JPS5867684A - 2-phenyltropane derivative, manufacture and medicinal composition containing same - 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 parent compounds, pharmaceutical compositions containing them, and methods for their preparation.

Racemic 3-(3-hydroxyphenyl)-N-n i
At low doses, a-virpiperazi7- (3-p p
presynaptic dopamln@autor
It is a known F-dopamine agonist that acts on @eaptor. At higher doses, one of the enantiomers becomes a postsynaptic F-pamine agonist.
c dopamineagonlst), while the other acts as a post-synadgic F pamine antagonist (p
ostgynaptiedopamine antag
onist). This compound is therefore potentially useful in the treatment of CNS disorders associated with excessive dopamine release.

The inventors have discovered a class of structurally distinct compounds that are also useful in the treatment of such disorders.

The present invention is based on the formula R.

[In the formula, R1#'i is human tetrachitaxy l-4 alkoxy or an acyloxy group that can be hydrolyzed in vivo, R, is hydrogen% C1-4 alkyl, hydroxy% C1
-4 alkoxy or an acyloxy group that can be hydrolyzed in vivo, or R1 and R, taken together to form ct-m alkylenedioxy, and an Ar1 group (wherein EFi or CHR).

, where pFiO~2, ZFiO spans S, n FiO is also #il, and when n is 0, one of R and R is Cl-4
alkyl, and the other is hydrogen or Ficl-a alkyl, or when Fin is 1, R6°R
1 and R, one #1cl-a alkyl, and the other two are the same or different, hydrogen or #1cl-a
-a alkyl, and R, #'ic, -, fur #l: group - (CN meaning) IRts
(wherein IFiO~2 and R11l
Fics-m cycloalkyl group), group -(CHI
)tR14 (where t is 1 or 2, and R1
4FiC! -1 alkenyl also Fic a alkoxy,
Trifluoromethyl, 710, nitro, carboxy, esterified carboxy and hydroxy, C-4
1 selected from Cl-4 alkyl optionally substituted with alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy;
In addition, Fi is a phenyl group which may be substituted with two substituents) or a chenyl group)] and its pharmaceutically suitable salts, as well as the compounds and their salts. Provide a solvate.

A preferred value for E is CCHs) x (CHx)P.

When E is a group represented by formula (A) defined above,
pti suitable KFiO MakuFi1. Preferably it is 0.

When E is a group represented by formula (B) defined above,
2 is O or S, preferably O.

When E is a group represented by formula (C) defined above,
Preferably each of R- and R1 in the case of FinxO and n
When Ra = 1, each skin of R1 and R is in the exo position.

Preferred examples of one of Ra and R1 when n = O'''c are methoxy, ethoxy, n-zoloxy, methyl, ethyl, n-zorobyl, medoxycarzanyl and hyethoxycarbonyl, hydroxy, hydroxymethyl hydroxyethyl, methoxymethyl, methoxyethyl,
Ethoxymethyl, ethoxyethyl, acetylmethyl and acetylethyl. Most preferred is methyl.

Preferred examples of R2 and R1 when ng=1 are methyl, ethyl and n-zolopykch.

When n = Q, the other of R and R1 and H =
The remaining two preferred examples when 1 are hydrogen, methyl, ethyl and n- and iso-propyl.

Examples of R1 and Rj include hydroxy, methoxy, ethoxy, n- and iso-propoxy and in vivo hydrolyzable acyloxy groups, such as Cl-4furcatuyloxy, e.g. acetoxy, prohionoxy, and n- and iso- Butyloxy-2,2-dimethylbutyloxy; substituted on the phenyl group by two substituents selected from Cl-4 alkyl, C-4 alkoxy, trifluoromethyl, halodane or nitro; benzoyloxy: a labile sulfonate group, e.g. alkanesulfonyloxy (e.g. methanesulfonyloxy), or a benzenesulfonyloxy substituted as in the case of benzoyloxy above, e.g. 1. toluenesulfonyloxy),
and - together include ethylenedioxy.

R1 may also be hydrogen or i'1cx-4 alkyl. Examples of suitable cl-4 alkyl groups include KFi methyl, ethyl and n- and iso-solvyl, preferably methyl.

R1 and/or R1 are hydroxy, methoxy, 22-dimethylgropanoyloxy or benzoyloxy, as appropriate.

R, is hydrogen or ViRl, depending on the case.

R1 usually has a reed in 3rd place, and R, #i usually 4 or 5
(according to standard numbering K for phenyl ring systems).

Preferred examples of R when C-traalkyl include methyl, ethyl, n- and in-zolopyl, and n-5ee
-, iso- and tert-ethyl, n-pentyl, n-
Includes hexyl, n-hethyl and 3-methylethyl.

Among the C toma groups, FiCl-s alkyl is useful.

Suitable examples of R when C1-5 alkyl include methyl, ethyl, n- and iso-zolopyl, especially n-zolopyl and iso-propyl.

Suitable examples of C4-7 alkyl include tfn-pentyl, n-hexyl and n-hethyl, especially those of formula (CHI
) uRlg (where u Fil or 2 and R+i Fisee −−4 or tert −(4
-, alkyl group), for example, 5
ee-ethyl, tert-7” thyl, n-pentyl, n
-hexyl and n-hethyl, and especially isoethyl, 3
-Methylbutyl, 22-dimethylzolopyl and 3.3-
Includes dimethylbutyl, 4-methylpentyl and 5-methylhexyl.

When R, is the group -(CH2)sRn as defined above,
Suitable examples of Rlm include FiCs-s cycloalkyl, preferably cyclohexyl, cyclopentyl or cyclozoethyl.

R, defined above -(CH,)tR14-1? altoki, tFii or #'i2 〇R14 is Cx-5 alkenyl, in such a group R, suitable examples thereof include vinyl, pro-1-chlor, solo-2-chloro, 1 -methylvinyl,buto-1
-enyl, de)-2-chloro, but-5-x-nyl, 1-
Includes methylenezolobyl, 1-)tylzolocy-1-chlor and l-methylderofu-2-enyl, all in the E and 2 forms. Such skin is preferably allyl.

When R14 is optionally substituted 7-enyl as defined above, suitable examples of such phenyl substituents include methyl, ethyl, n- and iso-propyl, n-, aee
- and tert-ethyl, preferably methyl, hydroxy, mefoxy, ethoxy, n- and iso-propyl and in vivo hydrolysable acyloxy groups, e.g. C14 alkanoyloxy, e.g. acetoxy , propionoxy and n- and iso-butoxy, 22-dimethylpropanoyloxy, C1-a alkyl, C-4 alkoxy, trifluoromethyl, halo I'y or nitro on the phenyl ring.
Also, as in the case of benzoyloxy which may be substituted with #i2 substituents, and unstable sulfonyloxy groups, such as C1-4 alkanesulfonyloxy (e.g. methanesulfonyloxy), or benzoyloxy, Alkyl groups optionally substituted with benzenesulfonyloxy which may be substituted with hydroxy, methoxy, 12-dimethylpropanoyloxy or benzoyloxy; methoxy, ethoxy, n- and in-propoxy, CF3, Contains fluor, chlor, or dememu. Preferably, R14Fi is unsubstituted in the case of optionally substituted phenyl. When R14 is chenyl, it may be ti2- or Vi3-chenyl.

Values of R include optionally substituted benzyl and phenethyl and thenylmethyl (also known as thenyl) as defined above. Optionally substituted benzyl and phenethyl are advantageous, benzyl and phenethyl are preferred.

Compounds of the formula (RI) can form acid addition salts at the bicyclic moiety nitrogen atom.

Pharmaceutically suitable salt KF of the compound represented by formula (1)
Included are acid addition salts with common acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid, lactic acid, acetic acid, and the like.

Since the compounds of formula (1) and their salts also form solvates, the invention also extends to such solvates.

It will, of course, be understood that the compound represented by formula (1) has at least one asymmetric center and can therefore exist as a number of stereoisomers.

In particular, the 1-phenyl dipyamyl bond is exo (exo) for bicycles.
) or endo orientation.

The invention extends to each of these stereoisomers, including enantiomers, and to mixtures thereof (including racemates).

One example of a compound 1ltE included in the compounds represented by formula (, 1) is ---(cHriP).

Another group of compounds included in the compounds represented by formula (1) are represented by formula (II) 1 (wherein the variables have the same meanings as in formula (1)K).

Appropriate and preferable R1t R, and R are as described under formula (1) A group of compounds included in the compound represented by formula (2m) is formula (Ill) (wherein R2 , C-4 alkoxy or in vivo hydrolyzable acyloxy, and
The remaining variables have the same meanings as in formula (1) K.

Appropriate and preferred R's and R's are as described under Formula (1).

Suitable and preferred residue variables are as described under formula (1).

A subgroup of compounds included in formula (1)K is the formula CM'
) (wherein RA is -1 alkyl or allyl),
and R1 and R4td (having the same meaning as in formula (III)).

Preferred examples of R- are allyl and R under formula (1).

As described for the Cx-ail substituent, a, n-propyl and isopropyl are preferred;

Preferred examples of H and H are as described under formula (I).

Another subgroup of compounds included in the compound represented by formula (II) is the compound represented by formula (V), where R: t; And R14 is the formula (1)
is phenyl which may be substituted as defined in (II) K is thenylmethyl, and R1 and R1 have the same meanings as in formula (II)K.

Suitable and preferred R; is the corresponding R under formula (1)
This is a circular written about saK.

Bi Benzyl and phenethyl are preferred.

Suitable and preferred R1 and R4 are as described under formula (1) ◇ Another subgroup of compounds encompassed by those represented by formula 1 is the compound of formula (1 [wherein Rz is C4 -1 alkyl or -(CHt)
sRts (where 3 is θ~2, and Rsm
FiCg-cycloalkyl) and R1 and R
1 has the same meaning as in formula (Ill).

Suitable and preferred R: #i corresponding R under formula (1),
This is a circular that describes the group.

Suitable and preferred R and R4 are as described under formula (1).

A group of O compounds encompassed by compounds of formula <Vt> include R: (CHH)IRts or (CH,)uRu as defined above, where 1, u, Rls and R1
1 has the same meaning as above).

Examples of R in these compounds include isozotyl,
3-methylbutyl, 12-dimethylpropyl, 3.3-
Includes dimethylbutyl, cyclopropylethyl, and cycloderobylmethyl.

Yet another subgroup of compounds encompassed by formula (1) is represented by formula (■) 1 , where the variables have the same meanings as in formula 1).

Suitable examples of R2 are as described under formula (W).

Suitable examples of R1 and R4 are as described under formula (mV).

Another group of sub-concepts encompassed by compounds of formula (1) of interest is represented by formula (■) in which the variables have the same meanings as in formula (V).

Suitable and preferred examples of RI are as described under formula (V).

Suitable and preferred examples of R1 and RA are as described under formula (IN).

Another subgroup of compounds included in the compounds represented by formula (carbonate) is represented by formula 1) (wherein the variables have the same meanings as in formula 1) K.

Suitable and preferred examples of RI are as described under formula (M).

Suitable and preferred examples of R1 and R- are as described under formula (1).

The second group of compounds encompassed by formula (1) is 1 (wherein is hydrogen or Cl-4 alkyl, and the remaining groups have the same meaning as in formula (1)K) ).

Appropriate and preferable R1 and Hi are R1 and Hi in formula (1).
1 and the associated Rm K).

Suitable and preferred remaining variables are the same as those described in formula (1).

One group of subconcepts of compounds included in formula (1) is the formula (X
I) 1 (wherein R41ict-i is alkyl or allyl, and Rs and Showa have the same meanings as in formula (X)).

Suitable examples of HA are allyl and RI under formula (I)
This is a general description of C1-1 alkyl.

Otori-Zorovir and Iso-Zorovir are preferred.

Suitable examples of R1 and RS are as described under formula (X).

Another group of compounds included in the compound represented by formula (X) is the compound of formula (XI) [wherein Bi is a group -(CH,)tili (wherein, t
Fil].

Suitable and preferred R; is the corresponding R under formula (1),
It is exactly as written about the base.

R, benzyl and 7-enethyl are preferred.

Suitable and preferable R1 and R: have the same meaning as in the formula (X). Another subgroup of compounds included in the compound represented by the formula (X) is the formula (XI) [wherein R : 1ltca-y alkyl or -(
CHm)sRg (in the formula, gourd is 0 to 2), and R*s #iCs is cycloalkyl), and R1 and Hi have the same meaning as in formula (X)]. It is what is expressed.

Suitable and preferred R: is the corresponding R under formula (1),
This is a circular that describes the group.

Suitable and preferred R1 and RI butterfly formulas (■) are as described below.

A group of O compounds included in the compound represented by formula (XI) ti R: CH(CH嘗)lRg 1 fcld (
CHm)uRu (in both formulas, m, u, RIB and R11Fi have the same meanings as above).

Examples of Bi 0 in these compounds include isodityl, 3-
Includes methylbutyl, z2-dimethylzolopyl, 3L3-dimethylbutyl, Schiff-tetrapropylmethyl.

An interesting subgroup of compounds encompassed by the compounds of formula (X) are those of formula (XI V)1, where the variables have the same meanings as in formula (1)K. A suitable example of O Hi is written under formula (1/) and is 9.

Suitable examples of R and R8 are as described under formula (X))
It is.

Another subgroup of compounds of interest subsumed by the compounds of formula (X) is the formula <XV>, in which the variables have the same meanings as in formula (V)K. A suitable and preferred example of OR3 is the formula (V)
This is the circular listed below.

Suitable and preferred examples of R1 and R are as described under formula (X)O.

Another subgroup of interest encompassed by compounds of formula (X) is those of formula (XM) 1 in which the variables have the same meanings as in formula (M)K. Preferred examples are as described under formula (M).

Suitable and preferred examples of R1 and Hi are as described under formula (X).

A third group of compounds included in the compounds represented by formula (1) are represented by formula (1) (wherein the variables have the same meanings as in formulas (1) and (1)). .

Suitable and preferred examples of R are the series described under formula (1). Suitable and preferred examples of R1 and Hi are the series described under formula (1). 2 is preferably 0. For a reason.

A group of compounds that are sub-concepts included in those represented by the formula (Jun) are represented by the formula (Jun) 1 (wherein, the variable groups have the same meanings as in the formula (■)).

Suitable and preferred variables are as described under formula (■).

Suitable and preferred R1 and Rs Id formulas are as described below.

Another subgroup of compounds encompassed by the compounds of formula (XVI'') is represented by formula (XI), in which the variables have the same meanings as in formula (XW)K.

Suitable and preferred variables are those described under formula (XNI).

Suitable and preferred R1 and R1 are written under the formula (C) and run through (C).

The fourth group of compounds included in formula (1)K is represented by formula (XX) 1 (wherein 83 hydrogen is Cl-4 alkyl)
, and the remaining variables have the same meanings as in formula CI)K.

Suitable and preferred R's are as described under formula (X)O Suitable and preferred remaining R's are as described under formula (I); preferably Fio It is.

A subgroup of compounds included in formula (XX) is represented by formula (XM) 1 (wherein, the variable group Fi(XX) has the same meaning as in the variable group Fi(XX)), R1 s R, and R, A suitable example is the formula <XX>
Other sub-concepts included in those represented by the formula <XX> A group of compounds are the compounds of the formula 001) R.

(wherein, the variable group has the same meaning as in formula (XX)).

Suitable and preferred R, l R1 and R are the same as described under formula (XX).

A fifth group of compounds encompassed by those represented by formula (1) is represented by formula (XXI) 1 (wherein R1 is HPO-C, C14 alkoxy or in vivo hydrolysable acylokita, and the remainder The variables CI have the same meaning as in formula CI)
It is expressed as

Appropriate and preferred R and R1 are as described under the formula (Seal).

Suitable and preferred residue variables have the same meanings as in formula (R).

A group of compounds that are a subconcept of the compound represented by formula (XXN) are represented by formula (Xff) 1 (in formula 7, the variables have the same meanings as in formula (XXI)).

One of R, and R1 is methyl or ethyl, as appropriate, and the other is hydrogen, methyl or ethyl. Preferred R, and suitable examples of R1 and Hi are of the formula (II
).

Another subgroup of compounds represented by formula (XX) that is also included are those represented by formula (XXV > (wherein the variables have the same meanings as in formula (XXI)K). It is.

One of R, R, and R is methyl or ethyl, as appropriate, and the other two are the same or different, and methyl, ethyl, and nine are hydrogen.

Preferred R, O is as described under formula (1). Suitable and preferred remaining variables are as described under formula (厘).

Formula (I)K includes os- to formula (XXM)Hi (X■) (wherein, old is hydrogen or alkyl, and the remainder)
The variable group has the same meaning as in formula (1)).

Suitable and preferred R1 and R are as described under formula (X). Suitable and preferred variables are as described under formula (, I).

Included in formula (XXVI) is a subgroup of compounds represented by formula (xxm>).

One of R and R1 is methyl or ethyl, as appropriate, and the other is hydrogen, methyl or ethyl.

Preferred Rs Fi is as described under formula (1).

Three suitable examples of R8 and R: are as described under formula (X).

Another subgroup of compounds included in the compound represented by formula (XXM) is the formula (xxvIB) (XI■B) (wherein, the variable group has the same meaning as in formula (XXVI)K) It is expressed as

One of Rs e Rv and R- is methyl or ethyl, as appropriate, and the other two are the same or different and are hydrogen, methyl, ethyl or hydrogen.

Preferred R is the same as described under formula (1).

Appropriate and preferred R1 and R are as defined in formula (X).

The present invention also provides a method for producing a compound represented by formula (1), wherein E is (wherein, the variable group has the same meaning as above) (where R1 is hydroxy and R1 is protected hydroxy)
, Roli water IA, Cl-4 alkyl, hydroxy or protected hydroxy, Rs #'i R with the same meaning as in formula (1)K
s 4 tah C5-v T k force/il, Jli
-CO(CHm)xR,.

(wherein xFiG or l, and R11 is of the formula (
) has the same meaning as in 1) is the group -CO(
CH,)7R14 (wherein, 7tiO1 or l, and Rsa tj:, excluding the Cto1 alkenyl, the formula (1
) K has the same meaning as in K, and the remaining variables in ) have the same meaning as in formula (1) K], and optionally R
, to R1, and convert s R1@ as desired or necessary.
Additionally, #'11Rii can be converted to R1 or #'iR2#C, if desired, R, can be converted to another KR1, and if desired, the obtained compound represented by formula (1) can be converted into a salt. including.

The logged hydroxyl groups of R1 and FiRo are common groups that can be easily converted to hydroxyl groups after the desired reaction), examples of which include c! -4 alkoxy and formula (1
) and R when it is in vivo hydrolyzable acyloxy as defined and described for R1 and R3 in or below, and benzyl or Fi7 enethyl on the phenyl ring.

This includes penzyloxy, which may be substituted in the same way as in the case of .

Reduction is conveniently accomplished in a single step using a metal-electron acceptor reducing couple - for example lithium in liquid ammonia.

When using lithium-liquid ammonia, the reaction is conveniently stopped on completion using ammonium chloride.

Alternatively, reduction can be accomplished in two steps without necessarily having to isolate the relevant intermediates.

Ibi compounds represented by formula (1) can be converted into compounds represented by formula (XXX)R1@ (wherein the variable groups have the same meanings as in formula (X[)K) by dehydration.

Dehydration can be accomplished using dilute strong acids, for example dilute mineral acids such as dilute sulfuric acid. Moderate heating to non-extreme heating temperatures, for example from ambient temperature to 90° C., is advantageous. Extremes in acidity and temperature can cause polymerization of the product and should be avoided. Other suitable acids include strong organic acids in organic solvents, such as toluenesulfonic acid in toxin.

Next, the compound represented by formula (XXK) is reduced,
Then, if necessary, Rs is converted to R1K, and if desired, s'' II or R11 is converted to R1 or R,K respectively, or R is converted to another R1, and the obtained The compound of formula (1) is converted into a salt if desired.

This process step forms an aspect of the present invention.

Reduction of a compound of formula (XXK) is where Rs is optionally substituted benzyl as defined or tj:Rt.Also optionally substituted benzyloxy as defined by FiRtl. When, and Rse
Rte again. If it is desired to avoid removal of pR11, this is conveniently accomplished (by conventional transition metal catalyzed hydrogenation) using mild reaction conditions. If a platinum or tetradium oxide catalyst at atmospheric pressure or slightly in excess is suitable,
Alternatively, if FiR, R1, or aRo retention is not desired, palladium- or platinum-
You can use charcoal. Ambient temperature is suitable and a dry inert polar solvent such as dry ethanol is suitable.

If the optionally substituted benzyl of R, is removed, the resulting second ann NH#i can be converted to Λ by conventional alkylation or to NR@ by acylation and reduction.

When R,1fc1-7furkanoylSC,--cycloalkyl-encs-malkanoyl or fcFic14 alkenoyl, conversion to the corresponding R is accomplished by reductive acylation, e.g., with an inorganic hydride reducing agent, e.g., borohydride. This can be achieved by reaction with the corresponding acid in the presence of sodium chloride.

Conversion to R,methyl can be accomplished using a mild reducing agent such as formaldehyde in the presence of sodium cyanoborohydride in an inert, highly oleaginous solvent such as a7toethryl.

It is convenient to reduce the aryl C with a strong inorganic hydride reducing agent such as the one defined by R.

When R1 is a protected hydroxyl group, Fi
When R is represented by the formula R1*0 (wherein Ru FiCl-4 alrylic), the conversion of R1 or R11 to R1 or 1ltRs hydroxy can be performed using pyridine hydrochloride, boron tribromide or triiodide. This is conveniently carried out by treatment with boron or iodotrimethylsilane, or by heating with an aqueous hydrobromic acid bath.

When R1 is C1-6 alkanoyl or optionally substituted benzoyl as defined, deprotection can be achieved by conventional methods, e.g. by acidic or basic hydrolysis. When benzyl is optionally substituted, conversion is carried out in the usual manner, for example at atmospheric pressure or slightly in excess. This method #'iRs is not suitable for the optionally substituted benzyl KFi, which tends to be removed prematurely.
-4 alkoxy or in vivo hydrolyzable acyloxy compounds where FiR1 and R8 are hydroxy, respectively, can be derived by conventional 0-alkylation or esterification reactions.

The reaction is carried out under conventional O-alkylation conditions using a compound of formula R41Q, where its a C1-4 alkyl and Q is a group that is readily substituted by a nucleophilic group. You can do it.

Preferred examples of Q11cdct%Br or halides such as
801 ・C4H6・pC)i, .

This includes unstable sulfonate groups such as

The reaction is generally carried out in an inert solvent at non-extreme temperatures, such as from ambient to mildly heated temperatures, eg, the reflux temperature of the solvent.

Those skilled in the art will appreciate that the 0-alkylation of compounds of formula (1) can be carried out by carrying out the acylation in the presence of a strong acid, such as trifluoroacetic acid, so that the nitrogen functionality is protected by protonation. If the %N nitrogen is not protected as such, quaternary N-alkylation of the I+=lINR1 moiety can also occur. Acids can also conveniently act as @ media.

In the case of in vivo hydrolyzable esters, the reaction is usually 2RF*w, where R?x h is an acyl group capable of forming an in vivo hydrolyzable acyloxy group, and *ti, e.g. Halides like chloride, C-4
The esterification can be carried out under conventional esterification conditions using a compound represented by acyloxy such as alkanoyloxy, or hydroxyloxy.

R7s is typically written under formula (1) and R1 and R
, which corresponds to the acyloxy group that can be hydrolyzed in vivo.

When W is parite, the reaction is generally carried out in the presence of a base, and when W is hydroxy? When , the reaction is generally carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

The reaction is generally carried out in an inert solvent at non-extreme temperatures, such as ambient to slightly heated temperatures, such as the reflux temperature of the solvent.

It will be understood that the above interconversions i may also be carried out in intermediates not represented by formula (1) or in compounds of formula (X[) or ti(XXK) themselves.

From the above description, the present invention #'i also provides a third method for producing a compound represented by formula (1) or a pharmaceutically suitable salt thereof, which method comprises formula %formula%) (wherein R1・Hydroxy was donated), RiI
is hydrogen, Ct4alkyl or hydroxyl and the remaining variables have the same meaning as in formula (1)K), and then, if desired, , O-alkylated or Fio-acylated with an acyloxy group that can be hydrolyzed in vivo, i.e., to form the resulting compound, and then, if desired, salt the resulting compound. Including.

Suitable process conditions are as described above for the associated first process step.

Reduction of a compound of formula (XXK) will remove the benzyl group as defined.

The present invention therefore provides a fourth method for producing a compound represented by formula (1), which method comprises formula (XX)1! ) (wherein R1 is hydroxy or 9-hydroxy, Rlt Fi hydrogen, Ct-a alkyl, hydroxyl or 9-hydroxy), and the remaining variables are as above. The compound represented by the formula <X)01>Q-Rs (having the same meaning)
XX)1) (wherein, Q is a group that can be easily substituted with a nucleophilic group,
and the remaining variable groups have the same meanings as above), and if necessary, R
Convert s to R, K, as desired and required! ! Depending on R,
@ Also convert tiRtt to R, 4 and 4'iRm respectively, R1s R, and #iRs to other Ri=Rtl
or RI and, if desired, converting the resulting compound of formula (Summer) into a salt.

Preferred examples of Q include halides such as ct, Br or I, and when Rs is defined as Rs, Q can also be O20. CH,f is O20,,C
, H4゜pCH, and when R3 is other than R, Q may also be C-alkanoyloxy such as aceFoxy or hydroxy.

The condensation of compounds of formulas (XXXI) and (XXXi) can be carried out in unstable protic solvents, such as ethers such as THF, hal hydrocarbons such as dichloromethane,
# in the extreme, or in a mixture of such solvents
It can be easily achieved at the same temperature.

The compound represented by the formula (XX) fl ) is novel and numerous;
As such, it therefore forms an aspect of the present invention.

Since the reaction generally removes the acid, the reaction can be combined with a base, e.g.
It is preferable to carry out the reaction in the presence of a mild inorganic base such as potassium carbonate or a stronger organic base such as triethylamine.

Variable interconversion can be achieved in the manner described above.

Acid addition salts of the compound represented by formula (1) can be prepared in a completely conventional manner by reacting the compound represented by formula (1) in basic form with a selected acid.

The compound represented by formula (Xl) is easily produced as described below and reacted on site without isolation of intermediates.

A compound represented by the formula (XXMI) is a compound represented by the formula (XXMI)
ie (wherein nL is hydrogen, RL is hydrogen, Cl-4 alkyl or hydrogen, and Mti is magnesium halide, preferably bromide). magnesium (-) or lithium) and the compound of the formula (XXXIV), where the variable group is of the formula (
1) having the same meaning as in 1), and then, as desired or necessary, R1@
In addition, FiRtt is defined as R1 and FiRxt.
Including tc conversion.

When M is magnesium(II) halide, the formula (
xxvl> can be generated in situ under the usual conditions for the Guinjard reagent. The conditions include dry, oil-free magnesium particles in a molar equivalent or excess of a halide, preferably bromide, corresponding to the compound of formula (XXXI') and a dry ether containing no protic solvent, e.g. , THF, dimethoxyethane or diethyl ether.

THF is the preferred solvent. The existence of true trace amount Ojibumuetan would be advantageous. Temperatures above ambient and non-extreme cooling temperatures, eg -15° C. from ambient, are preferred, although gradual initial heating may be advantageous.

When M is lithium, the compound of formula (XXm) is usually prepared in situ under indirect metallation conditions, for example by reacting the corresponding chloride, preferably bromide, with n-butyllithium. Can be generated. Temperatures of -60°C from ambient temperature are preferred. Once completed, the reaction is conveniently stopped with water.

Any hydroxy λ group in R-, as described above,
It will be appreciated that compounds of formula (XXM) are best preserved and, if desired, debonded after coupling. Conventional metallizations can be derived from the corresponding compounds substituted with by Grignard reactions.

These O-corresponding compounds are known compounds, or can be derived from known compounds by conventional methods, or can be prepared in a similar manner.Depending on the reaction steric factors, the formula ( 1) or (XX!Tl)
Compounds represented by c xxx > and (XXM') can be synthesized with an axial or equatorial (eq-uatoria) substitution orientation at the az-e Schiff 12 position, or can be infinitely varied. It is synthesized as a mixture of these forms in a ratio of 1 to 3. For example, reduction of a compound of the formula will give a mixture of both isomers. Such mixtures can be separated by conventional methods, for example by chromatography or fractional crystallization. Carrying out the latter method on acid addition salts is useful when the corresponding compound of formula (XXVI) is liquid under ambient conditions; the reaction conditions result in the production of an axial isomer. When desired, this can be converted to the corresponding equatorially bonded isomer by treatment with a strong base, e.g. butyllithium (which may be in complex with tetramethylethylenediamine). Diastereomers also exist in two enantiomeric forms due to asymmetric substitution of the azobicyclo ring.

A specific enantiomer can be obtained by using an asymmetric starting material, or by synthesizing the compound represented by formula (1) from two semi-intermediates, and converting the enantiomers by conventional methods such as salt formation with an asymmetric acid and Can be separated and divided into salts.

The compound represented by formula (1) is divided into diastereomers and/or
Or enanthio! The ability to synthesize nonsterically specific and asymmetrically from a mixture of - and separate and/or divide the compound represented by formula (1) (accordingly convenient O formula (XXXPI) The compound represented by the formula (XXXV
)0OC (wherein the variables have the same meanings as above) can be synthesized by the following conventional steps.

(XXXV) i) Na0C1/
(X X
The compound represented by xxxv > has the formula (XXXM) (
It can be synthesized from a compound represented by the formula RuFi organic group, such as Cl-4 alkyl, and the remaining groups have the same meanings as above, by the following conventional process.

0 0 (XXXM)
(XXXV) The dehydration step can be accomplished as described above for compounds of formula (XXIK').

Compounds of the formula (XXXVI') in which E is as defined are: ) is reacted with the corresponding dialdehyde of formula (XXXW) and an acetone-1,3-dicarboxylic acid monoester, e.g. (by conversion using conventional methods).

Reaction #i This is an example of a Robinson-8 chopf reaction, preferably carried out in an aqueous IJ buffer solution at pH 1'5.

A compound represented by the formula <XXXW) and R3-an Setosocarboxylic acid monoester is a known compound. be.

The compound represented by the formula (XXXW) is known or can be produced by a method analogous to the production of known compounds. On the other hand Fic to a alkyl)
, and the other is hydrogen or #1Ct-a alkyl,
Also, when n = l, RI * R? and R, have the same meanings as above, and R, has the same meanings as above).
) (wherein R'- to R$ and nFi have the same meanings as above), a known compound represented by the formula (XXX'W
) H, N -8ebopf conditions and then convert RI to R if desired.

It can be manufactured by converting to

Formula (XXXK)-c'swasah, in the formula, Rs and HiR
A compound in which one of y is #1C1-4 alkyl and the other is hydrogen or Cl-4 alkyl), and the number is 0 is represented by formula (XL) OCR.

(In the formula, one of R and R is #'1c1-4 alkyl) and the other is hydrogen-spanning cl-4 alkyl.

A compound represented by formula (XL) can be produced by catalytic hydrogenation of a compound represented by formula (XLI) (where H, 1 and R have the same meaning as in formula (XL)K).

Catalytic hydrogenation is usually carried out in methanol using hydrogen and palladium on charcoal.

It is represented by the formula (XXXV), where one of R and R1 is hydroxy) and the other is hydrogen! IC total 4 Compounds which are furkyl and where n is 0 have the formula (XLI
) (wherein one of R1 and Sho is hydrogen and the other is hydrogen or 'FiC*~4 alkyl).

The compounds represented by the formulas (XLI') and (XLI) are either R1 and B> defined for the formula (XL) K, respectively, or are each represented by the formula (X
R defined for LI ): and Aki ) is reacted with bromine and methanol,
The reaction of the compound of formula (XLIIt) with bromine and methanol is then carried out at about -40 DEG C., followed by a month.

(In the formula, R-~Rs #i has the same meaning as above, and n
= 1],
Ald@r etol,Annal,, 626.73
(1959) K can be prepared according to the nine procedures described.

The compounds of formula (XLJV) are known compounds, or can be spun from them, or can be prepared by lateral synthesis of known structurally similar compounds.

The compound represented by formula (1) is dopamine! −.

It is a dopamine agonist. ,
Some of them are α-adr'enoceptor agonl.
st).

The compound is presynaptic
and postsynades receptors (postsynades)
reeeptor). presynaptic autoreceptor (presynapti)
e dopamine@autor-ee@ptor)
The effect on K and the effect on dopamine receptors (po
stmynaptle dopamIne r@cpt
or) Due to the pattern of action in K., the compound may be used in central nervous system disorders associated with excessive dopamine release, such as psychosis such as schizophrenia and Huntington's
tington) Chorea, and central nervous system disorders associated with % or insufficient dopamine release for the treatment of hyperkinesia and movement disorders, such as Parkinson's (Park-1nson).
) disease and! It can be used to treat loractin hypersecretion syndrome.

Compound #i can also be used as a mood regulator in the treatment of disorders, especially in the treatment of anxiety.

Similar to other agonists, including the agonist-acting dopamine agonist 3-PPP, the compound of formula CI) has a high dopaminergic effect at high doses, i.e., at doses near the upper end of the dosage range described below. -1''=dopamlne ant-agonlst, acting specifically in a post-synathotic manner. As a post-synathotic dopamine antagonist, the compounds can be used in the treatment of disorders associated with dopamine excess, such as those mentioned above.

The specific profile of a given compound is readily ascertainable by routine pharmacological tests of the type described below, or is well known to those skilled in the art. Thus, for example, agonist activity at pre-synathous autoreceptors leads to compound inhibition of spontaneous climbing behavior in mice, whereas agonist activity at post-synathozoid receptors increases spontaneous climbing behavior in mice, and agonist activity at post-synathozoid receptors increases spontaneous climbing behavior in mice. Antagonist activity in the body can be confirmed by inhibition of apomorphine (dopane agonist)-induced climbing in mice, respectively.

It is believed that the compound represented by formula (X) has an activity profile in which "synaptic antagonist" activity is predominant.

Therefore, the present invention also provides a pharmaceutical composition comprising the compound represented by formula (1), a pharmaceutically suitable salt thereof, and a solvate of the salt of #'i the chemical compound, together with a pharmaceutically suitable carrier. do. Such compositions can be applied for oral or parenteral administration and can be used as such as tablets, capsules, oral liquid preparations, powders, granules, lozenges, powders for the preparation of liquids, solutions for injections and infusions, etc. The composition may be in the form of a suspension or a suppository. Orally administrable compositions are generally preferred.

It can contain fillers, tableting lubricants, disintegrants and appropriate fl#Il formulations. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may take the form of, for example, aqueous or oily suspensions, emulsions, syrups or elixirs, or as a dry powder, which can be mixed with water or other suitable vehicle before use. may be provided. Such liquid formulations as suspended copper emulsifiers, non-aqueous media (
It may contain conventional additives such as edible oils (including edible oils), preservatives, and, if desired, conventional flavoring or coloring agents.

For parenteral administration, liquid unit dosage forms are prepared using a compound of formula (1) and a sterile vehicle, with the compound either suspended or dissolved in the vehicle, depending on the vehicle and concentration used. To prepare solutions, the compound can be dissolved in water for injection, filter sterilized, filled into a suitable vial or ampoule, and sealed. Advantageously, local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in a medium in which the compound is dissolved in the vehicle, sterilized by exposure to ethylene oxide, and then filled into sterile vials or ampoules. Made in 1#. Advantageous KF
i. A surfactant or wetting agent is included in the composition to promote uniform distribution of the compound.

As is common practice, a composition is usually accompanied by handwritten or printed instructions for use in the relevant medical practice.

The precise dosage to be used in the treatment of any of the disorders mentioned above will vary depending on the actual compound of formula (1) used and other factors, such as the extent of the disorder being treated.

The present invention further provides an effective amount of the compound represented by formula (1) or a pharmaceutically suitable salt thereof, or a solvate of a ti-carboxylic compound or a salt to a mourning mammal, including a human being. Provided are methods for treating dopamine-dependent CNS disorders in patients. An "effective amount" usually depends on a number of factors, including the nature and extent of the disease being treated, the weight of the patient, and the actual compound used.

However, for purposes of illustration, one unit dose is preferably 0.
．． 01-20111f, e.g. 0.02-10q1"
Contains a compound represented by formula (1).

Also, by way of example, such a unit dose may be preferably 8 to 0.0 ml per day. OOO5~105w/
&p Once a day, for example, 1
It is preferably administered 2, 3, 4.5 or 6 times a day.

Hereinafter, the production of the compound represented by formula (1) will be described with reference to Examples, and the production of intermediates thereof will be described with reference to Production Examples.

The exo- and enene F stereochemistry of the following compounds is similar to “H
Attribution was made based on nmr data or preparation method.

In case of unintended nomenclature, it should be understood that the Hnmr data and/or I1ll manufacturing method is used to determine the structure.

Production example 1 8-benzyl-8-azobicyclo(12,1)octo-
2-ene-2-carboxylic hydrochloride (Dl) 8-benzyl-8-azubicyclo(341) oct-2-ene-2-
Methyl urponate (19, Of) in 5N hydrochloric acid (250
The solution in m) was heated at reflux in a nitrogen atmosphere for 20 hours and evaporated to dryness under vacuum to give the carboxylic acid (20?) as a foam.

The NMR spectrum ((■s)msO) corresponds to the starting material methyl ester, approximately 84 Kj? 9. Indicates a missing single line.

Production example 2 8-benzyl-8-azobicyclo(3,LI)octo-
2-en-2-carboxamide (D2) 8-benzyl-
8-Azobicyclo(&2.1.)oct-2-ene-carboxylic hydrochloride (18F) in chloroform (500 mg
) and DMF (α2-) middle phase suspension was mixed with oxalyl chloride (
20F), stirred for 3 hours at room temperature and evaporated to dryness under vacuum.
1740i was obtained as a yellow oil, which was reduced to −70″
lOK (cool acetone-dry ice), (35%)
It was treated with aqueous ammonia (400 m) and returned to room temperature.

After stirring for 2 hours at room temperature, solid potassium carbonate (approximately 100
f) and the mixture was dissolved in dichloromethane (sxyoI
mg). The organic layer was washed with water (10d), dried (Na1SO4), and evaporated to dryness under vacuum to obtain carboxamide (15F), which was ax
, ctl-'Et,o. Melting point 143~
145℃, horse mackerel maw (nujol): 3380.32
00 and 1660 1 (Experimental value: Ce73.15:H, 7,4:N, 11.
8゜CIIHI@N hook.

Theoretical value of 0.25H,0: C,73,0;H,7,55:N,11.
35X) Production Example 3 8-benzyl-8-azobicyclo 12.1) Octane-
2-one (D3) carboxamide (D2,8.Of) methanol (40
0m) solution at -10°C with α8N hypochlorous acid) I
It was treated by adding Jum solution (45 m) dropwise over 15 minutes while keeping the temperature below -50°C. Bring the solution back to +5°C (over 0.5 hours) and incubate for 15 minutes.
The mixture was heated to 70°C over a period of minutes. Concentrated hydrochloric acid (20i) was added and the solution heated at reflux for 0.5 hours and evaporated to dryness under vacuum. Treat the residue with water (400 mg) and solid potassium carbonate.1 Extract the mixture with methylene chloride! >X5O-)
, wash with water 10++d) and dry (Nag 5o4)
, evaporated to dryness under vacuum and the product chromatographed on silica gel (100f) in methane to give the 2-ketone (,5,5F), mp 39-41
Specializes in °C (from ether-hexane).

umax1718cm-”: δ(CD01m) 1.5
-2.5 (8H, m) -3,35 (2H, br,
s) 3.7 (2H, s) and 7.3 (5H, b
r, m) (experimental value: C, 76,3; I(, 7,95:
N, 6.35, C14H1yNOO,33H,0O
[Theoretical value: C, 7g, 0:H, &05:N, 6.33X
) Production Example 4 8-benzyl-2-(5'-methoxyphenyl)-8-
Dry surface (10
d) The medium solution was slowly added to a medium temperature mixture of dry magnesium (α125 mol) and iodine/crystals in dry THF (25 m) at room temperature and the mixture was stirred at room temperature for 2 hours until most of the magnesium had been consumed. Oops. The solution was cooled to -10°C and the ketone (D3) (0.05m
9. Dry the solution in HF (10 m) dropwise. The mixture was stirred at room temperature for α5 hours and then refluxed overnight. The product was acidified with excess 5N hydrochloric acid and evaporated to dryness under vacuum. Carbonate the residue to make it basic)
The crude olefin (D4) was obtained by extraction with dichloromethane, drying and evaporation.

Production Example 5 (±)-(2-exo)hydroxy and (2-endo)
Hydroxy-8-benzyl-2-(5'-methoxyphenyl)-8-adevicic o(3,2,1)octane (D
5) and (D6) (D5) (D6
) meta-bromoanisole (LOf') in dry THF
The solution in (25m) was treated with a solution of n-butyllithium in hexane (1,15M, 14m) at -55°C in a nitrogen atmosphere and the solution was stirred at this temperature for 2 hours. A solution of 8-benzyl-8-azobicyclo(311)-1cutane-2-o/(1Of) in dry THF (5+d) was added dropwise and the solution was allowed to warm to room temperature (over a period of 2 hours). The solution was quenched by careful addition of water O and evaporated to dryness under vacuum. The residue was dissolved in 5N hydrochloric acid (50mg) and extracted with ether (3X40m). To make the aqueous solution basic10
X sodium carbonate) and extracted with dichloromethane (3X50m). Organic 7-lactone was washed with water and dried (Na
1SO4), busy evaporating to dryness, t! the law of nature! A mixture of rn (D5) and endo (D6) alcohols was obtained as an oil (1159).

s+max (#membrane) 34403-':J (CLJ
CIm) 1.15-14 (8Hm) e 2.85
(m) and 3.15 (m) (total 2H), &45
(1) and 3L50 (s) (total 2H) s3.
80 (3H, s), 4.65 (IH, bra) (
(exchanged with Dlo), and 6.7-7.45 (9H, m)
.

Pure 2-exo-alcohol (D5) was obtained by crystallizing the crude product from ether-pentane. Melting point 70-71°C (Experiment @: C, 77,9;) i, 7.9; N, 4.
35. C1, H, NO, (2) [Logical value: C, 7g, 0
:H,78,0:Ht 7.8 :Np 4.35X
), wm*x.

(CHCb l@?%l) 3375cm-Weight: m/
e323 (4X) e306 (4) 232 (25),
173 (25), 173 (35), 160 (50)?
and 91 (100).

2-exo- and 2-endo-3-n-piovir-2-
Hydroxy-2'-(3'-methoxyphenyl)-8-
azobicyclor 3.2.1. ) octane (DI) and (D8), 2-exo- and 2-endo-8-iso-
Propyl-2-hydroxy-2-(5'-methoxyphenyl)-8-azobicyclora,zigo:Nifin (D9) 1 kU (DIO), 2-exo- and 2
-ene)'-8-7enethyl-2-hydroxy-2-(
5'-methoxyphenyl)-8-7rbi? riar3. ,
Ll] Ifi7 (DI 1) and (DI2) and 2-equino and 2-end-8(2-chenylmethyl)-2-hydroxy-2-(5'-methoxyphenyl)
-8-Azubicyclo[lL1]octane (DI3) and (DI4) were similarly prepared.

Example 1 (±)-8-Benzyl-2-(5'-methoxyphenyl)-8-7 debicyclo(3,11)octane (11 olefin (D4) (Q, 1 mole)
rr) x solution in ethanol (100 m) to pto
Hydrogenation was performed using iF) at atmospheric pressure and room temperature until hydrogen absorption stopped. The mixture was filtered (through Celite) and evaporated to dryness under vacuum to give the crude compound (1), which was purified by crystallization. endo)-8-benzyl-
2-(5'-methoxyphenyl)-8-azuVcyclo(
3,2,1) Octane (2) and (3) Kingy)' (3)
Dry tetrahydrofuran (TH
F') (25m) solution was stirred at -55°C in a nitrogen atmosphere, and a solution of Ll 5Mn-butyllithium in hexane (&15m) was added over 0.15 hours. friend. The solution was kept at this temperature for 2 hours, then 8-benzyl-8-azo-cyclo(3,2,1)octane-2
A solution of -one (1,1sy) in dry THF (10m) was added dropwise and after the addition was complete the solution was allowed to warm to room temperature (required 1.5 hours). The solution was cooled to -78°C and covered with lithium foil (0
, 5F, approximately 20 pieces) was added, followed by liquid ammonia (approximately 50 m). After 10 minutes, a blue color appears and 2
After minutes, ammonium chloride (5t) was carefully added to stop the reaction. The mixture was allowed to warm to room temperature and the solvent was evaporated to dryness. The residue was treated with 2N sodium carbonate and extracted with ether (5X). The combined ether extracts were washed with water, dried (Na@80a) and evaporated to dryness. The residue was dissolved in ethyl acetate-benkune (1:19) using silica gel BF254 and gypsum adsorbent (2).
IL r r -igon ChroInator
on 7924 fJ and the least polar exoisomer (2) (
Obtained as an oil.

(Experimental value: Lily ao7. t938, C, IH,
Theoretical value of NO; M2O3, 1936), ymax
, (thin film) 3050m-”j and 1718cm
-” has no absorption, J (250MHz-CDCI,)
1.43 (IH, m) t 1.7.4 (3H, m
), 1.9-2.3 (4H, m) e 2.71
(I He b r −d = J=6 Hz) t
a25 (2II -m) -3,36(I H-d
5J-12Hz), 3.43 (IH, d, J
-12H2), 3.75 (3H,I) C6,7
5 (IH, In) and 7.0-7.3 (8H, m)
: Exhibition 307 (50X) 278 (5), 216 (
10) 1186 (7)*7t2 (25), 158(
80) and 91 (100).

Treatment with ethanolic hydrogen chloride and recrystallization with ethanol-ether yields K hydrochloride, mp 150-151°C.
I got it.

7 (experimental value: C, 73, 3: H, 7, 8: N, 4.1
．． CI, 1G, 4°Ct*HzsNO, HCl) Jli
&fif: C, 73, 3s, H, 7, 6, N.

4.05: Cl, 10.396) Furthermore, the more polar endo-isomer (3) (0,33f
) was obtained as an oil.

Experimental value: Siri 30, 1942. Theoretical value of C snow tH goose sNO: M2O3, 1936), νmax, (thin IK) 3050cm-" above and 17183-
'IKFi no absorption: δ (250bnlz, CDC
11) 1.5 = 2.1 (8H, m) e 3.1-
3.32 (3H, m), 3J3 (2H, m)
.

3.79 (a) l, m) e 6.75 (3H,
m) and 7.15-7.5 (6H, m): treated with the same ethanolic hydrogen chloride as the m/e exo isomer and recrystallized from ethanol-ethyl acetate) hydrochloride raw hydrate, melting point 16
6-168°C was obtained.

(Experimental value: C,71,3:H,7,5; NtL95#
C1, 10, 2°C, IH,, NO, HCl α5n
, Theoretical value of o: C,71,45:)it7.7:N,
395:C1, IQ, 05X).

Cum (3) (Lithium (0,52F, about 25 pieces) was added to anhydrous knee 7'/I/(40m) of Metarp 45 Anisole (1,74F)
) in a nitrogen atmosphere, and after 3 hours at room temperature, 8
-Anhydrous ether of benzyl-8-azo-bicyclo(3,'ll)octan-2-one (1,Of) (1011t
) was added and the mixture was heated under mild reflux for 4 hours and then left overnight at room temperature. Liquid ammonia (approximately 50 m) was then added and after the formation of a blue color, the reaction was stopped with ammonium chloride (61>'i'). The product was collected and
Chromatography as described above yields the exo isomer (2) (0,02F) and the endo isomer (3) (0,04t), which have the same n, m as described above. , r, and mass spectra.

2-exo- and 2-endo-3-n-propyl-2-
(5'-methoxyphenyl)-8-azobicyclo r3.
Z1] octane (4) and (5), 2-exo- and 2
-Endo-8-iso-propyl-2-(5'-methoxyphene A;) -B-adebisic tetra[all]octane (6) and (7)% 2-x xo and 2-endo-
8-7enethyl-2-(3'-methoxyphenyl)-8
-Azobicyclo (& 2= 13 octane (8) and (9), and 2-equino and 2-endo-8-<2-
chenylmethyl)-2-(3'-methoxyphenyl)-
8-Azubicyclo (3111 octane) and aυ were similarly produced.

The above compounds (2) to Ql) Fi alcohol intermediate (D5
) to (D14) can be produced by a similar reduction process to tc.

Example 3 48% hydrogen bromide of (±)-8-benzyl-2-(5'-hydroxyphenyl)-8-azobiccyclo(3,21)octane hydrobromide Q3 (1) (Q, SF) m1C50+It
) The solution was heated at 110° C. in a nitrogen atmosphere for 2 hours and evaporated to dryness under vacuum. The residue was crystallized from ethanol/ether to give phenol hydrobromide a.

Example 4 (±)(2-exo)- and (2-endo)-8-benzyl-2-(5'-hydroxyphenyl)-8-azobiciclo(341)octane hydrobromide (13 and 0 vessels) Concave (2) b/HBr, HBrl 4 y-p 1) Exo-8-benzyl-2-(5'-methoxyphenyx)-g-azobiccyclo(3,2,1')octane 1
2) (0,13t) of 48% hydrobromic acid (40m)
The medium solution was heated to 110° C. for 2 hours under a nitrogen atmosphere and then evaporated to dryness under vacuum. The residue was crystallized from ethanol-ether to give Toshiexophenol hydrobromide <13 (α!5f) melting point 225-228°C.

(Experimental value: 'Cg 62.65: H* 6.4
: N p 3L65 : B r @ 21.35-
Theoretical value of exeHuNOHBr o, sH, o:
Ce 61615-: M.

6.55SN, 3.65:Br, 20.85%:m/@
293.1773°C8°H,, Theoretical value of No: M2
O3, 1780).

δ[CDC1m + (CDi)mso) 1.65
-185 (9H, m).

3.55-42 (3Hem) t445(s) and 4
65(s) (total IH).

6.35 (1'Ht de J=12Hz)
t 6.6-7.45 (8H, m), 7.7
(1) 1°by, a) and 9.0 (IH, 8)
.

Isomer 0 is Silicab Jl/ (Eastman) t
, tom, on-plate ethyl acetate development showed Rfα64.

b) Endo-8-benzyl-2-(5'-methoxyphenyl)-8-azobiccyclo(341)octane(3)(
A solution of 0.3r) in 48% hydrobromic acid (40 m) was heated to 110° C. for 2 hours in a nitrogen atmosphere and evaporated to dryness under vacuum. Endo-phenol hydrobromide (14) (0
, 28r) with a melting point of 133-137°C.

(Experimental value: C# 61.65: H@6.2:
N @ 3.6- Cs* Hss”oaHBr, 0
．． Theoretical value of 66HxO: C,62,2:H,6,6;
N, 3.65%: m/e293.1775. czeH
Theoretical value of gsNO: M2O3°1780).

JrCDCla + (CDm) Proverb SO] 1.6-15
(8H, rn), 3.7-4.5 (5He m)
, 6.7 (3)1 t rn) e' 7.15 (
I He m) e 7-5 (3Ha m) C7,
85 (2H, m), 9.1 (IH, a) and 10.4 (IH, br, g).

Isomer 04) has a solitary force (Eastman) j*t
, ethyl acetate development on an es plate showed Rfo, 59.

2-exo-3-n-propyl-2-(5'-hydroxyphenyl)-8-azobicyclo(3,2,1]octane, 2-exo- and 2-endo-8-47-zotz
Pyr-2(5'-hydroxyphenyl)-8-azo-bicyclo[3,2,,1]octane 07) and 0,2-
exo-8-7enethyl-2-(3'-hydroxyphenyl)-8-azobicyclor3.2.1]octane Q'
3. 2-echino and 2-endo-3-(2-thenylmethyl)-2-(3'-hydroxyphenyl)-8-
Azobicyclor 3.2.1 ) Octane C! υ and mouth were similarly prepared as their hydrobromide salts.

2-endo-3-n-propyl-2-(5'-hydroxyphenyl)-8-adevisic D[12,1]octane (le is similarly prepared from 5a, see Example 6), which has the following properties: It had

Melting point 210-215°C (experimental value: C, 55, 6: H, 7, 05: N435
*m/e245.

1786, C*sH*xNO, HBr, Hlo theoretical values: C, 55, 8: Hm7.6: N, 405"
, cls) (Theoretical value of 18No: N245°1780)
.

Hydrobromide L5 hydrate of 2-endo-8-phenethyl-2-(5'-hydroxyphenyl)-8-azobicyclo("a, zi,) octane was prepared from (9a) in the same manner as K.
M was manufactured (see Example 8). It had the following properties.

Melting point: 102-106°C, (experimental value: Ce 60.3 e # H # 6-6
: Np 1g pm/e 307-1919, CH
Theoretical values of HHNO, HBr, 1.5H, O; C.

60.7:H, 7,05:N, 3.35%, C,,
Theoretical value of H snow, No: N307.1889).

Example 5 (±)-(2-exo) and (2-endo)-2-(3
'-methoxyphenyl)-8-azobicyclo(12,1
) Octane hydrochloride (c) and (2) (2) Exo
Q ■ Exo and (3) End C24) End (&)
A solution of (2-exo)-6-benzyl-2-(5'-methoxyphenyl)-8-azobicyclo(a2.I)octane (21(0,65?') in ethanol (50 m) with 10% palladium - Hydrogenated with charcoal, (O,St) for 4 hours at room temperature.The solution was filtered (through Celite) and
(2-exo)-2-(3'-methoxyphenyl)-8-azobicyclo( &2.1) Octane hydrochloride CI! 3 (0,15F) was obtained.

ff1. p, 136-140'lc.

Experimental value: m/@217.1473. C□4H1,N0
rDflJ logical value; M 217-1466) −' (C
DCb) 1.5-! 7 (8H-m) * 3.0
(IH, br, s), 185 (3H, s), 4
．． 05 (2H, br, s+).

and 6.75-7.4 (4H, m).

(b) 2-:l-7V isomer (3) (0,65?
”) t-11K, but using an 18-hour hydrogenation time
-(endo)-2-(3'-methoxyphenyl)-8-
Azobicyclo(3,2,1)octane hydrochloride (goods) (0
, 47t) were obtained.

Melting point 165-166°C, (experimental value: C, 65,95:H, 7,95SN, 5.
5: C1,1&95゜m/e217.1465 C,,
H,, NOHCI (DJutkffi:Ct66.
25:H, 7,95,N, 5.5:C1,13,95%
, Theoretical value of Cxi'HtsNO: y7.1466):
δ (CDCI, ) 1.5-2.6 (8) 1゜m)
, 3.65 (IH, m), 3.8 (3H, s)
, 4.2 (2H, br, a).

6.65-7.4 (4H*m) and 9.85 (2
H, br, a).

Example 6 ±(2-endo)-8-n-propyl-2-(5'-methoxyphenyl)-8-azobicyclora, 2.11 octane hydrochloride (5a)c! 4 (
5m) HCz salt (2-endo)-2-(3'-methoxyphenyl)-8-74J''r 3.2,1
]ytly (0,25t) of propionic acid (5-)
The medium solution was mixed with propionic acid (10 g) and dry toluene (10 g).
*) and Hou 7 were added to a mixture of sodium dichloride (0.5F) and the mixture was heated under reflux for 3 hours. The zeta paste was evaporated to dryness under vacuum, basified with sodium carbonate, extracted with dichloromethane (3X), the organic fraction was washed with water, dried (Na B 80a)% and evaporated to dryness under vacuum. Ta.

The residue was treated with ethanolic hydrogen chloride and recrystallized from ethyl acetate-ether.
n-propyl-2-(5'-methoxyphenyl)-8-
Azabicyclo r3.2.1) Octane Hydrochloride C5m) (
0,245? ) A melting point of 180-182°C was obtained.

(Experimental values: C* 6 & 5: Hy 8.9: Ne
4)5. Theoretical value of HCI: C
, 69,0:H, &85:Ne4.75%).

Example 7 (±)-(2-endo)-8-yenethyl-2+ (3
#-methoxyphenyl)-8-azobicyclo[&λl]
HCl salt of octane hydrochloride (9 meters) (9) (2-endo)-2-(3'-methoxyphenyl)-8
-7 debicyclo[341]octane (0,4t'
, dry DMF (10ssg), phenethyl 2-deo
A mixture of (0,38F) and anhydrous potassium carbonate (2f) was heated to about 70°C for 2 hours in a nitrogen atmosphere. The mixture was evaporated to dryness under vacuum, dissolved in 5N hydrochloric acid and washed with ether. , basified with 10X sodium carbonate and extracted with dichloromethane)-8-7enethyl-2-
(3'-methoxyphenyl)-8-azobicyclo(11
11 octane hydrochloride (9m) (0,55F), melting point 14
5-146°C was obtained.

(Experimental values: C, 73,65:H, 7,84:N, 3.
9:C1,1α05; m/e 321-2085,
C8, Hxt No HC1) 311 Theory M: C*
73.85:Hy 7.9:N, 3.9:C19,
9X: CuHuNOC) theoretical value M321.2093).

Biological Data Test compound inhibits spontaneous crawling behavior in mice. This inhibitory effect is caused by the presynaptic dopaminergic autoreceptor (Pr@5ynaptle dopamine-
rgic auto*eeptor), ie, receptors that, when stimulated, cause dopamine synthesis and inhibition of dopaminergic I10 electrical activity.

Spontaneous climbing behavior FiM, P, Martrea et
al., Brlan-Rsmeareh, 1977
, 136, 319). This was done over a 10 minute period starting 3 minutes after subcutaneous administration of the compound.
This involves monitoring the frequency of the mouse's climbing behavior in an inverted food crawler.

Climbing is defined as when the mouse lifts all four legs off the floor. The experiment is conducted in 5 groups with a minimum of 10 animals per group, and one group is used as a control. The number of climbs exhibited by the drug-treated group is expressed as a percentage change from the number exhibited by the control group.

Compound Inhibition rate of spontaneous climbing%0, 2 q/
kq 13 24 14 38 16 49 20 12 No toxic effects were observed in the above test.

(′″ 1°11
ag, nj-ri 1st g.

1. Display of incidents 　Ganshota Z-No. 1/) Deφ0 No. 3. Person who makes corrections Relationship with the incident! to

Claims (1)

[Scope of Claims] (Formula 11 (R is a group, Rsu is hydrogen, Ct-a alkyl hydroxy, C-4 alkoxy, or a ryosyloxy group that can be hydrolyzed in vivo, or R, and R, taken together to form C5-5 alkylenedioxy, and A is a group (wherein E is or (C), where p is O~2, and 2 is O or #iS, n is Ol or l], and when is 0, one of R7 and R7 is Ct-a alkyl, and the other is hydrogen or ticl-a alkyl. , or when O is 1, one of Ri, R, and R is tic1-4 alkyl, and the other two are the same = and fi different, and hydrogen or FiCx-
a Alkyl, so L Te R1/d cm-y Aluminum?
Ru: M -(CHm)@Ru (wherein S is θ~2 and is a cycloalkyl group), group -(cH)tRtn (wherein tFilman f
i2 and R14 is C tos alkenyl i
c-, alkoxy, trif-C-4-alkoxy, carboxy, esterified or? C optionally substituted with acyloxy or acyloxy which can be hydrolyzed in vivo
a phenyl group optionally substituted with two substituents selected from l-4 alkyl), and Fi is a chenyl group), or a drug thereof; A suitable salt or solvate of the compound is a salt thereof. (2) The compound according to claim (1), which is E#i. (3) Formula 1) () (wherein R23 is hydrogen or Cl-4 alkyl,
and! ! The compound according to claim (2), wherein the variable group 4) is represented by aS (having the same meaning as in R1). (4) Formula (X) (in the formula, s Rm Fi9*-s akyl or allyl, and Rs Elbisho is defined in Claim No. 3
The compound according to claim (3), which has the same meaning as in claim (3). (5) Formula 0I) R. [In the formula, Rla fi -(CHs)tRi (in the formula,
tUl or 2, and RL is of the formula (optionally substituted phenyl as defined in RI) or thenylmethyl, and R1 and Ri Fi
A compound represented by claim (3) having the same meaning as in claim (3). (6) (±)-2-exo-8-benzyl-2-(5'
-Hydroxyphenyl)-8-adebisic tlr3.2
．． 1:]Octane hydrobromide, (±)-2-endo-
8-benzyl-2-(5'-hydroxyphenyl)-8
- azobicyclo r3.2.1) octane hydrobromide,
(±)-2-endo-3-n-propyl-2-(5'-
hydroxyphenyl)-8-azubicyclo r3.2.1
) octane hydrobromide hydrate, also (±)-2-endo-8-7enethyl-2-(3'-hydroxyphenyl)-8-azobicyclo r3.2.11
The compound according to any one of claims (1) to (5), which is octane hydrobromide hemihydrate. (7) Formula (XXK'') [wherein R1 is hydroxy or protected hydroxy, R11 is hydrogen s C1-4 alkyl, hydroxy or protected 9-hydroxy, R3 is formula (1) K R, which has the same meaning as in
Also 1tCt-1 alkanoyl, group -CO(CH*)
% Rls C In the formula, x #i0 or #il,
and Rlm has the same meaning as in claim (1)) or a group -CO(CH)FR14 (in the formula, y#io or #il
't' foot, and R14 is claim 1f@(13
(having the same meaning as in claim (1)) and the remaining variables #i having the same meaning as in claim (1)), and then optionally , convert R1 to R6, and convert R1 or R11 to 6 each R, or # as desired or necessary.
iR, or R,, R, or R, to another R1
z R and t′iR, and if desired,
A method for producing a compound according to claim (1), which comprises converting the obtained compound represented by formula (I) into a salt. (81 formula (XXK) table t) Salel compound formula a (XX
m) (wherein the variables have the same meanings as in claim (7)) produced in situ by dehydration of a compound represented by the method of. (9) Formula (XXM) (wherein R1@ is hydroxy or protected), RoFi hydrogen, Cl-4 alkyl, hydroxym9 is protected hydroxy, and the remaining variables are The compound represented by the formula (X
X) I) Q -R, (XX) [)
and the remaining variables have the same meanings as above), and if necessary, R
1 to R, and, as desired or necessary, R10 or R11 to R1 or R, respectively, R,, R, R, R. to other R1* R1 or R, if desired,
A method for producing a compound according to claim (1), which comprises converting the obtained compound represented by formula (1) into a salt. A pharmaceutical composition comprising a compound represented by formula (1), a pharmaceutically suitable salt thereof, or a solvate of the compound or its salt together with a pharmaceutically suitable carrier. ■ F-pamine in mammals, including humans, by administering the compound represented by formula (1), a pharmaceutically suitable salt thereof, or a solvate of the compound or a salt thereof. Methods of treating addictive CNS disorders. 1 Formula (XXM) R1@(XXXI) (wherein s R1 is hydroxy or saturated hydroxy, RstFi hydrogen s C1-4 alkyl, hydroxy or hydroxy is saturated, and the remaining variables The group is a compound represented by claim 1 (having the same meaning as in claim 11).