CA1162187A - Benzamide derivatives of bicycloheterocyclic compounds - Google Patents

Abstract

ABSTRACT

Compounds of the formula (1):

(I) and pharmaceutically acceptable salts and N-oxides thereof, wherein:
R1 is a C1-6 alkoxy group;
R2 and R3 are the same or different and are hydrogen, halogen, CF3, C1-7acyl, C1-7 acylamino, C1-6 alkyl-S(O)n wherein n is 0, 1 or 2, nitro, C1-6 alkoxy, hydroxy, or amino, aminocarbonyl or aminosulphonyl optionally substituted by one or two C 6 alkyl groups;
or R1 and R2 taken together are methyl-enedioxy or ethylenedioxy in which case R3 is any one of the groups given for R1 and R2 above;
R4 is hydrogen, C1-4 alkyl or phenyl;
R5 is hydrogen or C1-4alkyl;
X is an oxygen or sulphur atom; or a sulphoxide group >S?O;
p is 1 or 2; and r is 1 or 2; are useful in the treatment of disorders related to impaired gastro-intestinal motility.

Description

PHARMACEUTICALL~ ACTIVE COMPOUNDS

This invention relates to a group of novel com-pounds, their formulation as pharmaceutical compositions, and their use in the therapy of disorders.
West German Offenlegungsschrift No: 2,748,260.6 .
describes compounds of the formula (A), and pharma-ceutically acceptable salts thereof:
. R4 CO NH ~ ( 2)m ~ (CH ) ( CH2 ) n /\~U
,~ Rl R3 ~ (A) wherein:
is a ~ 6 alkoxy group;
R2 and R3 are the same or different and are hydrogen, halogen, CF3, hydroxy, Cl 6 alkoxy, C2 7 acyl, amino, amino substituted by one or two Cl_6 alkyl groups 7 C
acyl amino, aminocarbonyl or aminosulphone optionally substituted by one or two C1_6 alkyl groups, ~ 6 alkylsulphone or nitro groups;

i....
~.

l ~ 62187 X is either a nitrogen atom, in which case m+n is 3 to 5, m is 2 to 4 and n is 1 to 3; or X is CH in which case m~n is 2 to 5, m is 1 to 5, and n is 0 to 4;
....... .....p is 0 to 3; and ~ -R4 is hydrogen, Cl 6 alkyl, phenyl or phenyl-Cl 6 alkyl, either of which phenyl moiety may be sub-stituted by Cl 6 alkyl, Cl 6 alkoxy, CF3 or halogen, and R5 is hydrogen; or R4 and R5 are attached to two adjacent carbon atoms and form together with these two carbon atoms a fused benzene ring, which benzene ring may be substituted by Cl 6 alkyl, Cl 6 alkoxy, C~3 or halogen; as dopamine antagonists having use in the treatment of disorders of the gastro-intestinal function and/or in the treatment of emesis.
A novel class of compounds has now been discovered which is structurally distinct from the known compounds of the formula (I) but also has useful pharmacological activity, such as dopamine antagonist activity.
Accordingly the present invention provides a compound of the formula (I):

~ /R4 CO-- ( CH2 ) r ( CH2 ) p_ -1~ ~1 R 1 R3 ~

~2 (I) 7 ~ 6~187 and pharmaceutically acceptable salts and N-oxides thereof, wherein:
Rl is a Cl_6 alkoxy group;
R2 and R3 are the same or different and are hydrogen, halogen, CF3, C1_7 acyl, Cl_7 acylamino, Cl 6 alkyl-S()n wherein n is 0, 1 or 2, nitro, Cl 6 alkoxy, hydroxy, or amino, aminocarbonyl or aminosulphonyl optionally substituted by one or two Cl 6 alkyl groups;
or Rl and R2 taken together are methylenedioxy or ethylenedioxy in which case R3 is any one of the groups given for Rl and R2 above;
R4 is hydrogen, Cl 4 alkyl or phenyl; or phenyl Cl-4 alkyl;
R5 is hydrogen or Cl 4 alkyl;
X is an oxygen or sulphur atom; or a sulphoxide group >S~0;
p is l or 2; and r is 1 or 2.

Within formula (I) there is a group of compounds wherein Rl, R5, X, p and r as defined, R2 and R3 are the same or different and are hydrogen, halogen, CF3, Cl 7 acyl, Cl 7 acylamino, Cl 6 alkyl-S(O)n wherein n is 0, 1 or 2, nitro, or amino, aminocarbonyl or aminosulphonyl optionally substituted by one or two Cl 6 alkyl groups;
and R4 is hydrogen, Cl~ alkyl or phenyl and substitutes the carbon atom in the ~ ring ad~acent the nitrogen.
Within the group of compounds defined in the pre-ceding paragraph there is a further group of compounds wherein the variables Rl, R4, R5, p and r are as defined, R2 and R3 are as defined except that when alkyl-S()n, n must be 2 (ie alkylsulphonyl), and X may only be an oxygen or sulphur atom.
Suitable examples of the group Rl include methoxy, ethoxy and n- and iso-propoxy. Preferably Rl is a methoxy group.
Suitable examples of R2 and R3 include the following atoms and groups: hydrogen; chlorine, bromine; CF3;

~ J 62187 formyl, acetyl, propDnyl, n- and lso-butyryl; formylamino, acetylamino, propionylamino, _- and iso-butyrylamino;
methyl, ethyl and n- and iso-propylsulphone, -sulphinyl or -thia; nitro; methoxy, ethoxy and _- and iso-propoxy;
hydroxy; amino, aminocarbonyl and aminosulphonyl and amino, aminocarbonyl, and aminosulphonyl substituted by one or two methyl, ethyl, n- or iso-propyl groups.
When Rl and ~2 taken together are methylenedioxy or ethylenedioxy, they are most suitably ethylenedioxy.
Particuarly suitable R2 and R3 groups include hydrogen, halogen and amino; and as "intermediates", acyl-amino and nitro, which can conveniently be converted to the corresponding amino groups.
It is generally preferred that R2 i5 in the 4-position relative to the carbonyl side chain, for greater activity in the resultant compound of the formula (I). For the same reason, it is generally preferred that R3 is in the 5-position relative to the carbonyl side chain.
Particularly preferred R2 groups include 4-amino and 4-acylamino. Most preferably R2 is 4-amino. Particularly preferred R3 groups include 5-halo, such as 5~chloro.
In other useful compounds R2 is hydrogen, 4-halo (eg chloro), or amino; and R3 is 5-Cl_6 alkyl S()n (such as 5-methylsulphony]./--s~phinyl or -thia) or 5-optionally alkylated aminosulphonyl.
R4 may substitute any carbon in the X ring (apart from the bridgehead carbon), but preferably substitutes the carbon atom adjacent the nitrogen atom.
Suitable examples of R4 inc~ude hydrogen, methyl, ethyl, n- and iso-propyl, and phenyl and benzyl. Phenyl groups in R4 may be substituted by one or more Cl_4 alkoxy (such as methoxy), Cl_4 alkyl (such as methyl), fluoro, chloro or CF3. Often R4 will be hydrogen, Cl_4 alkyl or phenyl.
~ost suitably R4 is hydrogen or methyL ~ -Suitable examples of R5 include hydrogen, methyl, ethyl and _- and iso-propyl. More suitably R5 is hydrogen or methyl, preferably hydrogen.
Generally X is most suitably oxyaen.
(The X is >S~0 group has been referred to above as the sulphoxide group. The skilled chemist will appreciate that in naming a compound containing such a >S~0 group, the I l 6~187 group can be referred to as "oxothia", and indeed this terminolo~y has been used in Example 15).

Preferably p is 1.
Preferably r is 1.
It is generally pxeferred for higher activity that the bond between the benzamide moiety and the cyclic side chain (i.e. between the R5 substituted nitrogen atom and the ring carbon atom to which this nitrogen atom is joined) in the compounds of formula (I) ~s axial (When used herein in relation to this bond axial is'assigned with the bicyclic drawn with a trans rinb fusion, and is also referred to as ~. Equatorial is, similarly assigned, and is also referred to as ~.) The pharmaceutically acceptable salts of the com- -pound of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydro-bromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid and the like.
The pharmaceutically acceptable salts of the com-pounds of the formula (I) also include quaternary ammonium salts. Examples of such salts include salts with compounds such as R6 ~ Y wherein R6 is Cl 6 alkyl, phenyl - Cl 6 alkyl or C5 7 cycloalkyl, and Y is an anion of an acid. Suitable examples of R6 include methyl, ethyl and n- and iso-propyl; and benzyl and phenyl ethyl. Suitable examples of Y include the haLides such as chloride, bromine and iodide.
From the aforesaid it will be seen that suitably the moiety of formula (II): --' ~ (II~

l ~ ~2187 in a compound of the formula (I) will have the structure (III):
.. . . .
CO ~

Cl ~
I (III) ~ rom the aforesai.d it will also be appreciated that preferably the moiety of formula (IV):

- r~7<

(IV) i~ the compound of formula (I) is of the formula (V):

R~
~--~ 7 (V~

1 1 62~87.

.

Thus a preferred sub-group of compounds within formula (I) is of formula (V~):

- ~ ~ - R `
/ N ~
CO - NH ~--C~

~ 3 Cl ~ (VI) In formula (VI), suitably the bond indicated ~-is axial.
Also in formula tVI) suitably R4 is hydrogen or methyl~
Another preferred sub-group of compounds within formula (I) is of formula (VII):

CO- NH ~7 X' ~ OCH3 Cl ~ ,JJ
(VII) , NH2 wherein X' is S or S~O, preferably S.
In formula (VII), suitably the bond indicated __^
is axial.

Also in foxmula (VII) suitably R4 is hydrogen or methyl.
It will of course be realised that the compounds of ~he formula (I) have chiral centres, -and thus are capable of existing in a number ofsteroisomeric forms. The invention extends to each of these stereoisomeric forms, and to mixtures thereof (including racemates). The different steroisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
The invention also provides a process for the preparation of a compound of the formula (I), which process comprises reacting an acid of the formula (VIII):
COOH
R3 ~ Rl ~ (VIII) or a reactive derivative thereof, with a compound of the formula (IX):

HR5N ~ ~N ~ 4 SCH2)r, (CH2)p _ X (IX) l l 62187 . .

. g wherein the variable groups are as defined in formula (I); and thereafter if desired or necessary converting a group R2, R3 or X in the thus formed compound-to another group R2, R3 or X respectively.
"Reactive derivative" when used herein means a derivative of the compound (VIII) which can be reacted with the compound (IX) to form an amido linkage between the acid group of the compound (VIII) and the amino group of acid group of the compound (VIII) and the amino group of the compound of the formula (IX).
Often this reactive derivative will be the acid halide, such as the acid chloride, of the acid (VIII).
In such cases the reaction will normally be carried out in an inert solvent, preferably in the presence of an acid acceptor. The inert solvent can be any sol~ent inert to both reactants, such as benzene, toluene, diethyl ether or the like. The acid acceptor is suitably an organic base such as a tertiary amine, e.g.
triethylamine, trimethylamine, pyridine or picoline, or an inorganic acid acceptor, such as calcium carbonate, sodium carbonate, potassium carbonate or the like.
It should be noted also that it is possible to use certain acid acceptors as the inert solvent, for example organic bases.
Another useful reactive derivative of the acid (VIII) that may be used is an ester, such as a methyl, ethyl, prop~l or butyl ester, in which case the ~action is normally carried out by heating the reactants together in an inert solvent such as ethylene glycol.

.

-- 10 -- , The reaction may also be carried out by forming an anhydride of ~he acid (VIII) in the usual manner, and reacting tha* with the compound (IX); normally a conventional mixed anhydride-will be used; or by reacting the acid (VIII) and the compound (IX) in the presence of a dehydrating catalyst such as a carbodi-imide, for example dicyclohexylcarbodiimide.
It will be realised that in the compound of the formula (I) the linkage between the -NR5- moiety and the cyclic side chain may have an or ~ orientation with respect to the ring of the bicyclic moiety to - ~ -which it is attached. A mixture of a and ~ isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom, e.g. by chromatography;
or alternatively the a or ~ isomer may if desired be synthesised from the corresponding a or ~ form of the compound of the formula (IX).
Alternatively, a mixture of the and ~ isomers of the compound of the formula (IX) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom~ e.g. by chromatography.
However, in this case it is generally more convenient to react the mixture to give a mixture of a and ~
isomers of the compound of the formula (I) and to separate these if desired as hereinbefore described.

l l 6218~

The intermediates of lormula tIX) may be prepared by a process which depends on whether the a or ~ forms is desired, or a mixture thereof.
To prepare a or axial compounds of formula (IX), a compound of formula (X~`is reduced:

(CH2)~ ~ ~ (CH2)p (X) . . - .
.

This reduction is conveniently carried out with lithium aluminium hydride under the usual conditions.
Compounds of formula (X) may themselves be pre-pared by reaction of a compoùnd of the formula (XI):

X

I~"H
N ~
~` (XI) OH

to effect conversion of hydroxy to azido, with inversion of sterochemistry.
This reaction may be carried out in the general manner described in A.K. Bose et. al., Tetrahedron ~etters 1977, 23, 1977). ~or example, the reaction may be effected with triphenylphosphine, diethyl l 1 6~187 azodicarboxylate and diphenylphosphoryl azide.
Compounds of the formula (XI) are important inter-mediates, as from these compounds the ~ form of compounds of the formula (IX), and ~/~ mixtures thereof, may be prepared.
For example, reacti.on of a compound of formula (XI) with a base and fluorenone yields a compound of formula (X~I3: - -X
( CH2 ) ~ ( CH2 ) p _ R ~ N ~
4 l ~ (XII) ~/

The compounds of formula ~XII) may be converted to compounds of formula (XIII):

(CH2)r (CH2)p ~ NOH (XIII) with hydroxylamine. We have found that this reaction is suitably carried out with pyridine and hydroxylamine hydrochloride at reflux temperatures.
Reduction of a compound of formula (XIII).with lithium aluminium hydride gives a mixture of axial ~.~) and equatorial (~) amines of formula (IX) where R5 is H.

1 1 6~187 _ 13 -In constrast, a dissolving metal reduction of a com-pound of formula (XIII) is substantially ~ereospecific and yields mainly the ~ amines of formula (IX) (any minor prop-ortions of the undesired isomer prepared in this process can be separated in conventional manner). Such reductions may suitably be carried out with sodium and amyl alcohol.
Returning now to compounds of the formula (XI) 9 these compounds may be prepared from a compound of for-mula (XIV):

(CH2) ~ ( 2)p O N ~
¦ ¦ H (XIV) OCHO
by a process which depends on the nature of R4.
When R4 is hydrogen, the reaction may be carried out by reduction with for example lithium aluminium hydride.
When R4 is Cl 4 alkyl or phenyl, and substitutes the carbon adjacent the nitro~en, the compound of formula (XIV) is converted with first base, such as sodium hydro-xide, and second a silylating agent, such as (CH3)3SiCl or hexamethyldisilazane, to the silyl ether of formula (XV):
X
( CH2 )( CH 2 ) p r l~`H
O N ~ (XV) H
" ~ i(CH3~3 1 1 6218~

_ 14 -, which in turn is converted to the desired compound of formula (XI) with a R4 metal complex, such as R4Li, and subsequent reductionj for exampl.e with sodium borohydride.
The intermediates of formula (XIV) may themselves ~-be prepared by treating a compound of formula (XVI):

X i.
(CH2)ri ( 2)p O ~ N l OH
~ (XVI) with formic acid.
Compounds of formula (XVI) may be prepared by reduction, for example with sodium borohydride and hydrogen chloride, of a compound of formula (XVII):

(CH2)r ~CH2)p O ~ N ~ O

( ~ II) , which compounds of formula (XVII) may themselves be prepared by ~reaction of a compound of formula (XVIII):
X
(CH2)r - (C 2)p H (XVIII) with an alkylene halide, such as 4-brombut-l-ene, using base.

- 14a -To obtain a compound of the formula (XI) wherein R4 is Cl_4 alkyl or pheny~ or phenyl Cl 4 alkyl and substitutes the X ring at the carbon other than the carbon adJacent the nitrogen, a compound of formula (XIV)' is reduced, for example with lithium aluminium hydride:

(CH2) ~ 2)p 4 ~ N ~
H (XIV)' OCHO

(wherein R4 is Cl_4 alkyl or phenyl).
Such compounds of the fcrmula (XIV)' may be prepared by the (XVIII) -~ (XVII) to (XVI)- (XIV) route as described for compounds of formula (XIV), except that the R4 substituent is present in each of the compounds (XVIII), (XVII) and (XVI) to correspond to the R4 in compounds (XIV)'. (It will of course be appreciated that in such a reaction sequence the (XVII) to (XVI) reduction will give a mixture of isomers which can be separated by conventional means.) 1 J 621~7 _ 15 -The aforesaid processes of course yield a compound of the formula (IX) wherein R5 is hydrogen.
If a compound of formula (IX) wherein R5 is alkyl is desired, it may simply be prepared from the-corres- ;
ponding R5 is hydrogen compound by alkylation. This may be effected in any suitable manner, for example by acylation with an anhydride followed by reduction with lithium aluminium hydride.
It will be appreciated that any enantio~er, or 10 mixture of enantiomers, of the compounds of formulae . ~
(X), (XI), (XIV) and (XV) may be used provided it has the depicted spatial relationship between carbons a and b.
The intermediates of the formula (VIII) are known compounds, or may be prepared in analogous manner.
The N-oxides of the compounds of formula (I) may be prepared in conventional manner, for example by treatment with a per-acid, such as m-chloroperbenzoic acid.

~ - ~ ~
I 1 ~21~
.

' The acid addition salts of compounds of the formula (I) may be prepared in entirely conventional manner , by reacting a comp~und of,the formula (I) in~bas,e form with the chosen acid.
The quaternary ammonium s~lts of the'compounds of the formula (I) may be prepared in conventional manner for such salts, such as by reaction of the chosen compound of the formula (I) with a compound R6Y as defined. This reaction is suit~bly carried out in an appropriate solvent such as acetone, methanol, ethanol 9 ' ' -dimethylformamide and the like, at ambient or raised temperature and pressure.
The interconversion of suitable groups R2 and R3 after formation of a compound of the formula (I) or corresponding intermediate therefor may be carried : out by conventional methods. By way of example nitro groups may be reduced to amino groups in the normal manner, and acylami~o groups may be converted to amino groups also by conven~ional methods. Also a compound of the formula (I) wherein R2 or R3 is halogen can be prepared by a conventional halogenation of the cor-responding compound of the fQrmula (I) wherein the said R2 or R3 is hydrogen. Further, compounds wherein R2 or R3 are Cl 6 alkylsulphonyl may be prepared by oxidation,~of the corre~ ding Cl_6 alkyl sulphinyl ~ounds;
and su¢h Cl_6 alky1sulphinyl compounds may be prepared by oxidation of~the corresponding Cl_~
alkylthia compound. In regard to X, ~ is S comp~unds may be oxidised to X is S~0 compounds, suitably with sodium periodate. Accordingly it will be recalled that compounds of the formula (I) containing a R2, R3 or X group which is convertible to another R2, R3 or X group are useful intermediates, and as such form an important aspect of the invention .
As hereinbefore stated, the compounds of the formula (I) are dopamine antagonists.
The co~pounds of the formula (I) may be used in the treatment of disorders related to impaired gastro-intestinal motility, such as retarded gastric emptying, dyspepsia, flatu-lence, oesophagal reflux, peptic ulcer and emesis.
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Such compositions may be adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconsitutable powders, injectable and infusable solutions or suspensions and the like; the compositions may also be in the form of suppositories and the like. Normally, orally admini-strable compositions are preferred.

l 1 6~187 _18 _ -, .
Tablets and capsules for oral administration may be in unit dose presentation form~ and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable -wetting agents and the like. ~The tablets-may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for e~ample, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented in a dry product for reconstitution with water or other suitable vehicle before use. Such liquid pre~
parations may contain conventional additives such as ~ -suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preserva-tives, and if desired conventional flavouring or colouring agents, and the like.
~or parenteral administration, fluid unit dosage \ forms are prepared utilizing the compound of the formula (I)` and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and seaiing. ~dvantageously, adjuvants such as a local anaesthetic, 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 the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to '- . I J ~218.7 , facilitate uni~orm distribution of the compound.
As is common practice, the compositions will usually be accompanied by written or printed directions . fo~..use in *he medical treatme~nt concerned...~.;...`
It will of course be realised that the precise dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual co~pound of the ~ormula (I) used, and also on other factors such as the seriousness of the disorder being treated.
The invention further provides a method of treat-ment of maladies in humans comprising the administration - -of an effective amount bf.a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
The "effective amount" will depend in the usual way on a number of factors such as the nature and severity of the malady to be treated, the weight of the sufferex, and the actual compound.used.
However by way of illustration, unit doses will suitably contain 0.1 to 20 mgs of the compound of formula (I), for example O.S to 10 mgs.
~gain by way of illustration, such unit doses will suitably be administered more than once a qay, for example 2, 3, 4, 5 or 6 timeQ a day, in such a way that the total daily dose is suitably in the range 0.01 2S to 10 mg/kg per day.
Compounds of the formula (I) have the ability to potentiate the effect of conventional analgesics -in migraine treatment when administered con~urrently with the analgesic.

.

I ~ ~2187 . . .

, _ 20 _ , ' . - . ~ .
Thus the invention provides a pharmaceutical ' composition comprising a compound of the formula (I) and an analgesic~
The compound of the formula (I) and the analgesic, ~suc~ as aspir~in or paracetamol~,-'~iIl'be presènt 'in the-composition in amounts generally similar to their usual i' effective dose.
The composition can be a combination product; for ' example a tablet or capsule containing both a compound of the formula (I) and an analgesic for oral administration, or a twin pack comprising the two active ingredients _ made up for separate administration.
The invention accordingly provides a method of treatment of migraine comprising the adminîstration to the sufferer of a compound of the formula (I) and an analgesic.
The following Examples illustrate the pre~aration of the compounds of formula (I) and the following Descriptions illustrate the preparation of ~intermediates thereto.
In the Examples, ('-) of course indicates that the compound is a racemate. However, for the sake of con-venience, the structural formula of only one enantiomer has been shown.

. .

1 8 ~

.

- .
Description 1 (a) -(4-But-l-envl)morpholine-2~-dione (D.l~
O

I . i, 0~ ~N'~ O
¦ (D.l) To a stirred solution of morpholine-2,6-dione (11.6 9) in dry DMF (lOO ml) was added 80% sodium hydride (3.4 9).
On cessation of the gas evolution (ca. ~ hour), 4-bromobut-l-ene (13.6 9) was added and the whole refluxed for 2 hours. On cooling, the reaction mixture was poured into ice/water (300 n~ and extracted with ether (3 x 200 ml) and ethyl acetate (20Q ml).
Fractional distillation ~afforded the 1-(4-but-1-enyl)morpholine-2,~6-dione (D.l) (10.09, 60%).

b.p. 84-8/0.1 mm n.m.r. (~, CDC13): 6.05-5.35 (m, lHI H2C=CH-CH2);
5.2-4.75 (m, 2H, H2C=CH-);
4.25 (S9 4H, 0(CH2CO)2N-);
3-73 (t, 2H, ~N-CH2-CH2_; J=7Hz);

2.5-2 (m, 2H, -CH2-CH2-CH=).
.

: . ^
1 ~162187 .

.
.
(b) (-) l-aza 8~-For~ylox ~ 4-oxab - icvclor4?4 .Oldecane-2-one (D.2) - _ ~ ^ ~ N
HC0 ~
(D.2) The 1-(4-but-1-enyl)morpholine-2,6-dione (D.l) (5 9) was reduced with sodium borohydride (10.8 9) in absolute ethanol (300 ml) at -15C for 5 hours, durin~
which time 3-5 drops of ethanolic hydrogen chloride (4.5N) was added at 15 mimlte intervals.
The excess sodium borohydride was destroyed with excess ethanolic hydrogen chloride (to pH 3) and the ethanol removed by rotary evaporation. Addition of saturated aqueous sodium bicarbonate solution and extraction with methylene chioride gave the crude 1-(4-but-1-enyl)-2-hydroxymorpholine-6-one (6.0 9).
The crude 1-(4-but-1-enyl)-2-hydroxymorpholine-6-one was dissolved in 98% formic acid and the solution stored overnight at ambient temperatures. The formic acid was removed by rotary evaporation and the residue taken up in methylene chloride, washed with aqueous sodium bicarbonate solution and dried (MgS04). Removal of the solvent gave the crude (-) l-aza-8-formyloxy~-H-4-oxa bicyclo[4,4,0]decane-2-one (D.2) (5.6 g, ca. 100%).

n.m.r. (o. CDC13) 7.98 (s, lH, 02CH);
5.7-3.2 (m, 7H including 4.1;

s, 2H, -OCH2C-);

3.0-1.0 (m, 5H, remaining protons).

l 1 6~187 (c) (-? l-aza-8~-Hydr'oxy-6~-H-4-oxabicycloE4~4~o3decane ` (D '3') intermedia'te 'for'Compoun'd's l'and`2 / N
HO ~ O
H

(D.3) The crude (+) l-aza-8g-formyloxy-6~-H-4-oxabicyclo [4,4,0] decane-2-one (D.2) (2.8 g) was reduced with lithium aluminium hydride (0.8 g) in ether. Hydrolysis, filtration and distillation afforded the (-) l-aza-8~-hydroxy-6~-H-4-oxabicyclo [4,4,0] decane (D.3) (1.5 y, 65~ from D.l).
b.p. 85-96/0.1 mm.
n.m.r. (&, CDC13): 4.2-0.9 (m, 15 H, all protons).

(d) (-) l-aza-8a-Azido-6~-H-4-oxabicyclo [4,4, o3 decane (D.4) intermediate for Compounds 1 and 2 / ~~ N --~
~ ~ ~

(D.4) To a dry, stirred THF (30 ml) solution of triphenyl-phosphine (2.75 g) and diethyl azodicarboxylate (1.9 g~ at 0C
was added (+) l-aza-8B-hydroxy-6~-H-4-oxabicyclo ._~

~ J ~2187 ~4,4,0~ decane (D.3) (1.5 g). After stirring for 10 mins. di-phenylphosphoryl azide (2.9 g) in dry THF (10 ml) was added during 10 mins. and the mixture stirred at ambient temperature for 3 days.
The THF was removed and replaced by methylene chloride.
The product was extracted into 5N hydrochloric acid (10 ml) and washed with methylene chloride (3 x 50 ml). Basifieation and saturation with potassium carbonate, re-extraetion with methylene ehloride and removal of the solvent gave the crude ( ) l-aza-8~-azido-6~-H-4-oxabieyclo[4,4,0~deeane (D.4) (1.6 g, 90~).
i.r. (fil ) (N3) (e) (-) 8¢-Amino-l-aza-6a-H-4-oxabieyelo~4,4, oJ deeane (D.5) intermediate_for Compounds l and 2 / N

(D.5) The crude (+) l-aza-8~-azido-6~-H-4-oxabicyclo[4,4,0]
deeane (D.4) (1.6 g) was redueed with lithi.um aluminium hydride (0.3 g) in ether for 4 hours. Hydrolysis, extraetion with methylene ehloride and solvent removal afforded the erude (-) 8~-amino-1-aza-6~-H-4-oxabieyelo [4,4,0~deeane (D.5) (1.5 g, ea.
100%).

l l 62187 Description 2 (a) (-) 'l-Az'a'-'6'~-H-'4-oxab'i'c'clo~4','4','03de'ca'n'è'-'8-one (D.6) y intermediate for Compounds 3 and 4 /--____ N--~
O ~--O

(D.6) ; To a stirred solution of (+~ l-aza-8~-hydroxy-6~-H-4-oxabicyclo[4,4,0~decane (D.3) (2.8 g) and fluorenone (17 g) in dry benzene (70 ml) was added potassium tert. butoxide (5.6 g) and the solution stirred at room temperature for 30 mins. The product was extracted into SN hydrochloric acid (25 ml), and washed with methylene chloride (50 ml). The aqueous phase was neutralised then saturated with potassium carbonate and extracted with methylene chloride (3 x 100 ml). Removal of the solvent gave the crude (+) l-aza-6~-H-4-oxabicyclot4,4,0~decane-8-one (D.6) (3.0 g, ca 100~).

(b) (+) 1-Aza-6~-H-4-oxabicyclo L4,4, oJ decane-8-one oxime -tD.7) intermediate for Compounds 3 and 4 ~ -N _-~
HON ~ 1/ ~
H

(D.7) ~1 l 1 6218~

An ethanolic (30 ml) solution of (+)1-aza-6~-H-4-oxa-bicyclo[4,4,0]decane-8-one (D.6) (3.0 g) was treated with pyridine (3 ml) and hydroxylamine hydrochloride (3 gm) and the mixture heated under reflux for 30 mins. On cooling, the ethanol was removed by rotary evaporation and the residue treated with dilute potassium carbonate solution. The product was extracted with methylene chloride and dried (K2CO3). Removal of the solvent afforded the cru~e (-) l-aza-6~-H-4-oxabicyclo [4,4,0~decane-8-one oxime (D.7) (3.0 g, ca 95%).
(c) (-) 8 -Amino-l-aza-6~-H-4-oxabicycloC4,4,0~ decane (D.8) intermediate for Compounds 3 and 4 / N
H2~
H

(D.8) To a refluxing amyl alcohol (100 ml) solution of the crude (-) l-aza-6~-H-4-oxabicyclo[4,4,0] decane-8-one oxime (D.7) (3.0 g) was added sodium tca 3.0 g) portionwise over 1 hour. The cooled reaction mixture was then treated with 5N hydrochloric acid (ca 80 ml) and extracted with ethyl acetate. The acidic aqueous layer was separated, neutralised and saturated with potassium carbonate and re-extracted with methylene chloride (4 x 150 ml). Distillation of the organic extracts gave the (-) 8~-amino-1-aza-6~-H-4-oxabicyclo~4,4,0~decane (D.8) (1.5 g, 50~)-b.p. 58-62/0.1mm.

~ - 26 -~ J ~2187 Description 3 (a) (-) l-Aza-8~-hyaroxy-6~-H-4-oxabicyclo[4,4,03decane-2-one (~.9) intermedi-ate for Compounds 5 and 6 ~/~
HO ~ / O
H

(D.9) To an ethanolic solution (50 ml) of (-) 1-aza-8~-formyl-oxy-6~-H-4-oxabicyclo~4,4,0]decane-2-one (D.2) (7.0 g) was added aqueous 2.5N sodium hydroxide solution (14 ml) and the mixture stood for 10 mins. at room temperature. The ethanol was removed by rotary evaporation and the residue extracted with methylene chloride. Distillation of the organic extracts afforded the (-) l-aza-8~-hydroxy-6~-H-4-oxabicyclo[4,4,0]decane-2-one (D.9) (4.1 g, 68%).
b.p. 80-90/O.lmm.

(b) (-) l-Aza-8~-hydroxy-2~-methyl-6~-H-4-oxabicyclo~4,4,0 decane (D.10) intermediate for Compounds 5 and 6 HO_ ~ N
~~0 H (D.10) An immiscible mixture of (~ aza-8~-hydroxy-6~-H-4-oxabicyclo~4,4,0]decane-2-one (D.9) (2.3 g) and hexamethyldi-silazane (4 ml) was treated with 2 drops of conc. sulphuric acid and subsequently heated to 80 until a single phase was obtained (ca. ~ hour). On cooling, petroleum ether (40-60) (200 ml) was added and the solution washed with aqueous sodium bicarbonate (20 ml) and dried (MgSO4). Filtration and removal of the petroleum ether gave the crude trimethyl silyl ether (3.0 g).
To a cooled (-30) stirred solution of the trimethyl silyl ether in dry ether (50 ml) was added a 0.6M solution of methyl lithium (40 ml) with subse~uent stirring at room tempera-ture for 2 hours. Saturated sodium bicarbonate solution (20 ml) was added, the aqueous layer separated and extracted with methyl-ene chloride (3 x 50 ml). The combined organic extracts were dried (K2CO3), filtered and concentrated.
Ice-cold ethanol (50 ml) was added followed by 4.5M
ethanolic hydrogen chloride (5 ml) and subsequently stirred at 0C with sodium borohydride (3.0 g) for 2 hours.
The ethanol was removed by rotary evaporation and the residue extracted with methylene chloride (3 x 100 ml). Distil-lation of the organic extracts gave the (+) l-aza-8~-hydroxy-2~-methyl-6~-H-4-oxabicyclo~4,4,0~decane (D.10) (1.2 g, 55%).
b.p. 96/0.1 mm n.m.r. (~, CC14): 4.2-0.87 (m, 17H, includes 0.92, d, 3H,> CHCH3 J-6Hz).

l 3 621~7 (c) (+) l-Aza-8~-az'ido'-2~-methyl-6q-H'-4-'oXabiCyclor4r4 decane '(D.~l'l)''in'te'r _diate' for Compounds 5~ahd 6 ~ J~/
1~ o (D.ll) Following the procedures outlined in Description 1, the ~ aza- ~-hydroxy-?.~-methyl-6~-H-4-oxabicyclo ~4,4,0~ decane tD.10) (1.2 g) was converted to (-)-1-aza-8~-azido-2~-methyl-6~-H-4-oxabicyclo~4,4,0~decane (D.ll). (1.05 g, 75~).
i-r. (film) ~(N ): 2090 cm 1.

(d) (+)8 -Amino-l-aza-2~-methyl-6~-H-4-oxabicyclo~4,4,0]
decane '(D.12) intermediate for Compounds 5 and 6 (D.12) Following the procedures outlined in Description 1, the (-) l-aza-8~-azido-2~-methyl-6~-H-4-oxabicyclo E 4,0~decane (D.ll) (1.05 g) was converted to (+) 8~-amino-1-aza-2~-methyl-6~-H-4-oxabicyclo~4,4,0~ decane (D.12) (0.9 g, 100~).

,~i 18~
.
.
_ 30 -.
, . ,. - , - Descri~tion 4 (a) 1-(4-But-l-envl~thiomorpholine-2.6-dione ~D.13) _ I I i 0 ~ N 0 - 1 ' ~ (D.13) Following the procedures outlined in Description 1, the thiomorpholine-2,6-dione (18.8 9) was converted into l-(4-but-1-enyl)thiomorpholine-2,6-dione (D.13) b.p. 106/0.4 mm (16 9, 60%).

_ 5 n.m.r. (~, CD~13): 6.1-5.35 (m, lH, H2C=CH-CH2-);
5.2-4.75 (m, 2H, H2C=CH-);
3.83 (t, 2H, J 7Hz, ~ NCH2-);
3.48 (s, 4H, S(C_2C0)2N-);
2.5-2 (m, 2H, -CH2-CH2CH=);

-6a-H
(b)` (+~ l-Aza-8~-formvlox ~ 4-thiabicyclor4,4,01decane-2-one (D.14) O - ~
Ho =
~ S
H (D.14) .

l ~ 6~187 Following the procedures outlined in Description 1, the 1-(4-but 1-enyl)thiomorpholine-2,6-dione (D.13) (7.2 g) was converted into crude (+) l-aza-8~-formloxy-6~-H-4-thiabicyclo [4,4,0]decane-2-one (D.14) (6.6 g, 79%).
n.m.r. (~ , CDC13): 7.98 (s, lH, OOCH);
5.7-1.2 (m, 12H including 3.3, s, 2H, -SCH2~-).

tc~ (+)1-Aza-8~-hydroxy-6~-H-4-thiabicyclor4,4,03decane (D.15) / N
HO ~

(D.15) Following the procedures outlined in Description 1, the (-) l-aza-8~-formyloxy-6~-H-4-thiabicyclo[4,4,0~decane-2-one (D.14) ~9 g) was converted into (+) 1-aza-8~-hydroxy-6~-H-4-thiabicyclo ~4,4,03decane (D.15) (5.8 g, 80%).

b.p. 120/0.2 mm m.p. 130-3.

(d) (-? l-Az'a'-8~,~-'az'i'do-6~-H-4'-th'iabicyclo~4,'4, o3 decane (D.16'~ intermed'iate for Compo'und's 7 and 8 -/--~N
N ~ ~ ~

Following the procedures outlined in Description 1, the (-) l-aza-8~-hydroxy-6~-H-4-thiabicyclo[4,4,0]decane (D.153 (2.5 g) was converted into a crude isomeric mixture of (+) l-aza-8~-, and 1-aza-8~-azido-6~-H-4-thiabicyclo~4,4,0]decane (D.16) (2.8 g, 95%).

i.r. (film) ~ (N3) 2090 cm 1 (e) (+) 8~, ~Amino-l-aza-6~-H-4-thiabicycloC4,4,0~decane (D.17) intermediate for ComPounds 7 and 8 -2 ~ \ ~

(D.17) Following the procedures outlined in Description 1, the (-) l-aza-8~, ~-azido-6~-H-4-thiabicyclo[4,4,03decane (D.16) was converted into a crude isomeric mixture of (+) 8~, ~-amino-l-aza-6~-H-4-thiabicyclo~4,4,0~decane (D~17) (2.4 g, ca 100%).

l l 621~7 Description 5 (a) (-) l-Aza-6Q~H-4-thiabicyclo[4,4,0~decane-~8-one (D.18) ihtermediate for Compounds 9, 10, 19, 20 and 21 ~/~~~ ~
O ~ S

(D.18) Following the procedures outlined in Description 2, the (+-) l-aza-8~-hydroxy-6~-H-4-thiabicyclo~4,4,0~decane (D.lS) (prepared as in Description 15) (3.1 g) was converted into (-) l-~za-6~-H-4-thiabicyclo[4,4,0]decane-8~one (D.18) (2.6 g, 80%).

(b) (+-) l-Aza-6~-H-4-thiabicyclo~4,4,03 decane-8-one oxime (D.l9) intermediate for Compound 9 and 10 HON ~ ~ ~ ~
--S
(D.l9) Following the procedures outlined in Description 2, the (-) l-aza-6~-H-4-thiabicyclo[4,4,0~decane-8-one (D.18) (2.6 g) was converted into the crude (-+) l-aza-6~-H-4-thiabicyclo ~,4,0]
decane-8-one oxime (D.l9) (2.8 g, ca 100~), used without purifi-cation.

~ 33 -. ~

l l 62187 (c) (+) 8~-Ami'no-l-az'a-'6~-H-4-thiab'icyclo'r4,4, o3 decane (D.'2'0) in'termediat'e for Compounds 9 and 10 H2N-~N ~?
H

(D.20) Following the procedures in Description 2, the (-) 1-aza-6~-H-4-thiabicyclo ~4,4,0]decane-8-one oxime (D.l9) (2.8 g) was converted into the crude (~) 8~-amino-1-aza-6~-H-4-thia-bicyclo~4,4,0~decane (D.20) (2.5 g, ca 100~).

? ~ - 34 -- 35 -~

Description 6 (a~ Aza-8~-HYdroxY-2~-phenyl-6a-H-4-oxabic~clo [4,4,0]decane_(D.21) intexmediate for Com~ounds 11, 12, 13 and 14 Ph H ~-H (D.21) To a cooled (0C) stirred solu~ion of bromobenzene (6.2 g) in dry ether (50 ml) was added a 1.6M solution of n-butyl lithium in hexane (25 ml) and the solution was stirred at 0C for 30 minutes. On further cooling to -30C, a solution of (~) l-aza-8~-trimethylsiloxy-6a-H-4-oxabicyclo[4,4,0]decane-2-one (4.3 g crude) (see Description 3(b)) in dry ether (25 ml) was added over 5 minutes and the resu~ing solution stirred to room temperature over 2 hours, during which time a white precipitate formed. The stirred suspension was then cooled to 0C and 25 ml of a saturated aqueous potassium carbonate solution (25 ml), followed by methylene chloride (100 ml) was added and the organic upper layer separated, dried (K2C03), filtered and concentrated in vacuo.

~16~87 Ice-cold ethanol ~100 ml) was then added followed by 5N ethanolic hydrogen chloride (3.6 ml) and subsequently stirred at 0 C with sodium borohydride (4 g) for 2 hours.
The ethanol was removed by rotary evaporation and the residue extracted with methylene chloride (3 x 100 ml). Column chromatorgraphy (silica, ether eluent) gave the (') l-aza-8~-hydroxy-2~-phenyl-6a-H-4-oxabicyclo[4,4,0~ecane (D.21) as an oil (1.6 g, 24%).

(b) (') l-Aza-8a-azido-2~-phenyl-6a-H-4-oxabicyclo [4,4,0]decane (D.22) intermediate for Compounds 11 and 12 -(D.22) ~ ollowing the procedures outlined in Description 1, the (i) 1-aza-8~-hydroxy-2~-phenyl-6a-H-oxabicyclo [4,4p]decane (D.21) (1.6 g) was converted to (i) -1-aza-8~-azido-2~-phenyl-6a-H-4-oxabicyclo[4,4,0]decane (D. 22) (1.4 g, 75%).

I.r. tfilm) V(N3) : 2090 cm N.m.r. (~, CC14) : 7.6-7.0 (m, 5H, aromatic P C-H~

4.2-1.1 (m, 13H, remaining C-H)-(c) (') 8~-Amino-l-aza-2~-phenyl-6a-H-4-oxabicyclo [4,4,0~decane (D.23) intermediate for ComPounds 11 and 1_ Ph (D.23) Following the procedures outlined in Description 1, the (~) 1-aza-8a-azido-2~-phenyl-6a-H-4-oxabicyclo [4,4,0]decane (D.22) (1.4 g) was converted to (i) 8a-amino-l-aza-2~-phenyl-6a-H-4-oxabicyclo[4,4,0]decane (D~23) (1.3 g, 100%).

` ~ ~ 6~187 Description 7 (a) ~ Aza-2~-phenyl-6~-H-4-oxabicyclo[4,4,0]
decane-8-one (D. 24) intermediate for Compounds 13 and 14 Ph N
~ ~ _O
H
(D.24) Following the procedures outlined in Description 2(a), the (') 1-aza-8~-hydroxy-2~-phenyl 6a-H-oxabicyclo [4,4,0]decane (D.21) (2.6 g) was converted to (~) 1-aza-2~-phenyl-6a-H-4-oxabicyclo[4,4,0]decane-8-one (D.24) (2.4 g, 92%).

(b) (~) l-Aza-2~-phenyl-6~-H-4-oxabicyclo[4,4,0]decane -8-one oxime (D.25) intermediate for Compounds 13 and 14 Ph HON
H

(D.25) ~ ~æl~7 Following the procedures outlined in Description 2(b), the (i) 1-aza-2~-phenyl-6~-H-4-oxabicyclo[4,4,0]
decane-8-one (D.24) (2.4 g) was converted to (~) l-aza-2~-phenyl-6a-H-4-oxabicyclo[4,4,0]decane-8-one oxime (D.25) purified by column chromatography (silica, ether eluent) (2.3 g, 90%).

(c) (~) 8 ~Amino-l-aza-2~-phenyl-6~H~-oxabicyclo [4,4,0]decane (D.26) intermediate for_Compounds 13 and 14 -Ph / ~
H N

H (D.26) Following the procedures outlined in Description 2(c), the (*) 1-aæa-2~-phenyl-6~-H-4-oxabicyclo [4,4,0]decane-8-one oxime (D.25) (2.3 g) was converted to (~) 8~-amino-1-aza-2~-phenyl-6~-H-4-oxabicyclo [4,4,0]decane (D.26) (2.1 g, 95%).

1 ~ 62187 Example 1 (-~ 4-Acetamido-5-chloro-2-methoxy-N-('8~-1-aza-6~-H'-'4-oxabieyelo G 4,01de'eyl)benzamide (1 ~ -N
CONHl ~ ~ ~ O
~ OCH3 NHCOCH3 (1) To 4-acetamido-5-chloro-2-methoxybenzoyl chloride (3.4 g) in toluene (150 ml) and triethylamine (3 ml) was added the crude (-) 8G~amino-l-aza-6~-H-4-oxabicyelo L4,4,0~ decane (D.5) (1.5 g) in toluene (20 ml). The reaetion mixture was stirred at room tempera-ture for 4 hours, then treated with 2.SN aqueous sodium hydroxide (10 ml). The toluene layer was separated, the aqueous layer extracted with chloroform (3 x 100 ml) and the combined organie extraets dried (K2CO3). The solvent was removed and ehromatography of the produet (neutral alumina, Broekman II, ethylaeetate) gave the (+) 4-aeetamido-5-ehloro-2-methoxy-N-(8~-1-aza-6~-H-4-oxa-bicyelo [4,4,0~deeyl)benzamide (1) m.p. 189-92 (2.9 g, 80%).

n.m.r. (~ , CDC13): 8.27 (s, lH, aryl _);
8.12 (5 , lE~, aryl El);
8.2-7.2 (m, 2H, -CON_-CH~ , CH2CONH-Ar);

5.65-4.2 (m, lH, 8 -H);
4.].5-3 (m, 7H including 4.0 s, 3H, -OCH3);
3-1.2 (m, 12H = CH2 ineluding 2.27, s, 3H, -COC_3).

'~

l J 62187 Example 2 ( ) 4-Amino-5-chloro-2-methoxy-N-(8~-1-aza-6~-H-4-oxa bicyclo L4,4,0~decyl)benzamide` (2) ~ N-r~ O
CONH H

J~ I
Cl ~

(2) (1) (2.9 g) prepared as in Example 1) was refluxed with an aqueous ethanol (water 5 ml, ethanol 50 ml) solution of potassium hydroxide (1 g) for 2 hours. The mixture was then cooled to room temperature and the ethanol removed by rotary evaporation.
Trituration with water gave a white solid which was collected and recrystallised from ethylacetate yielding the (+) 4-amino-5-chloro-2-methoxy-N-(8~-1-aza-6~-H-4-oxa-bicyclo[4,4,0]decyl)benzamide (2) (1.35 g, 50%). m.p. = 190.

n.m.r. (~, CDC13): 8.3-7.8 (m, lH, ArCON~-C_=);
8.03 (s, lH, Acryl 6-_);

6.27 (s, lH, Acyl 3-_);
4.7-1.3 (m, 19H, includes 3.9, s, 3H, -OC_3).

Example 3 (-) 4-Acetamido-5-chlo'ro-2-methoxy-N-(8~ aza-'6~-H-'4'-oxabicyclo [4!4,0~decy1)benzami'de (3) / N
CONH ~ ~

(3) Following the procedures outlined in Example 1, the (-) 8~-amino-1-aza-6~-H-4-oxabicyclo[4,4,0] decane (D.8) (1.5 g) was converted to (-) 4-acetamido-5~chloro-2-methoxy-N-(8~-1-aza-6~-H-4-oxabicyclo t4,4,0]decyl)benzamide (3) (2.6 g, 70%) m.p. 188-9.

n.m.r. (S, CDC13): 8.18 (s, lH, aryl-_);
8.05 (s, lH, aryl-_);

7.9-7.4 (m, 2H, -CONHCH~ , CH3CONH-aryl);
4.2-0.8 (m, 20H, remaining H
including 3.87, s, 3H, OCH3 and 2.23, s, 3H, -COCH3).

~ - 42 -, j l 1 ~2187 Exam~e 4 (-) 4-Amino-~5-chloro-2-methoxy-N-(8 ~ aza-6~-H-4-oxabicyclo C4,4,~ decyl)benzamide (4) CONH~-- N\ /
~ OCH3 H

Cl J ~ J

(4) (3) (2.6 g) (~repared as in Examplé 3) was refluxed with an aqueous ethanol (water 5 ml, ethanol 50 ml) solution of potassium hydroxide (1 g) for 2 hours. On cooling, the ethanol was removed by rotary evaporation and the residue extracted with chloroform (2 x 50 ml) and dried (K2CO3). Filtration and removal of the solvent afforded the crude product, recrystallisation from ethyl acetate-petrol gave (-) 4-amino-5-chloro-2-methoxy-N- ~ 1-aza-6~-H-4-oxabicycl 4,4,0 decyl)benzamide (4) (1.3 g, 55%) m.p. 195-7.

n.m~r. (S, CDC13): 8.00 (s, lH, aryl-6-_);
7.6-7.4 (m, lH, -CON_-CH=);
6.23 (s, lH, aryl 3-H);
4.6-1.0 (m, l9H, remaining proton including 3.83, s, 3H, -OCH3).

Example 5 (-)4-Ace't'ami'd'o-'5-chlo'ro'-'2-methoxy-N-(8~-1-'aza-2~-methy1-6~-H-4-oxabicyclo~4,4, o3 decyl')ben'z'amide (5) CONH H
OCE~3 Cl/~

(5) Following the procedures outlined in Example 1, the (-)

8~-amino-1-aza-2~-methyl-6~-H-4-oxabicycl~4,4,0~decane (D.12) (0.9 g) was converted to 4-acetamido-5-chloro-2-methoxy-N-t8~-1-aza-2~-methyl-6~-H-4-oxabicyclo[4,4,03decyl)benzamide (5) (1.0 g, 47%) m.p. 165-6.

n.m.r. (~, CDC13): 8.4-7.7 (m, 2H, -CON_-CH=, CH3CONH);
8.28 (s, lH, aryl-H?;
8.14 (s, lH, aryl-_);
5.65-4.2 (m, lH, 8 -H);
4.2-3.0 (m, 8H including 4.0, s, 3H, -OCH3);
2.9-0.8 (m, 13H, including 2.27 s, 3H, -COCH3) and 0.95, d, 3H, =CH-CEI3, J=6Hz).

Example 6 (+) 4 Amino-5-chloro-2-methoxy-~-(8~ aza-2~-methy1-6~-H-4-_xabicyclor4,4,0~de'cy'1)b'en'z'amide`'(6) / ~ CH3 (~
CONH I ~ O

/J

(6) Following the procedures outlined in Example 4, the (-) 4-acetamido-5-chloro-2-methoxy-N-(8~-1-aza-2~-methyl-6~-H-4-oxabicyclo ~4,4,0~decyl)benæamide (5) (1.0 g) was converted to (-) 4-amino-5-chloro-2-methoxy-N-(8~-1-aza-2~-methyl-6~-H-4-oxabicyclo ~4,4,03decyl)benzamide (6) (0.7 g, 80~). m.p. 221-2.

n.m.r. (~, CDC13): 8.2-7.8 (m, lH, -CONH-CH=);
7.96 (s, lH, aryl 6-H);
6.24 (s, lH, aryl 3-H);
4.8-2.9 (m, llH includes 3.88, s, 3H, -OCH3);
2.6-0.8 (m, 10H includes 0.96, d, 3H, CH-C_3, J = 6Hz).

I l 62187 Example 7 (-) 4-Acetamido-5-chloro-2-methoxy-N-(8c~ aza-6~-H-4-thiabicyclo ~,4,0~decyl)benzamide (7) CONH
~OCH3 H
ll ,J
C~ ~

Following the procedures outlined in Example 1, the crude (-) 8~,~-amino-1-aza-6~-H-4-thiabicyclo [4,4,0~decane (D.17) (2.4 g) was converted to (+) 4-acetamido-5-chloro-2-methoxy-n-(8~r~-1-aza-6~-H-4-thiabicyclo E,4,0~decyl)benzamide (7) (5.1 g, 90~).
m.p. 185-9 (E to Ac).

n.m.r. (~, CDC13): 8.3-7.4 (m, 4H, aryl-H, -CONHC~ , CH3CONH-Aryl);
5.6-1.2 (m, 20H, includes 4.0, s, 2H, -OCH3 [~-isomer~;
3.9, s, lH, -OCH3 ~-isomer~ ;
2.27, s, 3H, COCH3).

~ - ~6 -~ J ~187 Example 8 (-) 4-Am'ino-5-chloro-2-methoxy-N-(8~ aza-6~-EI-4-thiabicyclo ~4,4, o3 decyl)benzamide (8) ~,/~ ~
CONEI H S

~ OCH3 Cl (8) Following the procedures outlined in Example 4, the (-) 4-acetamido-5-chloro-2-methoxy-N-(8~,~-1-aza-6~-H-4-thiabicyclo [4,4,0]decyl)benzamide (7) (2.0 g) was converted to the crude (-) 4-amino-5-chloro-2-methoxy-N-(8~,~-1-aza-6~-H-4-thiabicyclo[4,4,0 decyl)benzamide. Fractional recrystallisation from ethyl acetate afforded the pure (+) 4-amino-5-chloro-2-methoxy-N-(8~-1-aza-6~-H-4-thiabicyclo [4,4,0~decyl)benzamide (8) (0.8 g, 45%). m.p. 183-6.

n.m.r. (~, CDC13): 8.2-7.8 (m, lH, ,CONH-CH=);
8.05 (s, lH, aryl 6-_);
6.27 (s, lH, aryl 3-_);
4.1-4.6 (m, 3H, aryl-NE12, 8~-_);
3.93 (s, 3H, -OCH3);
3.4-1.4 (m, 13H, remaining protons).

l ~ 62187 Example 9 (-) 4-Acetamido-5-'ch'loro-2-methoxy-N-(8~-1-aza-6~-H-4-thlabicyclo [4,4,0~ decyl)ben'z-ami'de ~9) CON ~ S

Cl~ ~

(9) Following the procedures outlined in Example 1, the crude (-) 8~-amino-1-aza-6~-H-4-thiabicyclo[4,4,0~ decane) (D.20) (2.5 g) was converted to (-) 4-acetamido-5-chloro-2-methoxy-N-(8~ aza-6~-H-4-thiabicyclo[4,4,0]decyl benzamide (9) (2.2 g, 40%) m.p. ~ 210-3.

n.m.r. ( , CDC13): 8.25 (s, lH, aryl EI);
8.17 (s, lH, aryl H);
8.0-7.5 (m, 2H, -CONH-CH~ ;
CH3CONH-aryl) 4.3-3.6 (m, lH, - 8~-H);
3.9 (s, 3H, -OCH3);
3.3-1.0 (m, 16H, remaining protons including 2.27, s, 3EI, -C ~H3).

~ ~6`21~7 Example l_ (-) 4-Amino-5-chloro-2-methoxy-N-(8~ aza-6~-H-4-thiabicyclo ~4,4,03decyl)benzamide (10) CONH ~ N
~ ~ OCH3 H

Cl~ ~

(10) Following the procedures outlined in Example 4, the (+) 4-acetamido-5-chloro-2-methoxy-N-(8~-1-aza-6~-H-4-thiabicyclo [4,4,03decyl)benzamide (9) (1~2 g) was converted to (-) 4-amino-5-chloro-2-methoxy-N-(8~-1-aza-6~-H-4-thiabicyclo~4,4,0~decyl) benzamide (10) (0.73 g, 65%). m.p. 206-8.

n.m.r. (~, CDC13): 8.03 (s, lH, aryl 6H);
7.7-7.3 (m, lH, ,CONHCH=);
6.23 (s, lH, aryl 3H);
4.6-3.7 (m, 6H, 8~-_, aryl N-2 including 3.83, s, 3H, -OCH3);
3.5-1.0 (m, 13H, remaining protons).

.~

. --Example 11 (~) 4-Acetamido-5-chloro-2-methoxy-N-(8a-1-aza 2~-phenyl-6a-H-4-oxabicyclo[4l4~o]decyl)benzamide (11) Ph COWH ~ O

~ CH3 Cl ~ (11) Following the procedures outlined in Example 1, the (') 8a-amino-1-aza-2~-phenyl-6a-H-oxabicyclo [4,4,0]decane (D.23) (1.3 g) was converted to (~) 4 acetamido-5-chloro-2-methoxy-N-(8a-1-aza-2~-phenyl-6a-H-4-oxabicyclo[4,4,0]decyl)benzamide (11) (2.1 g, 80%) as an oil.

N.m.r. (~, CDC13) : 8.4-7.8 (m, 2H, CONH- and aryl-H);
8.23 (s, lH, aryl-H );
0 8.08 (s, lH, aryl-H);
7.6-6.9 (m, 5H, aryl-H);
4.5-1.0 (m, l9H, including 4.0, S, 3H-OCH3, 2.3, s, 3H, -COCH3).

l 1 62187 Example 12 (i) 4-Amino-5-chloro-2-methoxy-N-(8a-1-aza-2~-phenyl-6a-H-4-oxabicyclo[4,4,0]decyl)benzamide (12) Ph CONH H
ll I OCH3 Cl ~
NH2 (12) Following the procedures outlined in Example 4, the (i) 4-acetamido-5-chloro-2-methoxy-N-(8a-1-aza~
2~-phenyl-6a-H-4-oxabicyclo[4,4,0]decyl)benzamide

(11) (2.1 g) was converted to (~) 4-amino-5-chloro-2-methoxy-N-(8a-1-aza-2~-phenyl-6a-H-4-oxabicycl~
[4,4,0~decyl)benzamide (12) (1.0 g, 50%), mp 145-7.

N.m.r. (~, CDC13) : 8.3-7.9 (m, lH, -CONH-CH= and s, lH, aryl 6-H);
7.6-6.9 (m, 5H, aryl H);
6.3 (s, IH,aryl 3-H);
4.7-3.1 (m, llH, includes 3.93, s, 3H, -O CH3);
2.8-1.2 (m, 8H remaining C-H).

~ l 62187 . .

Example 13 (') 4-Acetamido-5-chloro-2-methoxy-N-(8~ aza-2~-phenyl-6~-H-4-oxabicyclo[4,4,0]decyl)benzamide (13) Ph ~ N
CONH ~-- ~--o ¦ H
~ OCH3 Cl ~
NHCOCH
3 (13) Following the procedures outlined in Example 1, the (~) 8~-amino-1-aza-2~-phenyl-6a-H-4-oxabicyclo [4,4,0]decane (D.26) (2.1 g) was converted to (i) 4-acetamido-5-chloro-2-methoxy-N-(8~-1-aza-2~-phenyl-6~-H-4-oxabicyclo[4,4,0]decyl)benzamide (13) (3.2 g, 75%) as an oil.

N.m.r. (~, CDC13) : 8.4-7.5 (m, 2H, -CONH-CH=, CH3CONH-);
8.25 (s, lH, aryl-H);
8.10 (s, lH, aryl-H);
7.4-7.2 (m, 5H, aryl-H);
4.7-1.0 (m, l9H, including s, 3H, 3.88, -OCH3; s, 3H, 2.22, -COCH3).

Example 14 (+) 4-Amino-5-chloro-2-methoxy-N-(8~-1-aza-~-phenyl-6a-H-4-oxabicyclo[4,4,0jdecyl)benzamide monohydrate (14) Ph CONH
~0 ~ OCH3 H

C ~ (14) Following the procedures outlined in Example 4, the (~) 4-acetamido-5-chloro-2-methoxy-N-t8~-1-aza-2~-phenyl-6a-H-4-oxabicyclo[4,4,0]decyl)benzamide (13) (3.2 g) was converted to (i) 4-amino-5-chloro-2-methoxy-N-(8~-1-aza-2~-phenyl-6~H-4-oxabicyclo[4,4,0]
decyl)benzamide monohydrate (14) (1.6 g, 50%) mp 138-45.

N.m.r. : 8.07 (s, lH, aryl 6-H);
7.7-7.2 (m, 6H, -CONH-CH= and aryl -H);
6.28 (s, lH, aryl 3-H);
4.6-1.0 (m, 20H, includes 3.86, s, 3H, -OCH3).

l ~ 62187 Example 15 (*J 4-Acetamido-5-chloro-2-methoxy-N-(8a,~-1-aza-6a-H-4-oxothiabicyclo[4~4,0]decyl)benzamide (15) CONH~
OCH3 H o ,J
Cl ~
NHCOCH3 (15) To a stirred solution of (+) 4-acetamido-5-chloro-2-methoxy-N-(8a,~-1-aZa-6~-H-4-thiabiCyCl0[4,4,0]deCyl) benzamide (7) (2.0 g) in methanol (50 ml) was added a solution of sodium periodate (1.5 g) dissolved in the minimum quantity of water, and the resulting reaction mixture stirred at room temperature for 3hours.
The solvent was removed in vacuo, water (10 ml) added, followed by chloroform (100 ml). Separation of the organic layer gave, on concentration and dryirig, (*) 4-acetamido-5-chloro-2-methoxy-N-(8a,~-1-aza-6~-H-4-oxothiabicyclo[4,4,0]decyl)benzamide (15) (2.1 g, 100%) as a foam.

N.m.r. (~, CDC13) : 8.2-7.5 tm, 2H, -CONH-);
8.43 (br.s, lH, aryl-Hl;
8.27 (br.s, lH, aryl-H);
4.8-1.1 (m, 20H, including 3 singlets, 3H, -OCH3; 4.03, 4.00, 3.95, 2.3, s, 3H, -COCH3).

I 1 62~7 Example 16 (~) 4-Amino-5-chloro~2-methoxy-N-(8a,~-1-aza-6a-H-4-oxothiabicyclo[4,4,0]decyl)benzamide (16) CONH ~ ~ - ~ -~ OCH3 H ~0 Cl ~ (16) Followtng the procedures outlined in Example 4, the (l) 4-acetamido-5-chloro-2-methoxy-N-(8a,~-1-aza-6a-H-4-oxothiabicyclo[4,4,0]decyl)benZamide (15) (2.1 g) was converted into (~) 4-amino-5-chloro-2-methoxy-N-(8a,~-1-aza-6a-H-4-oxothiabicyclo[4,4,0]decyl)benza mide (1.0 g, 50%), mp 130-8.

N.m.r. (~, CDC13) : 8.3-7.4 (m, lH, -CONH-CH=);
8.06 (br.s, lH, aryl 6-H);
6.30 (br.s, lH, aryl 3-H);
4.7-1.1 (m, l9H, includes 3.94, 3.91, 3.87, 3 singlets, 3H.-OCH3)~

l l 62187 . . .

Examp1~17 (i) 4-Acetamido-5-chloro-2-methox~-N-(8~ aza-6a -H-4-oxothiabicyclo[4,4,0]decyl)benzamide (17) CONH - ~
OCH3 o Il I .
Cl ~
NHCOCH3 (17) Following the procedures outlined in Example 15, the (i) 4-acetamido-5-chloro-2-methoxy-N-(8~-1-aza-6a-H-4-thiabicyclo[4,4,0]decyl)benzamide (9) (1.1 g) was converted to (i) 4-acetamido-5-chloro-2-methoxy-N-(8~-1-aza-6~-H-4-oxothiabicyclo[4,4,0]decyl)benzamide (17) (0.9 g, 80%). mp 245-6 (dec).

N.m.~ , CDC13) : 8.25 (s, lH, aryl-H);
8.15 (s, lH, aryl-H);
7.95-7.45 (m, 2H, -CONH-);
4.3-1.1 (m, 20H, including 3.95, s, 3H, -OCH3; 2.3, s, 3H, -COCH3).

l 1 62187 ~ . .

Example 18 (+) 4-Amino-5-chloro-2-methoxy-N-(8~-1-aza-6a-H-4-oxothiabicyclo[4,4,0]dec~1)benzamide(18) CONH ~ S~
~ ~ CH3 H O

Cl ~
NH2 (18) Following the procedures outlined in Example 4, the (l) 4-acetamido-5-chloro-2-methoxy-N-(8~-1-aza-6a-H-4-oxathiabicyclo[4,4,0]decyl)benzamide (17) (0.9 g) was converted to (i) 4-amino-5-chloro-2-methoxy-N-(8~-1-aza-6a-H-4-oxathiabicyclo[4,4,0]decyl) benzamide (18) (0.4 g, 50%). mp 209-11 N.m.r. (~, CDC13) : 8.06(s, lH, aryl 6-H);
7.8-7.4 (m, lH, -CONH-CH=);
6.30 (s, lH , aryl 3-H);
4.7-1.1 (m, l9H, inlcudes 3.87, s, 3H, -OCH3).

l ~ 62187 Example 19 (_)2-Methoxy-5-sulphonamido-N-(8~-1-aza-6~-H-4-thia-bicyclo[4,4,0~decyl)benzamide (19) ~ N
CONH

NH202S ~

(19) To a solution of 2-methoxy-5-sulphonamido benzoic acid (1.8 g) in dry DMF (30 ml) at 0C was added, dropwise, a solution of oxalyl chloride (0.68 ml) in chloroform (5 ml) over 20 minutes. On stirring for a further 30 minutes, a solution of triethylamine (3 ml) in chloroform (5 ml) followed by + 8~-amino-1-aza-6~-H-4-thiabicyclo[4,4,0]decane (D 20) (1.2 g) in chloroform ( 5 ml) was added and the whole stirred for a further 2 hours at room temperature. Water (10 ml) followed by saturated potassium carbonate solution was added and the organic phase separated and the aqueous phase extracted with chloroform (2 x 100 ml), dried (K2C03) and the solvent removed to yield an oil. Purification by column chromatography (Alumina + 10% water; chloroform + 2% methanol) gave the (+) 2-methoxy-5-sulphonamido-N-(88-1-aza-6~-H-4-thiabicyclo[4,4,0]decyl)benzamide (19) (0.3 g, 11%), mp 216-8 (ethyl acetate).

116218~ ~

N.m.r. (~, CDC13) : 8.62 (d, lH, J=2.5 Hz, aryl 6-_);
7.98 (d,d, lH, J=2.5, 8.7 Hæ, aryl 4-H);
7.7-7.57 (m, lH, CON~
7.06 (d, lH , J=8.7Hz, aryl 3-_);
6.7-6.25 (m, 2H, -S02NH2);
4.5-3.7 (m, 4H, CONHCH< including 4.0, s, 3H, -OCH3);
3.4-l.o (m, 13H, remaining protons).

Example 20 (~) 2,4-Dimethox~-N-(8~-l-aza-6~-H-4-thiabicyclo [4,4,0]decyl)benzamide (20) CON
OCH3 ~ S

CH3 (20) To a stirred solution of 2,4-dimethoxybenzoic acid (l.l g) in CH2Cl2 (lOO ml) was added oxalyl chloride (0.48 ml) and DMF (ca 5 drops) and the whole stirred until gas evolution ceased (ca 1 hour). The reaction mixture was cooled to 0C and triethylamine (2 ml) in C~2Cl2 (lO ml) followed by (+) 8~-amino-l-aza-6~-H-4-thiabicyclo[4,4,0]decane(D 20) (0.85 g) in CH2C12 (10 ml) added and the whole stirred at room temperature for 2 hours. Aqueous sodium hydroxide (2.5 N, 10 ml) was added and the o~ganic layer separated, dried (K2C03) and evaporated to give an oil, which was purified by chromatography (Alumina + lO~ water;
CH2Cl2) to give (+) 2,4-dimethoxy-N-(8~-l-aza-6~-H-4-thiabicyclo[4,4,0]decyl)benzamide (20)(1.08 g, 65%), mp 130-2 (EtoAc/petrol).

`` 1162187 N.m.r. (~, CDC13) : 8.15 (d, lH, J = 8.6 Hz, aryl 6H);
7 . 75-7 . 45 (m, lH , CONH);
6.59 (d,d, lH, J = 8.6 Hz, 2.3 Hz, aryl 5-H);
6.47 (d, lH, J = 2.3 Hz, aryl 3H);
4.8-3.7 (m, 7H, CON~CH= including 3.90, s, 3H, -OCH3 and 3.84, s, 3H, OCH3);
3.25-1.0 (m, 13~., remaining protons).

I 1 6~187 Example 21 (+) 4-Chloro-2-methoxy-N-(8~ aza-6~-E~ thia-bicyclo ~4,4,0]decyl)benz,amide (21) ~ N
CON

Cl (21) Following the procedures detai~ed in Example 20, the (+) 8~-amino-1-aza-6~-H-4-thiabicyclo[4,4,0]decane (D 20) (0.85 g) was converted to (+) 4-chloro-2-methoxy-N-(8~-1-aza-6~-H-4-thiabicyclo[4,4,0]decyl)benzamide (21) (1.0 g, 60~, mp = 145-7 (E tOAc/petrol).

N.m.r. (~, CDC13) : 8.12 (d, lH, J = 8.3 HZ, aryl 6_);
7.75-7.4 (m, lH, -CONH);
7.12.6.93 (m, 2H, aryl 5_, 3H);
4.3-3.75 (m, 4H, CONHCH= including 3.93, S~ 3H, OCH3);
3.25-1.0 (m, 13H, remaining protons).

~ l l 62187 Bioloaical Data Section ~astric Activ tv Increase in intraqastric pre~sure in the rat - Intragastric pressure changes:were recorded from previously starved conscious but retrained rats using a saline filled catheter inserted into the lumen of the stomach via a permanent gastric fistula. The catheter was connected to a physiological pressure transducer and pressure changes recorded on a hot wire pen recorder. In each animal a pre-dose period of 40 minutes was allowed to obtain a measure of spontaneous activity. An index of activity was obtained by measur-ing the average height of pressure waves during 10minute periods. Values for 4 such periods were obtained during assessment of spontaneous activity and for the 40 minute period after the subcutaneous administration of the compounds. Students 't' test was applied to the dîfference in average values obtained for spontaneous and post-compound activity.
Table I shows the minimum dose for activity.

Table I

Compound of Dose ma/ka Example No. Subcutaneouslv 2 0.5 0.5 4 1.0 n.t.
6 0.2 0.5 8 5.0 l~.t.
- 10 1.0 n.t.

n.t. = not tested 1 16~1g7 ~ ~.

Table I (cont) , Compound of Dose mg/kg Example No.
Subcutaneously Orally 14 1 n.t.

18 L n.t.

1 1 ~2~87 , .
' Compounds were also tes*ed for their ability to 'inhibit apomorphine induced climbing in the mouse.
Inactivity in this test may be indicative of a low propensity to-produce extra-pyramidal side-effects S - in~Man. 'The results a're shown~n the-Table ~"~el-ow:
The'-me'thod used for this test is as set out below:
Table 2 - - ~- - -_ Compound of-Example No Dose mg/kg ED50;~

6' 40 _ 8 Ia at 25

12 30 14 Ia at 10 po 16 Ia at 10 po . .. . .

Inhibition of apomorphine induced climbina in the mouse .
The test is based on that described by Protais, P., Constantin, J. and Schwartz, J.C. (1976), Psychopharmacology, 50, 1-6.
10Apomorphine 1 mg/kg s.c. induces mice to climb the wall of a wire'cage (inverted food hopper - 11 x 7.5 x 18 cm high). Mice acclimatised in their home cages in groups of 5 are placed under the hoppers immediately after the 'injection of apomorphine 1 mg/kg s.c. At 1510, 20 and 30 minutes after injection climbing behaviour is scored. The mice are observed for 30 seconds and scored according to the position in which they spend 'the majority of time, score 0 - four paws on floor of cage; score''l - fore paws only on walls; score 2 - all paws on wall of cage.

1 J ~187 The scores at all 3 times for each mouse are summed for apomorphine only and for apomorphine plus compound groups of mice.
Total scores are then calculated as the percentage inhibition of climbing as follows:

rTotal scores of drug treated group 1 x 100 I i ition 100 LTotal scores of apomorphine only group From graphical representation of the results ED50 vlaues (the dose that inhibits the apomorphine response by 50%) are then obtained.

Toxicity No toxic effects were observed in these tests.

l,b,

Claims (28)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of formula (I) (I) and pharmaceutically acceptable salts and N-oxides thereof, wherein:
R1 is a C1-6 alkoxy group:
R2 and R3 are the same or different and are hydrogen, halogen, CF3, C1-7 acyl, C1-7 acylamino, C1-6 alkyl-S(O)n wherein n is 0, 1 or 2, nitro, C1-6 alkoxy, hydroxy, or amino, aminocarbonyl or aminosulphonyl optionally substituted by one or two C1-6 alkyl groups, or R1 and R2 taken together are methylenedioxy or ethylenedioxy in which case R3 is any one of the groups given for R1 and R2 above R4 is hydrogen, C1-4 alkyl, phenyl or phenyl C1-4 alkyl;
R5 is hydrogen or C1-4 alkyl:
X is an oxygen or sulphur atom, or a sulphoxide group >S?;

p is 1 or 2; and r is 1 or 2 which comprises reacting an acid of the formula (VIII):

(VIII) or a reactive derivative thereof, with a compound of the formula (IX):

(IX) wherein the variable groups are as defined in formula (I), and thereafter if desired or necessary converting a group R2, R3 or X
in the thus formed compound to another R2, R3 or X respectively and recovering the compound of formula (I) and when required forming a pharmaceutically acceptable salt or N-oxide thereof and recovering same.

2. A compound of formula (I) (I) and pharmaceutically acceptable salts and N-oxides thereof, wherein:
R1 is a C1-6 alkoxy group;
R2 and R3 are the same or different and are hydrogen, halogen, CF3, C1-7 acyl, C1-7 acylamino, C1-6 alkyl-S(O)n wherein n is 0, 1 or 2, nitro, C1-6 alkoxy, hydroxy, or amino, aminocarbonyl or aminosulphonyl optionally substituted by one or two C1-6 alkyl groups or R1 and R2 taken together are methylenedioxy or ethylenedioxy in which case R3 is any one of the groups given for R1 and R2 above, R4 is hydrogen, C1-4 alkyl, phenyl or phenyl C1-4 alkyl;
R5 is hydrogen or C1-4 alkyl X is an oxygen or sulphur atom; or a sulphoxide group >S ?;
p is 1 or 2; and r is 1 or 2;
when prepared by the process of claim 1 or an obvious chemical equivalent.

3. A process as claimed in claim 1 wherein R2 and R3 in formulae (VIII) and (I) are the same or different and are hydrogen, halogen, CF3, C1-7 acyl, C1-7 acylamino, C1-6 alkyl-S(O)n wherein n is 0, 1 or 2, nitro or amino, aminocarbonyl or aminosulphonyl or said group substituted by one or two C1-6 alkyl groups; and R4 in formulae (IX) and (I) is hydrogen, C1-4 alkyl or phenyl and substitutes the carbon atom in the X ring adjacent the nitrogen.

4. A process as claimed in claim 3 wherein R2 and R3 in formulae (VIII) and (I) are as defined except that when alkyl-S(O)n, n must be 2, and X is an oxygen.

5. A process as claimed in claim 3 wherein in formulae (VIII) and (I) the benzamide moiety has the structure (III) (III)

6. A process as claimed in claim 2 wherein in formulae (IX) and (I) the bicyclic moiety has the structure (V) (V) wherein R4 and X are as defined.

7. A process as claimed in claim 5 wherein in formulae (IX) and (I) the bicyclic moiety is of formula wherein R4 is as defined.

8. A process as claimed in claim 5 wherein in formulae (IX) and (I) the bicyclic moiety is of formula wherein R4 is as defined and X' is S or S ?.

9. A process as claimed in claim 5, 6 or 7 wherein in formulae (IX) and (I) R4 is hydrogen or methyl.

10. A process according to claim 1 wherein in formula (I) there is an axial bond between the amide nitrogen and the ring carbon to which it is bound.

11. A process for the preparation of the compound (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.-1-aza-6.alpha.-H-4-oxabicyclo[4.4.0]-decyl)benzamide which comprises reacting 4-acetamido-5-chloro-2-methoxy-benzoyl chloride in toluene in the presence of triethylamine with (+) 8.alpha.-amino-1-aza-6.alpha.-H-4-oxabicyclo[4.4.0]-decane, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.alpha.-1-aza-6.alpha.-H-4-oxabicyclo[4.4.0]decyl)benzamide, reacting it with potassium hydroxide in aqueous ethanol and recovering the required compound.

12. (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.-1-aza-6.alpha.-H-4-oxabicyclo[4.4.0]decyl)benzamide when prepared by the process of claim 11 or an obvious chemical equivalent.

13. A process for the preparation of the compound t+) 4-amino-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-oxabicyclo[4.4.0]-decyl)benzamide which comprises reacting 4-acetamido-5-chloro-2-methoxy benzoyl chloride in toluene in the presence of triethyl-amine with (+) 8.beta.-amino-1-aza-6.alpha.-H-4-oxabicyclo[4.4.0]decane, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-oxabicyclo[4.4.0]decyl)benzylamide, reacting it with potassium hydroxide in aqueous ethanol and recovering the required compound.

14. (+) 4-amino-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-oxabicyclo[4.4.0]decyl)benzamide when prepared by the process of claim 13 or an obvious chemical equivalent.

15. A process for the preparation of the compound (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.-1-aza-2.beta.-methyl-6.alpha.-H-4-oxa-bicyclo[4.4Ø]decyl)benzamide which comprises reacting 4-acetamido-5-chloro-2-methoxy benzoyl chloride with (+) 8.alpha.-amino-1-aza-2.beta.-methyl-6.alpha.-H-4-oxabicyclo[4.4.0]decane in toluene in the presence of triethylamine, recovering (+) 4-acetamido-5-chloro-2-methyoxy-N-(8.alpha.-1-aza-2.beta.-methyl-6.alpha.-H-4-oxabicylo-[4.4.0]decyl)benzamide, reacting it with potassium hydroxide in aqueous ethanol and recovering the required compound.

16. (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.-1-aza-2.beta.-methyl-6.alpha.-H-4-oxabicyclo[4.4.0]decyl)benzamide when prepared by the process of claim 15 or an obvious chemical equivalent.

17. A process for the preparation of the compound (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]-decyl)benzamide which comprises reacting 4-acetamido-5-chloro-2-methoxy benzoyl chloride with 8.alpha.,.beta.-amino-1-aza-6.alpha.-H-4-thia-bicyclo[4.4.0]decane in toluene in the presence of triethylamine, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.alpha.,.beta.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decyl)benzamide, reacting it with potassium hydroxide in aqueous ethanol, recovering (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.,.beta.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decyl)benzamide and by fractional crystallization recovering the required compound.

18. (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decyl)benzamide when prepared by the process of claim 17 or an obvious chemical equivalent.

19. A process for the preparation of the compound (+) 4-amino-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]-decyl)benzamide which comprises reacting 4-acetamido-5-chloro-2-methoxy benzoyl chloride with (+) 8.beta.-amino-1-aza-6.alpha.-H-4-thia-bicyclo[4.4.0]decane in toluene in the presence of triethylamine, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decyl)benzamide, reacting it with potassium hydroxide in aqueous ethanol and recovering the required compound.

20. (+) 4-amino-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decyl)benzamide when prepared by the process of claim 19 or an obvious chemical equivalent.

21. A process for the preparation of the compound (+) 4-amlno-5-chloro-2-methoxy-N-(8.beta.-1-aza-2.beta.-phenyl-6.alpha.-H-4-oxa-bicyclo[4.4.0]decyl)benzamide monohydrate which comprises reacting 4-acetamido-5-chloro-2-methoxy benzoyl chloride with (+) 8.beta.-amino-1-aza-2.beta.-phenyl-6.alpha.-H-4-oxabicyclo[4.4.0]decane in toluene in the presence of triethylamine, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.beta.-1-aza-2.beta.-phenyl-6.alpha.-H-4-oxabicyclo[4.4.0]decyl)benzamide, reacting it with potassium hydroxide in aqueous ethanol and recovering the required compound.

22. (+) 4-amino-5-chloro-2-methoxy-N-(8.beta.-1-aza-2.beta.-phenyl-6.alpha.-H-4-oxabicyclol4.4.0]decyljbenzamide monohydrate when prepared by the process of claim 21 or an obvious chemical equivalent.

23. A process for the preparation of the compound (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.,.beta.-1-aza-6.alpha.-H-4-oxothiabicyclo-[4.4.0]decyl)benzamide which comprises reacting 4-acetamido-5-chloro-2-methoxy benzoyl chloride with (+) 8.alpha.,.beta.-amino-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decane in toluene in the presence of triethylamine, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.alpha.,.beta.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decyl)benzamide, treating it in methanol with sodium periodate in water, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.alpha.,.beta.-1-aza-6.alpha.-H-4-oxo-thiabicyclo[4.4.0]decyl)benzamide, reacting it with potassium hydroxide in aqueous ethanol and recovering the required compound.

24. (+) 4-amino-5-chloro-2-methoxy-N-(8.alpha.,.beta.-1-aza-6.alpha.-H-4-oxothiabicyclo[4.4.0]decyl)benzamide when prepared by the process of claim 23 or an obvious chemical equivalent.

25. A process for the preparation of the compound (+) 4-amino-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-oxothiabicyclo-[4.4.0]decyl)benzamide which comprises reacting 4-acetamido-5-chloro-2-methoxy benzoyl chloride with (+) 8.beta.-amino-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decane in toluene in the presence of triethylamine, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]decyl)benzamide, treating it in methanol with sodium periodate in water, recovering (+) 4-acetamido-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-oxothiabicyclo-[4.4.0]decyl)benzamide, reacting it with potassium hydroxide in aqueous ethanol and recovering the required compound.

26. (+) 4-amino-5-chloro-2-methoxy-N-(8.beta.-1-aza-6.alpha.-H-4-oxo-thiabicyclo[4.4.0]decyl)benzamide when prepared by the process of claim 25 or an obvious chemical equivalent.

27. A process for the preparation of the compound (+) 2-methoxy-5-sulfonamido-N-(8.beta.-1-aza-6.alpha.-H-4-thiabicyclo[4.4.0]-decyl)benzamide which comprises reacting 2-methoxy-5-sulfonamido benzoic acid chloride with (+) 8.beta.-amino-1-aza-6.alpha.-H-4-thia-bicyclo[4.4.0]decane in dimethylformamide in the presence of triethylamine and recovering the recovered compound.

28. (+) 2-methoxy-5-sulfonamido-N-(8.beta.-1-aza-6.alpha.-H-4-thiabi-cyclo[4.4.0]decyl)benzamide when prepared by the process of claim 27 or an obvious chemical equivalent.