtlander P, F, et al., N
europharn+ac010(IY, 17. 37
5-81.1978), it was discovered that the compounds of the present invention are active in regulating noradrenaline (NA) balance.

For example, J, Bus La5sen, Europe,
J. Pharmacol, 47. 351~
358 (1978), the compounds of the invention are sensitive to the potentiation test of 5-hydroxytryptophan-induced inhibition of locomotor hexagonism in mice and rats. It was also discovered that it is active in regulating serotonin (5-H) balance, both of which are blood component balances.

It has been found that it can also be used therapeutically as an antidepressant alone.

Various doses were administered once orally to rats and mice.

The compounds of the invention can be administered in various dosage forms, for example orally in the form of tablets, capsules, sugar-coated or film-coated encapsulants, liquid solutions or suspensions, rectally in the form of suppositories, or rectally in the form of suppositories.
It may be administered parenterally, for example by intramuscular or intravenous injection or infusion.

Intravenous administration is preferred in emergencies.

Suitable dosages are preferably administered by the usual routes of administration and by the usual methods of administration of known drugs having similar pharmacological activity. For example, for the treatment of depression in adults, approximately 5 to
about 2507 Ig/day, preferably about 10-1001 m9
The compounds of the invention are administered at a dosage in the range of /day.

The invention also encompasses pharmaceutical compositions comprising a compound of the invention together with a pharmaceutically acceptable excipient (which may be a carrier or diluent).

Contains the compound of the present invention. Pharmaceutical compositions are conventionally manufactured in conventional manner and administered in a pharmaceutically suitable form.

For example, solid oral forms contain the active compound together with diluents such as lactose, dextrose, sucrose.

Cellulose, corn starch or potato starch: lubricants such as silica, talc, stearic acid,
Magnesium or calcium stearate and/or polyethylene glycol: Binders 2 such as starch, gum arabic, gelatin.

Methyl cell or polyvinyl and O-lidone; disintegrants, e.g. starch,
Alginic acid, algine-1 or sodium starch glycolate: foaming mixture: flavoring agent; sweetener; humectant,
For example lecithin, polysorbate.

lauryl sulfate-1; and -contains non-toxic and pharmacologically inert substances used in intra-shell pharmaceutical formulations. The pharmaceutical preparation can be prepared by any known method such as mixing, granulating, tabletting, etc. ，! i) Vine produced by coating or film coating method.

Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions. Syrups contain as carriers, for example, sucrose or sucrose together with glycerin and/or mannicol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example natural moth polyvinyl alcohol. Suspensions or solutions for intramuscular injection include the active compound together with a pharmaceutically acceptable carrier such as sterile water, olive oil.

It contains ethyl oleate, glycols such as propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.

Solutions for intravenous injection or infusion may contain as a carrier sterile water or, preferably, sterile isotonic saline solution.

Suppositories contain the active compound together with a pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol.

Contains polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The NMR spectra were preferably determined by R91ffi chromatography on ready-to-use silica gel plates with a TM thickness of 90 M-Hertz R, value 0.2541 II+.

The following examples illustrate but do not limit the invention.

Yufukudan” Literature [(JAC8, Niji, 1745. (1945)]
2-cyano-3,4-dihydro-1 (
2H)-naphthalenone 8.79g (0,0513nol
) to 100 d of ether and 8 rd of absolute ethanol (0,
15nol).

Allow HCl to enter the solution for 2 hours. Concentrate the solution to live mother and cool. The precipitate is filtered, washed with ether and dried with a yield of 66%, mp 119-120. The midide is dissolved in anhydrous ethanofluor (50rd) and ethylenediamine (2,88rttR, 0,043n+ol) is added.

When air-dried at 100°C in the presence of P2O5, the melting point is 2.
3,4-dihydro-2-(2-imidazolin-2-yl)-1(2H)-naphthalenone at 56-259°C 5.7
Get 79.

The compounds mentioned exist in enol form as evidenced by the NMR data obtained.

Elemental analysis: Measured value: C72,76: H6,60: N13.1
1; Calculated value of C13H14N20: C72,73;
H6,58: N 13.07 T, L, C,: Eluent CHCl: CH30l-1=
180:20 R, = 0.52 N, M, R, (DMSO-d6) δp, p, n+, :
2.40- 2.133 (4H, II, CH2CH2
); 3.54 (4H, n, NCH2-CH2N); 7
, OO-7,75 (4H, l.

aromatic); 9.90 (11-1, br s, OHI-nol).

Similarly, the following compounds can be prepared; in the case of the hydrochloride salts, they are obtained from the corresponding free bases as described in Example 6.

3.4-dihydro-2-(2-imidazolin-2-yl)-6-methoxy 1(2H)-naphthalenone FA salt, melting point 228-232°C (02 to 150 H
) Elemental analysis: Measured value: C58,01: H5,99: H9,70
; CI 12.33 : CHCj N2O2 calculation value:
C59,89: H6,10; H9,97; C11
2,68 T, L, C,: Eluent CHCj: CH30H=
180:20 RF=0.47 N, M, R, (DMSO-d6) δp, p, r*,:
2.40 (2H, m, CH2CH,CH); 3.05
(2H, II, rising 2CH2CH); 3.83 (3H,
S, OCH3); 3.88 (4H, s.

NCHCH2N); 4.18TIH, dd.

CH-CH2-CH) 6.90-7.81 (31-1,
11, aroma #); 10.40 [2H, br s.

ten NH).

3.4-dihydro-2-(2-imidazolin-2-yl)-7-meI.xy-1(2H)-naphthalenone hydrochloride, melting point 296-300°C Elemental analysis: Measured value: C59,58: H6 ,17; H9,85
:C112,54: Calculated value of C14H17CρN2O2: C59,89; H6,10; H9,97:C
I 12. G2 T, L, C,: Eluent CHCl: CH30H-1
80:20 Rf=0.51 N, M, R, (DMSO-d6) δp, p, n,:
2.40 (2H, In, CH2 Danjo 20 I-1); 3
．． 00(2)1. n, rising, CH2CH); 3.80
(3H, s, OC1-13); 3.88 (4H, s, N
CH-CH2N); 4.25 (IH, dd.

CH2CH2 and); 7.30 (3H, city, aroma 1); 1
0.4(2)1,brs,NH)
.

3.4-'dihydro-2-(2-imidazolinyl-2-
yl)-8-methoxy-1(2H)-naphthalenone hydrochloride: and 3,4-dihydro-2-(2-imidazolinyl-2-yl)-5-methoxy-1(2H)-naphthalenol hydrochloride, melting point n , p.

300℃ (decomposition).

Example 2 Initial pressure 50psi (3,42atI11) par
3. 5 hours at room temperature in an r-3urgess low pressure apparatus.
4-dihydro-2-(2-imidazolin-2-yl)
-1(2H)-naphthalenone z v ta (1,7g>
, 10% palladium on activated carbon and methanol (10%
Hydrogen enrichment of the mixture of 01i).

At the end of this time, l! [! 96% of the hydrogen in the paper is adsorbed. The catalyst is separated and washed with methanol, the solution is evaporated under vacuum to less than ff1 (20+t),
Treat with ether (50#+1!). The white precipitate is filtered and dried to yield trans-1,2,3,4-tetrahydro-2-(2-imidazolin-2-yl)-1-naphthalenol hydrochloride with a melting point of 207-210°C. .

Elemental analysis: Measured value: C61,66: H6,79: N11.0
5: C114,07: CHClN2O total t'>1: C61,77; H6,77: N 1
1.08: CI 14.02 T, L, C,: Eluent CHCρ: CH30H:CH
3CO0H=15:35:o, s R, = 0.16 N, M, R, (DMSO-d6) δp, p, n+, :
2.07(2f-1,n+,CFl □ 0 8
2 0 H); 2.90 (31-1, n, rising. CH
2nd half = 10Hz); 3.84(4H,s
, NCH2CH2N ); 4.93 (IH, ra,
C top OH.

J = IOHz); 5.80 (IH, br s,
OH); 6.90-7.58 (4H, tm, aromatic); 10.3 (2H.

br, s, NH) The following compounds can also be produced in the same manner: Nidoran-1,
2,3,4-tetrahydro-2-(2-imidazoline-
2-yl)-6-methoxy-1-naphthalenol hydrochloride, melting point 198-200°C: Elemental analysis: Measured values: C59,50: H6,87; N9.88;
CI212.56; Calculated value of C14H19CaN20°: C59,46: H6,77; N 9.90
: C112゜53 : T, L, C, : Eluent CHCN : CH3CO0H
=80:20:2 R, =0.375 :N, M, R
, ([)MSO-d6)δp, p, n, : 2.02
(2H, II, CH2CH20H); 2.80 (2H,
n, CHCH2CH); 2.90 (1 to 1.

□2 n, CH2CH20H, J=10Hz ); 3.72 (
3H,s,OCH3);3,85(4H.

br s, NCHC82N); 4.90 (IH, dd
, CHOH, J=10Hz ); 6.00 (IH, b
r s, OH); 6.65-7.41 (31-1
, n, aromatic); 10.45 (2H, br, s.

NH) trans-1,2,3,4-tetrahydro-2-(2-
Imidazolin-2-yl)-7-methoxy-1-naphthalenol hydrochloride, melting point 225-230°C; Elemental analysis: Measured values: C59,15: H6,75: H9,79
: CaI2.45 : Calculated value of CHClN2O2:
C59,46: H6,77; H9,90; CaI2
．． 53: T, L, C,: Eluent CHCρ: CH3011:j
l111NH4QH=50:50:IR,=0.11: N, M, R, (DMSO-d6) δp, p, Im, :
2.03 (2H, n, Cl-12 summer, CH);
2.77 (2H, Im, (ΣH20H, 2CH);
2.9 (1t!

n, on CH2082C, J=10Hz); 3.75(
3H, s, OCH3); 3.86 (ti.

br　s,　N　CH2CH2N); 4.92 (IH.

d, CHOH, J=10Hz); 6.7G-7,02
(3H, n, aromatic); 10.3 (2H, br.

S, NH > 1-lance-1,2,3,4-tetrahydro-2-(2
-imidazolin-2-yl)-8-methoxy-1-naphthalenol hydrochloride, trans-1,2,3,4-tetrahydro-2-(2-
imidazolin-2-yl)-5-methoxy-1-naphthalenol hydrochloride, melting point 225°C (decomposed) and trans-1,2,3,4-tetrahydro-7-hydro
xy-2-(2-imidazolin-2-yl)-1-naphthalenol J10ρ hydrochloride, melting point. 〉℃: Elemental analysis: Calculated value: C58,10 16.37: N10.4
2: C913, 19: T, L, C,: Eluent CH30H: JIAeiN H4
0FI/:e=a-= 100: 2 R,=
0.14; N, M, R, (DMSO-d6)δl),
+1.11. : 1.80-2.20 (2H, Ill
, CH2 Tachitan 2CH); 2.60-3.00 (3H,
Il, Cdan2CH2劃)；3.82(什、S、NC
1 (2CH2N,) groove #; 4.83 (11-1, br
d.CHOH.

J = 101 (z); 6,60-6,95 (3H, l, aromatic); 8.70-
10.50 (3H, br, OH+NH)
.

Example 3 Trans-1,2,3,4-tetrahydro-2-(2-
A solution of (imidazolin-2-yl)-6-methoxy-1-naphthalenol (>6 g), glacial acetic acid (100 d) and 96% sulfuric acid (10 d) is stirred at room temperature for 3 hours.

The solution is poured into ice water (2007) and neutralized with 40 tl of concentrated NH. The precipitate is filtered, washed with water and dried under vacuum at 100°C to give 2-(3,4-dihydro-6-methoxy-naphthalen-2-yl)-2- with a melting point of 114-116°C.
4.8 g of imidazoline are obtained.

Elemental analysis: Measured value: C73,63; H7,10: N12.2
7;014th 16N20 81 calculation value: C73,05
Nido 1 7.06; N12.27;
T, L, C,: Eluent CHCρ: 0H30H:No'I, NH40H = 70:30:1; R, = 0.37; N, M, R, (DMSO-d6) l), 1), 1 ．．
: 2.3-2.6 (4)! , m, CH
CH-C=);□2□2 3.50 (4tI, s, NCt-12CH2N)
;3.73 Similarly, the following compounds can also be prepared; in the case of the hydrochloride salts, they are obtained from the corresponding free bases as described in Example 6. 2-(3,4-dihydro-naphthalene-
2-yl)-2-imidazoline salt iS! 2 salt, melting point 26
2-265℃; Elemental analysis: Flood temperature: C66,10; f-1
6,45; N11.87; Cfi 14.98
;Calculated value of ci3to115CIN2: C66,5
2; H6,44; N11.93 : C115,10 T,, L, C,: Eluent CHCj : CH30H:
fisuNH40H=70:30:1; R,=0.53: N, M, R, (DMSO-d6)δl), p, 1m,
: 2.60-2.90 (4H, re, CH2CH2
C= ); 3” (4H, s, NGH2Cto1 2 N
); 7.30 (4H.

S, aromatic); 7.77 (IH, br s, CH=C
-9f; 10.3 (2H, br S, NH); 2-
(3,4-dihydro-7-methoxy-naphthalene-2-
Il π-imidazo11. Salt Mg, melting point, 68-2□.・
.

Elemental analysis: Measured value: C63,14: 1=lL37; N10.
41: Cρ13.27; C14 day 1□0ρN20 total q value: C63,51: H6,47; N 10.5
8; (Jl 13.39 T, L, C,: Eluent CHCρ: CH30H: Mesu NH40H = 70:30:1; R, = 0.48; N, M, R, (DMSOJ6) I), D ,n, :
? , 80 Liao (4th, n, rise, summer 2 C=); 3.76t3t-
+, s, oc 13); 3.92 (4H, S
.

NC; H, 20H2N): 6.84-7.20 (3H.

m, aromatic); 7.72 (IH, br s, CI-l
=C-);==;10.40 (2H, br s,
Nt()5.6-dihydro-7-(2-imidazolin-2-yl)-2-naphthalenol salt V salt, melting point 295
~297°C elemental analysis: Measured value: C62,02: H6,03; N10.0
6; Cj 14.24: C13H15Cj N
2C1) Calculated value: C62,27;
3; N11.17: Cj 14.13 T, L, C,: Eluent CH301-1: $IJNH4O
f-1=100:2 R,=0.29N,M,R,(
DMSO-66) δp, p, Im, : 2.3-2
．． 9 (4H, III, CH2 Danjo 2 (?=); 3.
88 (41-1, s, NC820H2N); 6.78-
7.07 (3H, II, aroma/[X); 7.60 (11
-1, br s.

CH=C-); 9.53 (IH, br s, OH);
10.14 (2H,br,NH)2-(3,4-
Dihydro-8-methoxy-naphthalene-2-ite Q-2
-Imidazoline salt; 2-(3,4-dihydro-5-methoxy-naphthalene-
2-yl)-2-imidazoline melting point 253-256°C;
5.6-dihydro 0-7-(2-imidazolin-2-yl)-1-naphthalenol, 8-dihydro-6-(2-imidazolin-2-yl)-2-naphthalenol; 7.8-dihydro -6-(2-imidazolin-2-yl)-1-naphthalenol: 2-(3,4-dihydro-7,8-dimethoxy-naphthalen-2-yl)-2-imidazoline; 2-(3,4- Dihydro-6,7-dimethoxy-naphthalen-2-yl)-2-imidazoline: 2-(3,4-dihydro-5,6-dimethoxy-naphthalen-2-yl)-2-imidazoline: 5,6-dihydro 0-7-(2-imidazolin-2-yl)-1,2-naphthalenediol: 5.6-dihydro-7-(2-imidazolin-2-yl)-2,3-naphthalenediol; and 7.8 -dihydro-6-(2-imidazolin-2-yl)-1,2-naphthalenediol.

Example 4 Following a similar procedure as described in Example 2, 2-(3,
4-dihydro-naphthalen-2-yl)-2-imidazoline hydrochloride (0,99) + absolute ethanol (1507)
and hydrogenation of 10% palladium on activated carbon gives 2-(1,2,3,4-tetrahydro-naphthalen-2-yl)-2-imidazoline salt B@
0.799 is obtained.

Dissolve the crude hydrochloride in water, make the solution alkaline with 20% NaOH and extract with ethyl acetate (2x 100 udl). Dry the organic solution over Na2SO4 and evaporate to dryness.

The composition of the free base was analyzed by silica gel chromatography (eluent CHCp3:Ct130H:aJN).
14 0 1 = 70:30:1), we get 2
-(1,2,3,/I-tetrahydro-naphthalene-2
-yl)-2-imidazoline (melting point 71-72°C) 0
．． 63 g is obtained.

Elemental analysis: Measured value: C77,69: H8,04: N 13.
Total value of 77013H16N2: C77,96:H8
,05; N 13.98; T, L, C,: Eluent CHC,e: CH30H
:fi shooting NH4,0H=70:30: IR,=0.2
7 N, M, R, (DMSO-d6) δp, p, n+, :
1.5-2.4 (2H, m, CH2C- on i 2
CH); 2.6-3.0 (5H,i,CH,,
CH2C;HCH,);:(hi)”: 寥工, toyu, 辷
3,39 (4H, S, N C + 2CH, N)
, "##TE Co., Ltd. 7.04 (41-1, s, aromatic) Similarly, the following compound is obtained: 2-(1,2,3,4-tetrahydro-6-methoxy-
naphthalen-2-yl)-2-imidazoline, melting point 10
6-108°C: Elemental analysis: Measured value: C72,82; H7,85: N 12.
Calculated value for 06014th 18N20: C73,01;H
7,88: N12.16: T, L, C,: Eluent CHCl: CH30H:Me51xH40H=70:30:1:R,=0.31 N, M, R, (CDCI!3ter δp, p , n+,
: 1.6-2.4 (21-1, ra, CI-12
Natsukami, CH); 2.5-3.05 (5H, n, CH
2G To1. 3-HC engineering ui horn standing #±3
．． 3 (1H, br s, N H); 3.6 (4t
i br s, N CH2CH2N
); 3.78 (3H, s, OCH3); 6.60-7.
10 (3H.

t, aromatic) 2-(1,2,3,4-TeI・Rahydro8-MeI・Xy-naphthalen-2-yl)-2-imidazoline; 2-
(1,2,3,4-tetrahytoconvex-5-methoxy-naphthalen-2-yl)-2-imidazoline, B1; point 26
8°C (decomposition); 2-(1,2,3,4-tetrahydrolymethoxynaphthalen-2-yl)-2-imidazoline, melting point 265
~267°C; 5,6.7.8-tetrahydro-(2-imidazolin-2-yl)-1-naphthalenol: 5.6,7.8-tetrahydro-7-(2-imidazolin-2-yl) -2-naphthalenol: 5,6.7.8-tetrahydro-6-(2-imidazolin-2-yl)-2-naphthalenol: 5.6,7.8-tetrahydro-6-(2-imidazolin-2-yl) yl)-1-naphthalenol; 2-(1,2,3,4-tetrahydro-7,8-dimethoxy-naphthalen-2-yl)-2-imidazoline; 2
-(1,2,3,4-tetrahydro-6,7-dimethoxy-naphthalen-2-yl)-2-imidazoline; 2-
(1,2,3,4-tetrahydro-5,6-dimethoxy-naphthalen-2-yl)-2-imidazoline; 5.6
, 7.8-tetrahydro-7-(2-imidazoline-2
-yl)-1,2-naphthalenediol; 5.6,7.8-tetrahydro-6-(2-imidazolin-2-yl)-2,3-naphthalenediol;
6,7.8-tetrahydro-6-(2-imidazoline-
2-yl)-1,2-naphthalenediol.

Example 5 The solution is poured into ice/water and made alkaline with 2N N1aOH solution. The precipitated solid is filtered, washed with water and dried. Recrystallization of the crude product (EtOH) gives a melting point of 2
2.62 g of 3,4-dihydro-〇-hydroxy-2-(2-imidazolin-2-yl)-1(2H)-naphthalenone are obtained at 82-284°C.

As evidenced by NMR data, the mentioned compounds exist in the form of enoneimidazolidine.

Elemental analysis: Measured value: C66,90 nido IG, 12:N
12.09C13H14N202 Lou threshold: C67,
81 Nido 16.13: N12.16 T, L,, C,:? El Effluent CH
CI: CH301-1=180:
20: R(= 0.27N, M, R, (DMSO
-d6) δp, p, 1. : 2. ．． 20-2.80(
4H,n,CH2CH2G= )3.30 - 3.7
0 (4H, ra, N C to ICH2 = nsoid) 9.55 (IH, br s, 9 with C=O
9.75 (IH, br s, OH) Analogously, the following compounds can be prepared; in the case of the hydrochloride salts, they are obtained from the corresponding free bases as described in Example 6.

3.4-dihydro-7-hydroxy-2-(2-imidazolin-2-yl)-1(2H)-naphthalenone hydrochloride, melting point 300°C; Elemental analysis: Measured value: C57,95; 1"5.63 : N 1
Calculated value of 0.45Cρ13.23C13H15CρN20□: C58,54: H5,66: N 10.5
0; Cρ13.29 T, L, C,: Eluent CHCρ: CH30H=18
0:20: R, = 0.43 N, M, R, (DMSO-d6) δp, p, n, :
2.32 (2H, 1, CH Yu CHO2C To 1)
;2.94(2H,l,CHCH2CH);=3.90
□2 (4H, S, NCHc+2N); 4.19 (IH, dd, CH2CH, 2 rising); 7,0
2-7.33 (3H, ra, aromatic); 9.88 (IH
.

s, OH); 10.40 (2H, s, N H>3.
4-dihydro-8-hydroxy-2-(2-imidazolin-2-yl l-1(2H)-naphthalene hydrochloride; and 3,4-dihydro-5-hydroxy-2-(2-imidazolin-2- il)-1(2H)-su7'7 shi>m'
et salt.

Example 6 3.4-dihydro-6-hydroxy-2-(2-imidazolin-2-yl)-H2H)-naphthalenone 4.89
is dissolved in methanol (400 precepts) and HCj gas is bubbled into the solution while maintaining the temperature below 20°C. After evaporation to a low ff1 (50d), diethyl ether is added until precipitation is complete. The product is filtered, washed with ether and dried to give a 3.4-
Dihydro-6-hydroxy-2-(2-imidazoline-
2-yl)-1(2H)-naphthalenone hydrochloride 4.05
9 is obtained.

Elemental analysis: Measured value: C58,03; )(5,C9; N1<
1.47CI 13.22 CHCj Calculated value of N2O2: C58,54; )-15,66: N10.5
0: (d) 13.29 N, M, R, (DMSO-d6) δp, p, m, :
2.32 (2H, II, Cl-12CH2CH);2.
92(2)1. i, Part 2 C1-+2CH); 3.90
(4H, s, NGH,, CH2N); 4.11 (IH, dd, CH2C t1 2 (
λ-11); 6.71-7゜82 (3H, l, aromatic)
; 10.36 (2H, s, NH); 10.82 (
1 to 1. s,0 t1) In the same mashing procedure, using the appropriate hydrohalic acid, the following compounds are blued: 5.6,7.8-tetrahydro-7-(2-imidazolin-2-y 5.6,7.8-tetrahydro-6-(2-imidazolin-2-yl)-1-naphthalenol, melting point 260°C (
decomposition) (as hydrochloride); °C (decomposition).

Example 7 Tablets containing a small amount of 1507II pi and containing 50 m9 of active substance are VyB as follows: Composition (10,000 tablets) Trans-1,2,3,4-tetrahydro-2 -(2-
imidazolin-2-yl)-1-naphthalenol JW
IW J2200g Lactose 710g Corn starch 237.59 Talc powder
37.59 Magnesium stearate 15g trans-1,2,3,4-tetrahydro-2-(2-imidazolin-2-yl)-1-naphthalenol hydrochloride, lactose and half of the corn starch are mixed and the mixture is reduced to 0. .Sift through a 51 nm pore sieve. Corn starch (18g) in warm water (1
80d). The resulting paste is used to granulate the powder. Dry the granules, sieve size i,
Sieve through 4 mm, then add the remaining starch, talc and magnesium, mix carefully and sieve through 8 m diameter.
Form into tablets using a tn punch.

Claims (8)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -CH = or -CH_2-; R is hydrogen, C_1-C_6 alkyl or phenyl; R_1 is hydrogen, C_1-C_6 alkyl or phenyl-
C_1 to C_4 alkyl; each of X_1, X_2, X_3 and X_4 may be the same or different, hydrogen, hydroxy, halogen, C_1
~C_6 alkyl, C_1-C_6 alkoxy or trihalo-C_1-C_4 alkyl; or X_1, X
one of _2, X_3 and X_4, each phenyl ring is hydroxy, halogen, C_1-C_4 alkyl and C_1
1, 2 or 3 independently selected from ~C_4 alkoxy
a substituent selected from phenyl, phenylthio, phenoxy and benzyl, substituted or unsubstituted with one substituent, the others being as defined above] and pharmaceutically acceptable salts thereof . (2) A is as defined in claim 1; R is hydrogen or C_1-C_4 alkyl; R_1 is hydrogen or C_1-C_4 alkyl or benzyl; X_1, X_2, X_3 and X_4 each may be the same or different, hydrogen, halogen, hydroxy or C_
1 to C_4 alkoxy; or X_1, X_2,
Compounds of formula (I) according to claim 1, wherein one of X_3 and X_4 is a substituent selected from phenyl, phenylthio, phenoxy and benzyl, the others being as defined in claim 1 and pharmaceutically acceptable salts thereof. (3) A is defined in claim 1; R and R_1 are hydrogen; X_1, X_2, X_3
and each of X_4 is independently hydrogen, hydroxy or C_
A compound of formula (I) according to claim 1, which is 1-C_4 alkoxy, and a pharmaceutically acceptable salt thereof. (4) 3,4-dihydro-2-(2-imidazoline-2
-yl)-1(2H)-naphthalenone; 3,4-dihydro-2-(2-imidazolin-2-yl)-8-methoxy-1(2H)-naphthalenone; 3,4-dihydro-2-(2 -imidazolin-2-yl)-7-methoxy-1(2H)-naphthalenone; 3,4-dihydro-2-(2-imidazolin-2-yl)-6-methoxy-1(2H)-naphthalenone; 3, 4-dihydro-2-(2-imidazolin-2-yl)-5-methoxy-1(2H)-naphthalenone; 1,2,3,4-tetrahydro-2-(2-imidazolin-2-yl)-1 -naphthalenol (trans-isomer); 1,2,3,4-tetrahydro-2-(2-imidazolin-2-yl)-8-methoxy-1-naphthalenol (trans-isomer); 1,2,3 , 4-tetrahydro-2-(2-imidazolin-2-yl)-7-methoxy-1-naphthalenol (
trans-isomer); 1,2,3,4-tetrahydro-2-(2-imidazolin-2-yl)-6-methoxy-1-naphthalenol (
trans-isomer); 1,2,3,4-tetrahydro-2-(2-imidazolin-2-yl)-5-methoxy-1-naphthalenol (
trans-isomer); 2-(3,4-dihydro-naphthalen-2-yl)-2
-imidazoline; 2-(3,4-dihydro-8-methoxy-naphthalene-
2-yl)-2-imidazoline; 2-(3,4-dihydro-7-methoxy-naphthalene-
2-yl)-2-imidazoline; 2-(3,4-dihydro-6-methoxy-naphthalene-
2-yl)-2-imidazoline; 2-(3,4-dihydro-5-methoxy-naphthalene-
2-yl)-2-imidazoline; 5,6-dihydro-7-(2-imidazolin-2-yl)-1-naphthalenol; 5,6-dihydro-7-(2-imidazolin-2-yl)-2 -naphthalenol; 7,8-dihydro-6-(2-imidazolin-2-yl)-2-naphthalenol; 7,8-dihydro-6-(2-imidazolin-2-yl)-1-naphthalenol; 2-( 3,4-dihydro-7,8-dimethoxy-naphthalen-2-yl)-2-imidazoline; 2-(3,4-dihydro-6,7-dimethoxy-naphthalen-2-yl)-2-imidazoline; 2 -(3,4-dihydro-5,6-dimethoxy-naphthalen-2-yl)-2-imidazoline; 5,6-dihydro-7-(2-imidazolin-2-yl)-1,2-naphthalenediol; 5,6-dihydro-7-(2-imidazolin-2-yl)-2,3-naphthalenediol; 7,8-dihydro-6-(2-imidazolin-2-yl)-1,2-naphthalenediol; 2-(1,2,3,4-tetrahydro-naphthalene-2
-yl)-2-imidazoline; 2-(1,2,3,4-tetrahydro-8-methoxy-
naphthalen-2-yl)-2-imidazoline; 2-(1,2,3,4-tetrahydro-7-methoxy-
naphthalen-2-yl)-2-imidazoline; 2-(1,2,3,4-tetrahydro-6-methoxy-
naphthalen-2-yl)-2-imidazoline; 2-(1,2,3,4-tetrahydro-5-methoxy-
5,6,7,8-tetrahydro-7-(2-imidazolin-2-yl)-1-naphthalenol; 5,6,7,8-tetrahydro-7-( 2-imidazolin-2-yl)-2-naphthalenol; 5,6,7,8-tetrahydro-6-(2-imidazolin-2-yl)-2-naphthalenol; 5,6,7,8-tetrahydro-6 -(2-imidazolin-2-yl)-1-naphthalenol; 2-(1,2,3,4-tetrahydro-7,8-dimethoxy-naphthalen-2-yl)-2-imidazoline; 2
-(1,2,3,4-tetrahydro-6,7-dimethoxy-naphthalen-2-yl)-2-imidazoline; 2-
(1,2,3,4-tetrahydro-5,6-dimethoxy-naphthalen-2-yl)-2-imidazoline; 5,6
,7,8-tetrahydro-7-(2-imidazoline-2
-yl)-1,2-naphthalenediol; 5,6,7,8-tetrahydro-6-(2-imidazolin-2-yl)-2,3-naphthalenediol; 5,6,7,8-tetrahydro- 6-(2-imidazolin-2-yl)-1,2-naphthalenediol; and a pharmaceutically acceptable salt thereof. (5) A method for producing a compound of formula (I) and a pharmaceutically acceptable salt thereof as set forth in claim 1, comprising: (a) Formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼(II) [In the formula, X_1, X_2, X_3, X_4 and R are as defined in claim 1, and R_2 is C_
1 to C_4 alkyl, and Y is halogen] and the compound of formula (III) H_2N-CH_2-CH_2-NH-R_1 (III)
Reacting the compound [wherein R_1 is as defined in claim 1] to obtain a compound of formula (I) in which A is ▲a numerical formula, a chemical formula, a table, etc.▼; or, (b) Formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, X_1, X_2, X_3, X_4, R and R_
1 is as defined in claim 1, and M is hydrogen or the residue of an active derivative of an acid. or (c) Formula ( I a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) [In the formula, X_1, X_2, X_3, X_4, R and R_
1 is as defined in Claim 1] or a salt thereof is reduced to obtain a compound of formula (I) in which A is ▲ ▲ Numerical formula, chemical formula, table, etc. ▼; or ( d) Formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, X_1, X_2, X_3, X_4, R and R_
1 is as defined in claim 1 to obtain a compound of formula (I) in which A is -CH_2-; converting the compound into another compound of formula (I) and/or converting the compound of formula (I), if desired, into a pharmaceutically acceptable salt thereof; A process consisting of obtaining a compound of formula (I) free from the salt and/or, if desired, separating the isomer mixture to obtain each isomer. (6) Formula (I) according to claim 1 as a pharmaceutically acceptable carrier and/or diluent and active substance.
or a pharmaceutically acceptable salt thereof. (7) A compound of formula (I) or a salt thereof according to claim 1, which is used to adjust noradrenaline balance. (8) A compound of formula (I) or a salt thereof according to claim 1, which is used to adjust serotonin balance.