JPS5810578A - Sulfinyl derivatives, manufacture and medicinal composition containing them - 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 provides novel compounds Th, pharmaceutical compositions containing them,
Regarding their manufacturing methods.

European Patent Application No. 793029786 and US Patent Application No. 107413 disclose that compounds of formula 1 (4) and their pharmaceutical salts have useful pharmacological activity.

In the formula, R1#'ltO1-g alkoxy group, R- and R
II is the same or! ! hydrogen, halogen* 0F8b
01-? Acyl group.

at-7 acryl amino group, or when KFil to 2 C
Amino group, aminocarzenyl group or azeta-nosulfone group substituted with 1-6 alkyl group b 0s-s alkylnulfone group or nitro group, sRl dihydrogen or 1'10
t-@alfluoryl group and 5RsFict-? Alkyl group or -(OHM)sR? group (however, in .5tiO~2, 0.R? is C1-, a cycloalkyl group) or -
(OH,)tR.

group (where t is 1 or Fi2, R4#-iC
*-s alkeni k group 511d K u 01-s is a phenyl group substituted with one or two substituents selected from an arcel group, an alkoxy group, a trifluoromethyl group, and a halogen) and 4 a @ n @
p and Qt-1 are each 0 to 2. One more set (
Compounds of Al are stated to be useful in the treatment of disorders related to impaired gastrointestinal motility and/or disorders of the central nervous system. All compounds are stated to have anti-emetic activity.

The above-mentioned European and United States patent applications, the summaries of which are cited by reference, broadly exemplify the representative compounds of the world and their pharmacological activities: 1 Formula (A)K:! The stated utility of a series of five defined compounds has been demonstrated.

In the above formula (4), s R3 may be a C1-6 alkylsulfonyl group (R-80!-). Compounds having a structure generally similar to the compounds of major powers, but in which R3 is a 01-6 arforosulfinyl group (n, -5o-), are ri
Tomo discovered that it has useful pharmacological activity similar to fU.

Accordingly, the present invention provides compounds of formula (1), pharmaceutically useful salts and N-oxides thereof, and solvent adducts thereof, wherein b' *9 and q are each from 0 to 2, and s'
Rm is hydrogen or CI-・alkyl group, and S RS is C
1-7 alkyl group or -(OH2)s Rt group (tomodashi, S is 0 to 2 and SR?ke aS-S cycloalkyl group) or -(OH)1R8 group (tomodashi, t is Q, R with 1 or 2.

is a C2-6 alkyl group *01-4 is a C2-6 alkyl group or a phenyl group substituted with one or two substituents selected from alkoxy group, trifluoromethyl group and halogen), or a chenyl group* R
t + Rz + Rsl and Rss are the following (at or F
i(b). (a) RS is an at-S alkoxy group or a 01-6 alkylthio group, R,,R
, 11 and Rljl, one is a 01-6 alkylnulfinyl group, the other two are C01 alkylenedioxy groups, or one of the other two is hydrogen, and the others are halogen, trifluoromethyl group, 01-@al group e
C1-8 alkoxy group 10 t-7 acyl group, hydroxy group, or sometimes tiO+-・alkyl group t 03-1 cycloalkyl group *0s-s cycloalkyl c, -4 alkyl group, phenyl group or phenC1-4 alkyl N-substituted with one or two groups selected from the group or 04-
@Polymethylene is N-disubstituted to form a 9-amino or aminocarzenyl group. (b) Rs and R1 are both [01-@alkylene dioxy group, % Rt is CI-, alkylsulfinyl group, s R11 hydrogen, ), rogene, trifluoromethyl group, s 0x-s
Arphor group r Ct-6 alkoxy group.

CI-, acyl g, ol-, acylamino group, 01
-alkylsulfonyl group + 0t-s alkylsulfinyl group.

Hydroxy group, nitro group or amino group or when KFiC troalkyl&#03-II cycloalkyl group, 03
-m cycloalkyl Cl-4alruyl group, phenyl group or 7ene01-4aryl group and then or at times #104-h aminocaryNyl group substituted with EryN-disubstituted polymethylene group selected from.

The group of compounds within formula (1) is represented by formula (IA).

RSViOt-s is an alkoxy group and a C1-6 alkylthio group, FL is hydrogen or a 01-8 alkyl group, and R6 is a 01-7 alkyl group or -(OHM)rR
7 groups (S is 0 to 2, #1, &yFiOs-s
) which is a cycloalkyl group is -(OH,)tR8 group (
However, t is 1 or 2, and at the time of Rat, C1-
6 alkyl group + 0f-4 alkoxy group, trifluoromethyl group, and O buty-alkenyl group or phenyl group or chenyl group substituted with 7'jl or 2 substituents) or chenyl group And that s
FI to R*tU eight logen, Of-? 7 ShiJ, Moto, C! 1-＠ Al: 7 $ cy group, am-s"yl, ruthio group or hydroxy group 1: 1 or 2 C troalkyl group* O+-s alkoxy group j c, -.alkylthio group or hydroxy group In the substituted aminocarginyl group, R1 is cl-, and in the alkylnurfinyl group, Q, n, p and q are each 0 to 2.

The second group of compounds within formula (1) is represented by formula 1 (IB).

R, Hydrogen #i 0. -, argyl group "mR@ketcl-7 alkyl group or -(OHM)sR7 group (however, 3 is 0 to 2 and I'L is a cycloalkyl group) or -( OH, > Electric R Hatake (however, tke1
It's a double.

When Rsti, KFiOt-.alkyl group, Cto4 alkoxy group.

) +1 fluoromethyl group and halogen selected 1
or a 7tOs-s alkenyl group or a phenyl group substituted with two substituents) or a chenyl group and 5R
41 is hydrogen, halogen, OF3.01-, acyl group,
01-? Acylamide 7 groups also Iri, amino group, cl-
alkoxy group, at-@alkylthio group, hydroxyl group or nitro group, or sometimes 1 to 2 01-6 argyl groups Cr-5 alkoxy group, a, --al.1
Gylthio group.

It is a friend aminocarzenyl group substituted with a hydroxy group or a nitro group, and it is an R1g#101-・alkylnurfinyl group, and s''+D*Q and rij are each 0 to 2
It is. r is preferably #i0 or #'i1, more preferably #i1.

Examples of s C1-alkylsulfinyl groups in formula (1) are methyl-, ethyl- and n- and iso-propylsulfinyl groups, preferably methyl- or ethyl-1, especially methyl-sulfinyl groups.

This 1 group is azabicyclylaminocar7 as 1.
The 5 position with respect to the p-nyl side chain is generally preferred.

Preferably, 5-menal or #-15-ethylsulfinyl s-methylnurfinylteal.

Preferred examples of R1 are methoxy, ethoxy, n- and in-proxy, methylthio, methylthio, n- and iso-propylthio. In particular, R1
Vi is a methoxy group.

In such compounds, one of R and R11 is 5
et4-rukylsulfinyl group, the other two are preferably both ethylenedioxy or ethylenedioxy groups, or one is hydrogen and the other is chlorine, bromine and one or #-i2 methyl group, ethyl 4% n- or iso-propyl group, n, 5ee- or utert
-f 1-substituted thyl group, cyclohefosyl group, phenyl group or benzyl group or C4-spanning 0. /rimethylene group, methoxy group, ethoxy group.

It is selected from n- and in-propoxy groups, methyl groups, ethyl groups, and amino groups monosubstituted on n- and in-propyl groups.

Preferably, the other one is a chloro group, a bromo group or a methoxy group.

On the other hand, R1 and R are both a methylene dioxy group or an ethylene dioxy group, and 5R11 is preferably a hydrogen, chlorine, bromine, axi) group, %c1-4-lkanoyl, terimino group, for example, a formylamino group, an acetate group, etc. 7 groups, propionylamino groups, n- and isobutyrylamino groups, and l
Also, Fi2@I is substituted with methyl group, ethyl group, n- or iso-propyl group, n-,5et- or fi tert-methyl group, cyclohexyl group, 7-enyl group or FiA andyl group, and Viot or 05# An amino group N-disubstituted with a rimethylene group, a nitro group, a methoxy group, an ethoxy group, an n- and iso-propoxy group, a methyl group, an ethyl group, or an n- or iso-zolobyl group.

Preferably, R11Fi is hydrogen, chloro or amino group. Often h R11 is hydrogen.

Preferred examples where R@ is 01-4 alkyl group include methyl group, ethyl group, n- and iso-zorobyl Its n-
, 5ee-, iso- and tert-butyl groups,
In particular the methyl, fl-propyl and see-methyl groups.

Similarly, in the h at-y group, 0 to! Alkyl groups are preferred.

R1 is 0. -, alkykiliIO, preferred examples include R-pentyl as at-hecacyl group, n-heptyl group, 3-methylbunal group, 4-methylypentyl group and 5-
It is a methylhexyl group.

When R6 is a -(ORB)sRv group, a preferred example of B is an alkyl group, preferably a cyclohexyl group. @ is preferably l.

When a is -(OH,)tR, t is preferably Fi
It is l.

When %am is an at-i alkenyl group in the R group,
One preferable example thereof is a vinyl group, a prop-1-enyl group,
f rope-2-enyl 1-methylvinyl group, sauté-1-enyl group, futi-2-enyl group.

But-3-enyl group, 1-methylenepropyl group.

l-methylprope+1+enyl group and 1-methylprop-2-enyl group, and when optical isomerism exists, they are B and zW.

A preferred 01-s alkenyl R8 group is a vinyl group, preferably an allyl group.

When R- is an optionally substituted phenyl group.

A preferred example of the phenyl substituent is a methyl group.

Ethyl group, n- and iso-propyl group, n, 5ee
- and tert-ethyl groups, methophoxy groups, ethoxy groups.

n- and iso-propoxy groups s O''s groups m fluoro group, chloro group or bromo group. Preferred R is.

Sometimes substituted phenyl groups are unsubstituted. R
, is a chenyl group, it is also 2- or Fi3-chenyl i, generally a 2-chenyl group.

Two groups #i of R6, substituted when mentioned above (ndyl group and chenylmethyl group (or called chenyl group)
It is.

When R. is an 01-4 alkyl group, the preferable f! of the mai-4 alder group is PO#'i, methyl group, ethyl group,
and hiisopropyl group, n+, iso-1 sec −+ and 1@r t.

-Butyl group, particularly methyl group.

When R is -(oH,)tR, the most preferred example is when t is 1 and R11 is an unpurchased phenyl group or a monoa
l% of my enyl is a mono-p-substituted phenyl group. Examples of preferred p-substituents Fi.

Methyl group, trifluoromethyl group, fluoro group.

Chloro and bromo groups, especially fluoro groups.

These are particularly preferred examples of unsubstituted 4-and-4-benzyl group, p-fluoro-4-and-zyl group, and p-chlorobenzyl group 1klJp to methylbenzyl group Fi1.

nll is preferably 0. q is preferably 0 to 1, particularly preferably 1. pFi is preferably 0 to 1, especially 0.

Often, AmiF and side chain nitrogen! ! Atomic Fi, minimum 2-3
carbon atoms, preferably Fi3 carbon atoms.

When the separation is made by 3 atoms and n is O.

The 00 N R1 moiety is preferably in equatorial orientation relative to the bicyclo system.

Pharmaceutically useful salts of the compound of formula (1) include 1 common acids such as hydrochloric acid, aqueous bromide acid, phosphoric acid, oleic acid, citric acid, tartaric acid,
It is an acid addition salt with lactic acid, acetic acid, etc.

Pharmaceutically useful salts of compounds of formula (1) are also quaternary ammonium salts. Examples of this salt include compounds such as Rs-Y
(Friend, R・ket-S alkyl group,) 12ru C1
-6 alkyl group or f7rog-7 cycloalkyl group, which is an anion of Ykemeshi) Contains K-engineered quaternized compounds. A preferred example of R9 is 1. These are methyl group, ethyl group, n- and iso-propyl group, benzyl group, and phenylethyl group. Preferences for Y-fPO are halides such as chloride, chloride, and romide.

Includes iodite.

Compounds of formula (1), their salts and N-ogicides are
It also forms a solvent adduct, and the present invention encompasses such a solvent adduct.

From the above, it can be seen that the formula (1) in the compound of formula (1) on the − plane
), it can be seen that it has the structure (N5 (7t, R14Fi 0t-s furkyl group, Tosb R11 is halogen) t-.

A suitable 1'L, 480, is as described for I'Lts in equation (1).

Preferred is R+s#i chloro group. Preferred R14 is a methyl group or an ethyl group, especially a methyl group.

In the group consisting of compounds in the compound of formula (1), 1
The part of formula (II) is that of formula (In), and the part of formula (IV
) has a part #'i1 of formula (V) (where pores, p, and holes are the same as those of formula (1)), and these compounds of formula (1) have formula (W)1m (where h R@*R1m5R14+p+Q is the same as above).

Preferred R14 is the same as described for 2-.

Preferably p is 0 or l, especially 0.

Preferably q is l and the moiety of formula (2) is then added at the 3-position (the usual counting) and is in the β-orientation.

Preferred examples of B• in 2M include those shown in formula (1) for R-, where examples of R- are 01=? Contains alkyl groups and cyclohexylmethyl groups. A particularly preferred example of R@ is a benzyl group sometimes substituted with a phenyl ring as defined in formula (I).

Groups of compounds within those of formula M are those of formula II, where Bl. is a C1-4 alkyl group.

Preferred examples of R1- are as described for the B.01-4 alkyl group of formula (I).

It is preferable that the moiety of formula (1) is in the β orientation with respect to the nortronozone ring.

Preferred group 11 of compounds within them of formula (to) (where ELM- is c, ~7 alkyl group, -(CH
,)tR''s group (where t is 1 or 2 and R1- is a substituted phenyl group, cyclohexylmethyl group or chenylmethyl group as defined in formula (1)).

Preferred R- groups are as described for the corresponding R6 group in Formula 1 (I).

Particularly preferred is the Bm-benzyl group.

It is preferable that the moiety 2〇 is β-coordinated with respect to the northronozone ring.

Preferred groups of compounds of formula (to) are:
These are those of the formula (IX) [where R@1 is the same as the formula].

A preferred example of R.1 is the excess mentioned for 2).

Another group of compounds within preferred formula (b) is Rl
i [where B- is as defined in equation (4)].

Preferable B2. An example of this is Equation 2 (the overload mentioned in a).

A second preferred group of compounds within the preferred formula (1) is the formula (to) [where % R14 and B6 are as defined in the formula (to), and Rfg is an alkoxy group or a hydroxy group from 01 to G. They are those of

Preferably, the 00 N H moiety is in the β-orientation with respect to the nortronozone ring.

Preferred aSSs are as described for the alkoxyl t/Rtt group of formula (1).

RIS preferably includes a methoxy group.

2,3-dimethoxy and 2,4-dimethoxy nuclei (1 to 10ONH-) are particularly preferred.

Preferable R1 is the same as that described for formula 1 (to).

A preferred group of compounds within formula (XI) is the formula [where Bl is as described for formula (-)]
%R14 and R11 are as described for formula (XI)].

Preferable B1. is as described in the formula cVM).

Preferred R14 and Rli u@ the excess mentioned in formula (XI).

A second group of compounds within the preferred formula (XI) [where 几- is the same as in 9 mentioned for formula (4),
Rta and Recommendation sla (XI)].

Preferable Bl is as described in formula 1 (4).

Preferable R14 and Rli are as defined in formula (XI).

A third group of preferred compounds within formula (XI) is 5
Formula (XIV) [However, 几1. is as defined in Formula (4).

8 ports and RIIS are as defined in formula (XI)]
These are those.

Preferable R1- is as described in formula (■).

Preferably R14 and Rls are in excess as stated in formula (M).

A fourth group of compounds within preferred formula (Xi) is
Formula (XV) [However, B!・ is as defined in formula (to), and R
14 and Rts are those of the formula (as defined in X).

Preferable Bl is as described in formula (a).

Preferable RI4 and atS are as defined in formula (Xi).

The third group of compounds within formula (1) is of formula (XM)
[However, n' is l or 2, and R@ v R11*
R14el)? Q is the same as formula (■)].

Preferable p and q are O or 1, respectively.

Preferably p is O and Q is 1. Preferably n is l
It is.

Preferable 6 m R11 and R14 are as described in formula (Vl).

Formula ■ in the compound of formula (I) R.

The image part has the structure ('xvM) atS (where B!- is an amino group, chloro group, or alkoxy group, and 8!4 is 01 to @alkyl group).

Preferably 5Rxaij: methyl group or ethyl group, especially methyl group.

A fourth group of compounds within formula (I) and their useful salts are those of formula (XI) (where s'l s"14yR111+ p# Q
Fi is the same as above).

The preferred shame 4 is the tsuyaku mentioned on the second page.

Preferably p is 0 or f'il, and is preferably O.

Preferably, q is 1, and the part of the formula (■) is added at the 3rd position (normal counting method) to have a β orientation.

A preferred example of the formula 6 is represented by formula (1) for R6. A particularly preferred example of R@ is.

O1-7 alkyl group and cyclohexylmethyl group. Particularly preferred examples of B- include benzyl groups sometimes substituted with phenyl rings as defined in Bunmu (I).

The group of compounds in formula (X@) is represented by formula (XIX)tt
s (However, 几16 is 01-4 alkyl group).

A preferable example of 几16 is as described in the formula (Vrl).

Preferably, the moiety of formula (Aπ) is β-oriented with respect to the nortronone ξ ring.

A preferred group of compounds within formula (X14) is formula R1
・ [Tatashi, R”6 id 01-77 Ru4 Ru group,
-(OHM)till group, where tUt or 2 and - is a phenyl group, sometimes substituted as defined in formula (I).

It is a cyclohexylmethyl group or a thenylmethyl group]
These are those.

Preferred R"sFi is as described for the R6 group in the formula.

Particularly preferred is the R''@yJ group.

Preferably, the moiety of formula (XVII) is in the β orientation relative to the nortropane ring.

A preferred group of compounds within formula (VI) are those of formula where R61 is the same as defined in formula (W).

A preferred example of B, 1 is as described in the formula CVM>,
Ru.

Another group of compounds within formula (Vl) that are preferred are those of 2003Dill, where Bm- is as defined in formula (4).

A preferable example of Bj is as defined in equation (4).

A fifth preferred group of compounds within the preferred formula (1) are those of the formula (XXI[), where R14 and B.

Preferably, the 0ONH moiety is oriented β with respect to the northronozone ring.

Preferable R@ and R14 are the same as those described in formula (■).

Preferred groups of compounds within the formula (XXI!
However, R, 1, and 几14 are as defined in the formula.

Preferable R. 凰 is as described in formula (Vll).

Preferable R14 is as described in formula (XX[).

A second group of compounds within formula (XXI) which are preferred are those of formula (XXV) where R:6 and R14 are as defined in formula (4).

Preferable R2 is as described in formula 1 (■).

Preferred R14 is as defined in formula CX)01).

A third group of compounds within the preferred formula (XXHI) [
However, R- and 114 are the undervalues defined by formula (4).

Preferred R- is as described in Nibi).

Preferred R14 and RIS are as described in formula (XXII).

A fourth group of compounds within the preferred formula (XXIII) is a compound of the formula (XEI) [9 and Bl. is as defined in the formula (to), and 1
14 is defined by the formula (seal) and there are nine ways.

Preferably, it is too small as described in Expanded Formula 1 (2). There are nine preferred 814a formulas (XXI).

The sixth group of compounds within formula (1) has the formula R
14 is as defined by formula (II), and %R11 is the undervalue as defined by formula (I).

Preferably, p and q are each 0 or Fi1.

Preferably, p is 0 and bqtil. Preferably n is 1.

Preferred "le R11p R14 is as described in formula (1) as well as on the side.

It is, of course, to be understood that compounds of formula (1) may have chiral or zochiral centers and exist in multiple stereoisomeric forms.

The present invention also covers each of these stereoisomeric forms and mixtures thereof (including racemates). The different isomers can be separated one from the other by a variety of conventional methods. Certain isomers are derived by stereospecific or asymmetric synthesis.

Compounds of formula (I) are prepared in a manner analogous to the large-scale compounds.

Therefore, the present invention provides a method for producing the compound of formula (I), and the method of the present invention includes nine methods of formula (XMX). However, when R1 is 01~・alkoxy,
These third groups are 01-6 alkylthio. ) acid or its reactive derivative and formula 1 (nX) [wherein,
R6 is as defined in formula (I), and the remaining variables are as defined in formula (I). ] and then react with the compound of ! Depending on the generation R11 or R1! , convert R6 to other R6, and form the formula (
The resulting compound of I) may be formed into a pharmaceutically acceptable salt.

As used herein, "reactive derivative" refers to a compound (Xxx
) reaction compound <ya>cv acid group and formula (XXX)
A derivative of the compound (X[X) that forms an amide bond with the amine group of the compound (X).

This reactive derivative is often an acid, a halide of the acid <xxix>, such as an acid chloride. In these cases, the reaction is usually carried out in an inert solvent, preferably in the presence of an acid acceptor. An inert solvent is any solvent that is inert towards both reactants, for example benzene, toluene, diethyl ether or dichloromethane. The acid acceptor is a tertiary amine, e.g., triethylsamine, trimethylamine, pyridine, an organic base such as picoline,
or inorganic acid acceptors such as calcium carbonate, sodium carbonate, potassium carbonate or other similar are suitable. It should be noted that it is also possible to use certain acid acceptors, such as organic bases, as inert solvents.

These reaction temperatures may be carried out at less extreme temperatures, such as from -10° to 100° and more suitably from 06° to 80°. Higher reaction temperatures are used with lower active acids of formula (XXIX), whereas lower temperatures are used with lower active acids of formula (XXIX).
X) is used with the more reactive acids.

When ambient temperature is used, other useful reactive derivatives of II (XXIX) are highly activated esters such as pentachlorophenyl ester. The reaction is generally carried out in an inert polar solvent such as dimethylformamide.

The reaction may be carried out by forming the anhydride of acid <XXX> in a conventional manner and reacting it with compound (XXX). In this case, the customary mixed anhydrides are used. The reaction is also carried out in the presence of a dehydration catalyst such as cal/diimide, e.g. dicyclohexyl cardiimide (XX
It is carried out by reaction of [X) with compound CXXX).

Intermediates of formulas (XX[X) and (XXX) are both well known compounds and can be produced by analogous methods for known compounds.

-00-N R1-(OR2)n- in the compound of formula (1)
A bond is understood to have an α or β orientation with respect to the ring of the bicyclic moiety to which it is attached. Mixtures of α and β isomers of compounds of formula (I) may be synthesized non-stereospecifically. The desired isomers are separated from these by conventional methods, such as chromatography. The α or β isomer can be selectively synthesized as desired from the corresponding α or β form of the compound of formula (XXX).

Synthesis of compounds of formula (Xn) from the corresponding α or β isomers is generally preferred.

The α or β forms of compounds of formula (xvllll) can be produced if desired by well-known stereospecific methods. For example, these methods lead to the α and β isomers of the illustrated compounds of formula (XXX). Furthermore, for the α-isomer, European Patent Application No. 79302978.6 and U.S. Patent Application No.
It is described in 30.4A and 4C of No. 1107,413.

Zolecasser, a compound of formula (XXX), is synthesized stereospecifically, for example as az)'(D3) of Description 2 of the aforementioned European and US patent applications, and then, while retaining the configuration, Under non-stereospecific conditions the formula (XXX
) is converted into the corresponding desired isomer of the compound.

Optionally, the precursor may contain itself (zolo)tyral center ((
pro)chiral centre) but is converted under stereospecific conditions to the desired isomer of the compound of formula (XXX).

Alternatively, mixtures of α and β isomers of compounds of formula 1 <XXX> can be synthesized non-stereospecifically and the desired isomer advantageously separated from the mixture, for example by chromatography. However, it is usually convenient in this case to react the mixture to obtain a mixture of the α and β isomers of the compound of formula (1) and, if desired, to separate these as already mentioned above.

Table 1 below illustrates stereospecific and non-stereospecific synthetic routes for intermediates of formula (XXX) where n is O.

Table 2 below illustrates the production route for the intermediate of formula (xxx) where n is 1 and 2.

Acid addition salts of compounds of formula (I) can be produced in a completely conventional manner by reacting the basic form of a compound of formula (I) with a selected nonacid.

Quaternary ammonium salts of compounds of formula (I) can be prepared using conventional methods for such salts, for example by combining selected compounds of formula (1) with compounds R, Y (where R9 and Y are previously defined). ) can be produced by reacting with The reaction is advantageously carried out in a suitable solvent such as acetone, methanol, ethanol, dimethylformamide and the like at ambient or elevated temperature and pressure. The nitrogen atom of the moiety of formula (IV) forms an N-oxide to produce an internal N-oxide salt of the compound of formula (1). N-oxides can be produced by conventional methods such as reaction of selected compounds of formula (1) with organic peracids such as m-chlorobenzoic acid. This reaction is suitably carried out in an organic solvent at a temperature below ambient temperature.

It is clear that the reaction product of compounds of formula (XXIX) and (XXX) is a compound of formula (XXXI).

The variables in the compounds of formula (XX)G) have the meanings given in formulas (XXIX) and (m). Convert to R to 11 or Rlm1. ,'4 le Ih, R11t f
Compounds of formula (XXXI) containing c haRtt are useful intermediates and form an important aspect of the invention.

Some compounds of formula (XXXI) will be included within the scope of Wenmu (I).

"4 e R11m"1 which can be converted into other corresponding groups
Compounds of formula (I) containing 1 or R6 groups are also useful intermediates and form an important aspect of the invention.

Through examples of such transformations, we will discuss the R11 nitro group! 1 Conversion to an amino group can be accomplished by conventional methods such as by reduction. Therefore, any process method provided by the present invention in the production of compounds of formula (1) substituted by amino groups involves reduction of the corresponding intermediates of formula correspondingly substituted by nitro groups.

Reduction of intermediates containing nitro groups may be carried out with well-known reagents applicable to reducing nitroanisole to aminoanisole. A suitable reagent for this reduction is stannous chloride in hydrochloric acid or in a mixture of hydrochloric acid and acetic acid.

The desired amino compound is obtained from the reaction mixture by neutralizing the reaction mixture, then extracting with a water-immiscible solvent such as ethyl acetate, and recovering the solvent by evaporation.

Transition metals such as Kel are often used. The desired compound is obtained from the reaction mixture by filtration and evaporation to dryness.

In both cases the initial crude product can be purified by chromatography or crystallization or by forming acid addition salts which can be recrystallized.

However, in general, the corresponding 01-1 acylamino acids are derived from their reactive derivatives containing amino groups of the formula (1
) and so produced compounds of formula (I)
It is more convenient to deacylate the compound.

C1~! Those compounds of the invention substituted by an azilatino group can be produced from the corresponding intermediates containing a 7-mino group by reaction with acylated derivatives, which may already be described as suitable acylated derivatives. The reaction may proceed as described for the reaction of compounds of formula. Acylation with formamide KII can be carried out with the free acid.

The present invention thus also provides any method for the production of compounds of formula (1) substituted by an ahno group.

This optional method then comprises a deacylation reaction of the corresponding compound of formula (1) correspondingly substituted by zero to one acylamino group.

Generally, the hydrolysis reaction can be carried out by treatment with a base such as an alkali metal hydroxide.

As noted < Although R11 can be nitro, it is generally preferred that R11 be an all group other than nitro.

The optionally substituted benzyl group, X
XXII) A compound of 11 is obtained, where the variables are as defined in the formula. Furthermore, a compound of formula (XXXII) can be converted into one compound of formula (I) with a different R6.

The present invention also provides the corresponding compounds of the formula (XXXII) mentioned above and the compound QR [wherein R6 is 9 as defined in formula (1) and Q is a group easily substituted by a nucleophilic group] or an atom], and RR+R'll
and R''11 to stones, R41 and R1!, respectively, which may further form a pharmaceutically acceptable salt or N-oxide of the resulting compound of formula (I).
Optional methods of preparing compounds of I) are provided.

Suitable groups or groups for Q are Ot, Br, I.

oso goose OH, or oso goose 0. H, I) OH.

Preferred atoms for Q include OL, Br and I.

Particularly suitable compounds QR are embodied benzyls or benzyl chloride such as benzyl chloride.

The reaction may be carried out under conventional alkylation reaction conditions, for example in the presence of an acid acceptor such as potassium carbonate, in an inert solvent such as dimethylformamide. Generally the reaction is carried out at less extreme temperatures, such as ambient or slightly elevated temperatures.

However, it is generally more convenient to interconvert Re in the compound of formula (XXX) before carrying out the coupling with formula (XXIX) or a derivative thereof.

Such interconversion is conveniently carried out under the conditions mentioned above. It is desirable to protect the amino function with a group that can be easily removed by acid decomposition, such as an O,-1 alkanoyl group, prior to the R6 interconversion.

R11! 01-s alkylthio is defined as Rt
It can be converted to Z.

Another method according to the invention is thus prepared by preparing a compound of the formula (XXX[I) as previously defined, in which R is c-to-alkoxy and one of the R or R is 01～
- alkylthio) and then, if necessary, the radical 1 in the compound thus formed! , 几'
11 e Rlm Yuki or R-舅+”
ll@R1m or 几6 and optionally forming a pharmaceutically acceptable salt of the resulting compound of formula (I) or its N-oxide.

These oxidation reactions are usually carried out at temperatures below ambient temperature using stoichiometric amounts of organic peracids in non-aqueous inert reaction media, preferably chlorinated hydrocarbon solvents, such as peracetic acid;
Alternatively, it may be conveniently carried out using an inorganic oxidant such as chromium trioxide in acid and vinegar.

It will be recognized by those skilled in the art that depending on the other specific substituents in the compound of formula (1), its oxidation in the compound of formula (1) may form an N-oxide on the bicyclic moiety in the compound. Will.

One skilled in the art will readily determine whether this interconversion is desirable once a given particular substituent is desired and one has determined whether the compound or its N-oxyP is desired. .

However, it is generally more convenient to prepare the compounds of formula (I) from the corresponding 01-6 alkylsulfinyl acids or reactive derivatives thereof.

R1'' v R11'' * Any transformation of ass' or ⇠ can be performed in any desired or necessary order.

Compounds of formula (I) are do-somin antagonists.

Depending on their balance between peripheral and central effects on the nervous system, compounds of formula (1) may cause disorders related to impaired gastrointestinal motility, such as delayed gastric emptying, dyspepsia, flatulence, 2 intraesophageal It can be used in the treatment of reflux and peptic ulcers and emesis, and/or in the treatment of disorders of the central nervous system, such as neurological diseases.

All compounds of formula (I) can be used in the treatment of emesis.

The quaternary ammonium salts of compounds of formula (1) are of interest because of their beneficial effects on gastric motility.

The compounds in the formula s R1 is 01 to alkoxy and one of R, , R1, and Rlm is nitro correspond to British Patent Application No. 8019936 and applications claiming priority from this application. It is specifically described as an intermediate for pharmacologically active amino compounds. It is now believed that these compounds of formula (I) are pharmacologically active per se.

Therefore, in the present invention, R1 is 01~・alkoxy is C1
~・alkylthio, and R1 as defined in formula (1)
, R1, and the third one of aSS is nitro (
There is further provided a pharmaceutical composition comprising a compound of I).

Compounds of the invention which are of particular interest because of their beneficial effect on gastric motility are quaternary ammonium salts of formula (I) and N-
It is an oxide.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, or a solvent adduct as described above and a pharmaceutically acceptable carrier. It is.

Such compositions can be produced by mixing and made suitable for oral or parenteral administration, such as tablets, capsules, oral liquid preparations, granules, lozenges, reconstituted powders, solutions for injections and infusions. Alternatively, it can take a dosage form such as a suspension or suppository. Compositions that can be administered orally are preferred.

Tablets and capsules for oral administration are always presented in unit dosages and contain the usual excipients, such as binders, fillers,
Contains tablets, lubricants, disintegrants and wetting agents. The tablets can be coated according to methods well known in the art. Oral liquid preparations include aqueous or oily suspensions, solutions,
They usually take the form of emulsions, syrups or elixirs, or are provided as dry powders for reconstitution with water or other suitable vehicle before use. Such liquid preparations contain the usual additives, such as suspending agents, emulsifying agents,
It may also contain a non-aqueous medium (which may contain edible oil), preservatives, flavoring or coloring agents, and the like.

For parenteral administration, liquid unit dosage forms are prepared containing a compound of the invention and a sterile vehicle.

The compound, depending on the vehicle and concentration, is either suspended or dissolved. Parenteral solutions are conventionally prepared by dissolving the compound in a vehicle and filter sterilizing the compound before filling and sealing in a suitable vial or ampoule. Preferably, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Parenteral suspensions can be prepared by suspending the compound in a vehicle and sterilizing the compound by exposure to ethylene oxide before suspending in a sterile vehicle to promote uniform distribution of the compound. can.

The present invention further provides the aforementioned methods in mammals, including humans, by administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, or a solvent adduct thereof as described above. It provides a method to treat certain diseases.

Effective amounts for treating the previously mentioned diseases will be based on the relative efficacy of the compounds, the nature and extent of the disease to be treated, and the weight of the mammal. However, a unit dose may be from 0.1 to 20 μ, such as from 0.5 to 1 O, of a compound of the invention.
Usually contains qm. The unit dose is usually administered several times a day, for example 2, 3°4.5 or 6 times a day, so that the total daily dose is within the range of 06O1-1Olv'kf. be done.

The compounds of the present invention have the ability to enhance the effectiveness of common analgesics in the treatment of migraine when administered concurrently with analgesic systems.

Accordingly, the invention also provides pharmaceutical compositions comprising a compound of the invention and an analgesic.

The compound of the invention and the analgesic agent, such as aspirin or nozoracetamol, are present in the composition in amounts similar to the normal effective i.

The composition may be a combination product, such as a tablet or capsule containing both a compound of the invention and an analgesic for oral administration, or a paired package separately enriched with the two active ingredients.

Accordingly, the invention provides a method of treating migraine headaches comprising administering an effective amount of a compound of the invention and an analgesic.

The following examples illustrate the preparation of compounds of the invention, and the following reference examples illustrate the preparation of intermediates.

Reference Example 1 2,3-ethylenedioxy-5-methylthiobenzoic acid (69) and sodium metaperiodate (5,16t) in water (tsofRls) and methanol (150ms)
) was stirred for 16 hours in a simmering oven. The reaction mixture was then poured into ice water and the resulting precipitate
2゜3-:L f L/dioxy-5-methylsulfinyl! tl: M, aromatic acid (3
, 6f, 56.3%).

Example 1 HM2,3-:r-7-)oxy-5-methylsulfinylbenzoic acid (0,84f) was dissolved in dry dimethylformamide (2sd) before cooling to 0<0>C. Triethylamine (0.5m) was added.

This reaction mixture was added to ethyl chloroformate (0,34-
) was added dropwise. During this time the temperature was maintained at 0°C.

The mixture was then stirred at this temperature for 15 minutes.

3β-amino- in dry dimethylform 7mide (5-)
8-Benzyl-8-7zabicyclo (3°2,1) octane <0.769) was added in portion to the reaction mixture before stirring for 15 minutes at room temperature.

The solvent was removed in vacuo leaving an oil. The title compound was purified by 2-layer chromatography to obtain a foam (1,3
f, 841G).

Theoretical mass 440.1767 mar (ODo 1g) τ2.15 (I H, d
, aromatic H).

2-45-2.9 (7H, d aad m , aromatic H, -0ONH-and -NOH@Os Hs
) e 5.4-4-6-0 (5Ht -o -O per 0
H11-0-and 3αH), 6.45 (2H,s,
-NOH.

Os Ha) e 6-75 (2H, m, blip head H'8).

7-3 (3H=8.-800!!5)-7-7-8-6
(8H, si+, methylene H' 8 ).

Example 2 Inylbenzoic acid (IF) was dissolved in dry dichloromethane (30s
ds) with oxalyl chloride and dry dimethylformamide (0.5 m) was added. The mixture was stirred at room temperature until homogeneous. The solution was cooled to 0 °C and triethylamine (1,5
ads) dropwise, then dry dichloromethane (15 m
The temperature is kept below this throughout the dropwise addition of the 3β-amino-8-benzyl-8-azobiccyclo-(3,2,1)octane (0,86F) in s).

The reaction mixture was diluted with a 10% solution of sodium hydroxide (10 sd
Warm to room temperature before shaking and mixing with s). The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to give a colorless oil (2t). The resulting oil was purified by column chromatography (silica, 3% methanol in ethyl acetate as developer) and ethanol ether to give compound (1).

4-chloro-5-methylfurfinyl-2-methoxy-
N-(3,β-(8-benzyl-8-azabicyclo-(
3,2,1)octyl]benzado (2) was obtained in a similar manner.

Intragastric pressure changes were recorded from restrained rats already conscious of fasting using a catheter filled with medicated salts inserted into the lumen of the stomach through an intact gastrostomy tube. The catheter is coupled to a physical pressure transmission device and pressure changes are recorded on a hot wire pen recording device. 40 in each rat
A pre-administration period of 1 minute was established to obtain the magnitude of spontaneous activity. An indicator of activity was obtained by measuring the average height of the pressure wave in lO minutes. Values for four cycles and for 40 minutes after compound administration were obtained through assessment of natural activity. The Student's "t" test was applied to the difference between the mean values obtained for the natural activity and the subsequent activity of the compound.

Compound (1) greatly increased the activity index after administration at 1wv' to 1B-0- dosing regimen.

Antiemetic activity in dogs The compound was administered subcutaneously 30 minutes before administration of a standard dose of apomorphine HCt (0,111 g/kf subcutaneously administered);
The nausea response was compared to administration of apomorphine 1-101 and vehicle alone. A dose was obtained that suppressed the gagging response in 50% or more of the dogs.

HD for compound l, · is 0.5 C, 0. Met.

No toxic effects were observed in the studies reported above.

Agent Patent attorney Masaaki Akizawa Mitsuru 1 person 61''J゛ 1937, May 1939, Director General of the Patent Office 1, Indication of tenant work qki Gansho 2 - 1st σri 65'' 6 case Relationship: Hirorinso Location: Taiyo Building, 12-1 Nihonbashi Kabutocho, Chuo-ku, Tokyo Name (5792) Patent attorney! :Masamitsu Akizawa 5.41″1′ & 6 date Showa year month day (
Shipping) Notice of reasons for refusal 6, number of inventions increased by amendment 7, subject of amendment B11tΦt

Claims (1)

[Scope of Claims] (1) General formula (1) [wherein s nmP and q are each independently KO to 2, bRI is hydrogen or Id 0t-s alkyl,
Rse: t0t-7ryugil or group-(OHt)
sR7 (where 3 is 0 to 2 and is a C3-S cycloalkyl group), or the group -(OHt)tRs
(where the electrode is 1 or #: t2 and % R-ke 0.-6 argyl r C1-4 alkoxy. substituted with one or two substituents selected from trifluoromethyl and) 0N-J alkenyl or phenyl group, or chenyl group f),
) or chenyl group, and R71-01-11
Arcogyshi matate C1-6 alkylthio de nine R snow #R1
One of 1 and RSS is 01-6 alkylnulfynyl, and the other two are both 01-1 alkylenedioxy, or one of the other two is hydrogen and the other is , trifluoromethyl@at-S
Alkalh C1-@alkohoshi+ Cl-77sil,
Hydrocoir, or C1-6 alkyl + 01-1 cycloalkyl + aS-S cycloalkyl Of-4 alkyl. phenyl 4 L <, /ke phen 01-4 An a2-nocarboxylic group substituted with one or five selected from alkyl groups or with 04-rimethylene and substituted with 9 amino or N-substituted; or R1 and R are both Ol-*alkylenedioxy, R
■tiOt-6 alkylsulfinyl, J1a hydrogen. halogen, ) +7 fluoromethyl, C1-6 alkyl. c, 4 alkoxy+ 01-t acyl e 01-? Acylamino. 0, -@alkylsulfonyl, C11 alkylnulfinyl, nitra, or C-alkyl,
C3- cycloalkyl, C, cycloalkyl 01-
4 alkyl, quenyl % I, < d phenyl 01-4 May be N-substituted by one or two groups selected from alkyl groups %/h 1 or 04-s N-disubstituted by polymethyl selected from the group consisting of aminocarzenyl or aminosulfonyl, which may be It's either one or the other. ], or a soil-acceptable salt or N-oxide thereof, or any solvent adduct. (2) The compound has the general formula (1 person) [In the formula, RltiOs-s alkoxy or 01-6 alkyl preio and 0. R1 is hydrogen or Cl-6 alkyl, BatlOt-7 alkyl, or the group -(OH
g) sRy (where $ is 0 to 2 and IhtiOs-
acycloalkyl group), or group -(OHg)tRs
(Here, t is 1 or 2. R. may be substituted with one or two substituents selected from alkyl, alkoxy, trifluoromethyl, and halogen.) i alkenyl or phenyl group, or chenyl group), or chenyl group, and fjmRxx is halogen, OFg, 0
1-t acyl, aminocarzeni optionally substituted by one or two C troalkyl groups” t os-
s alkoxy, 014 alkylthio, hydroxy or nitro, s l'Lsg is 01-1 alkylsulfinyl, and "slP and q are each independently KO to 2." (3) The compound has the general formula (IB) [wherein Rs is hydrogen or #10t-6 alkyl;
R11 is C1-, alkal, spanning group -(OHg)
sR4 (where S is 0 to 2 and is a C3-8 cycloalkyl group)% or the group -(OH snow)tRs
(where tFil or 2 is 1RsFiOt-6 alkyl, 0-4 alkoxy; 0.-, which may be substituted by one or two substituents selected from trifluoromethyl and halogen);
s is an alkenyl or phenyl group, t is a chenyl group) V or a chenyl group. Rtttj hydrogen, halogen, OF3.01-theacyl s
01-7 Acylamino, amino or aminocarzenyl, which may be substituted by one or two 01-1 alkyl groups, Ol-alkoxy set-s alkylthio. hydroxy or nitro, atX is C1-.alkylnulfinyl, and "e 9 *Q and r are each independently 0 to 2." Compound described in section 1). (41 (tl compound) general formula (XXIII)
is C1-6 alkyl. (5) The compound has the general formula (XXV) [wherein R- is O, -y alkyl, group -(OHs)tR
's (where ltl and s Bl are optionally substituted phenyl as defined in claim (1) 31), cyclohexylmethyl or chenyl. It is methyl. ] The compound according to claim (4). (6) Claim No. 2, wherein the compound is 2,3-ethylenedioxy-5-methylsulfinyl-N[3β(8-benzyl-8-azapicict'l[3,2,1)octyl)(nzamide) The compound according to claim (1). (7) The method for producing the compound according to claim (1), wherein le”
11 and R'll * m have the meanings defined in R11 and R1. When tomodashi mR1 is 01-@alkoxy, these third groups are C1-6 furkylthio. ) or a reactive derivative thereof with a compound having the general formula ( ) in which R- has the meaning given above and the other variable groups have the meaning given above; Then, if necessary, the group R'm s R'tm t or R
``ll to other R4# R11 to R11 respectively, R@ to other R@, and the prepared compound having general formula (1) is formed into a pharmaceutically acceptable salt. A method for producing a compound according to claim (1), characterized in that the compound according to claim (1) is A pharmaceutical composition comprising an N-O-C-C-I or any IW-mediated adduct and a pharmaceutically acceptable carrier. (9) Claims for use in the treatment of emesis and/or disorders related to gastrointestinal motility. The compound according to claim (1), its pharmaceutically acceptable salt, its N-oxide or any solvent adduct. (2) The compound according to claim (1), its pharmaceutically acceptable salt. , its N-oxide, or any *S adduct thereof.