Compounds of formula (I), wherein A is selected from (a), (b), (c), (d), (e), (f) and B is selected from (g), (h), and (i), wherein W is a carbonyl, sulphonyl or sulphinyl group, and X is a carbonyl, sulphonyl or sulphinyl group or --C(O)--CH.sub.2 -- (in which the carbonyl group is bonded to Y), provided that at least one of W and X contains carbonyl, Y is R.sub.9 --O-- or R.sub.9 --N(R.sub.10)--, Z is selected from (i), (ii), (iii), (iv) or Z is absent and W is H, with a number of provisions and phamaceutically acceptable salts thereof are ligands at CCK and/or gastrin receptors. ##STR1##

This is a 371 of PCT/GB93/0101 filed Jun. 18, 1993. This invention relates 
to bicyclooctane and bicycloheptane derivatives, and more particularly to 
bicyclooctane and bicycloheptane derivatives which bind to cholecystokinin 
(CCK) and/or gastrin receptors. The invention also relates to methods for 
preparing such bicyclooctane and bicycloheptane derivatives and to 
compounds which are useful as intermediates in such methods. 
Gastrin and the CCK's are structurally-related neuropeptides which exist in 
gastrointestinal tissue and in the CNS (see Mutt V., Gastrointestinal 
Hormones, Glass G. B. J., ed., Raven Press, N.Y., p 169 and Nisson G., 
ibid, p. 127). 
Gastrin is one of the three primary stimulants of gastric acid secretion. 
Several forms of gastrin are found including 34-, 17-, and 14-amino acid 
species with the minimum active fragment being the C-terminal tetrapeptide 
(TrpMetAspPhe--NH.sub.2) which is reported in the literature to have full 
pharmacological activity (see Tracey H. J. and Gregory R. A., Nature 
(London), 1964, 204, 935). Much effort has been devoted to the synthesis 
of analogues of this tetrapeptide (and the N-protected derivative 
Boc-TrpMetAspPhe-NH2) in an attempt to elucidate the relationship between 
structure and activity. 
Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal 
5 amino acids of which are identical to those of gastrin. Also found 
naturally is the C-terminal octapeptide (CCK-8) of CCK-33. 
The cholecystokinins are reported to be important in the regulation of 
appetite. They stimulate intestinal motility, gall bladder contraction, 
pancreatic enzyme secretion, and are known to have a trophic action on the 
pancreas. They also inhibit gastric emptying and have various effects in 
the CNS. 
Compounds which bind to cholecystokinin and/or gastrin receptors are 
important because of their potential pharmaceutical use as antagonists of 
the natural peptides. 
A number of gastrin antagonists have been proposed for various therapeutic 
applications, including the prevention of gastrin-related disorders, 
gastrointestinal ulcers, Zollinger-Ellison syndrome, antral G cell 
hyperplasia and other conditions in which lowered gastrin activity is 
desirable. The hormone has also been shown to have a trophic action on 
cells in the stomach and so an antagonist may be expected to be useful in 
the treatment of cancers, particularly in the stomach. 
Possible therapeutic uses for cholecystokinin antagonists include the 
control of appetite disorders such as anorexia nervosa, and the treatment 
of pancreatic inflammation, biliary tract disease and various psychiatric 
disorders. Other possible uses are in the potentiation of opiate (e.g. 
morphine) analgesia, and in the treatment of cancers, especially of the 
pancreas. Moreover, ligands for cholecystokinin receptors in the brain 
(so-called CCK.sub.B receptors) have been claimed to possess anxiolytic 
activity. 
According to the present invention, medicaments for counteracting an effect 
of cholecystokinin or gastrin in a patient are prepared using a compound 
of the formula 
##STR2## 
wherein A is selected from 
##STR3## 
and B is selected from 
##STR4## 
(provided that A is not 
##STR5## 
when B is 
##STR6## 
, and A is not 
##STR7## 
when B is 
##STR8## 
wherein W is a carbonyl, sulphonyl or sulphinyl group, and X is a 
carbonyl, sulphonyl or sulphinyl group or --C(O)--CH.sub.2 -- (in which 
the carbonyl group is bonded to Y), provided that at least one of W and X 
contains carbonyl 
Y is R.sub.9 --O-- or R.sub.9 --N(R.sub.10)-- (wherein R.sub.9 is H or 
C.sub.1 to C.sub.15 hydrocarbyl, up to two carbon atoms of the hydrocarbyl 
moiety optionally being replaced by a nitrogen, oxygen or sulphur atom 
provided that Y does not contain a --O--O-- group, and R.sub.10 is H, 
C.sub.1 to C.sub.3 alkyl, carboxymethyl or esterified carboxymethyl), 
Z is selected from 
i) --O--R.sub.11 
wherein R.sub.11 is H, C.sub.1 to C.sub.5 alkyl, phenyl, substituted 
phenyl, benzyl or substituted benzyl; 
ii) 
##STR9## 
wherein Q is H, C.sub.1 to C.sub.5 hydrocarbyl, or -R.sub.12 -U, wherein 
R.sub.12 is a bond or C.sub.1 to C.sub.3 alkylene and U is aryl, 
substituted aryl, heterocyclic, or substituted heterocyclic, 
iii) 
##STR10## 
wherein a is 0 or 1 and b is from 0 to 3, 
R.sub.13 is H or methyl, 
R.sub.14 is H or methyl; or R.sub.14 is CH.sub.2 .dbd. and Q' is absent; or 
R.sub.13 and R.sub.14 are linked to form a 3- to 7-membered ring, 
R.sub.15 is a bond or C.sub.1 to C.sub.5 hydrocarbylene, 
G is a bond, --CHOH-- or --C(O)-- 
Q' is as recited above for Q or --R.sub.2 --(C(O)).sub.d --L--(C(O)),.sub.e 
--R.sub.11 (wherein R.sub.11 and R.sub.12 are as defined above, L is O, S 
or --N(R.sub.16)--, in which R.sub.16 is as defined above for R.sub.10, 
and d and e are 0 or 1, provided that d+e&lt;2); or Q' and R.sub.14, together 
with the carbon atom to which they are attached, form a 3- to 7-membered 
ring, 
Q is as defined above; or Q and R.sub.4 together form a group of the 
formula --(CH.sub.2).sub.f --V--(CH.sub.2).sub.g -- wherein V is --S--, 
--S(O)--, --S(O).sub.2 --, --CH.sub.2 --, --CHOH-- or --C(O)--, f is from 
0 to 2 and g is from 0 to 3; or, when Q' is --R.sub.12 --U and U is an 
aromatic group, Q may additionally represent a methylene link to U, which 
link is ortho to the R.sub.12 link to U, 
T is H, cyano, C.sub.1 to C.sub.4 alkyl, --CH.sub.2 OH, carboxy, esterified 
carboxy, amidated carboxy or tetrazolyl; or 
iv) 
##STR11## 
wherein R.sub.11 and R.sub.12 are as defined above, R.sub.17 is as 
defined above for R.sub.10, and R.sub.18 and R.sub.19 are independently a 
bond or C.sub.1 to C.sub.3 alkylene, provided that R.sub.18 and R.sub.19 
together provide from 2 to 4 carbon atoms in the ring, 
or Z is absent and W is H, 
R.sub.1 is H, methyl, halo, carboxy, esterified carboxy, amidated carboxy, 
tetrazolyl, carboxymethyl, esterified carboxymethyl, amidated 
carboxymethyl or tetrazolylmethyl, 
R.sub.2 is selected from the groups recited above for R.sub.1 ; or, when Z 
is absent and W is H, R.sub.2 may additionally represent --C(O)--Z' 
wherein Z' is selected from the groups recited above for Z; or R.sub.1 and 
R.sub.2 together form a second bond between the carbon atoms to which they 
are attached, 
R.sub.3 and R.sub.4 are independently selected from hydrogen, halo, amino, 
nitro, cyano, sulphamoyl, C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3 
alkoxy, carboxy, esterified carboxy, amidated carboxy or tetrazolyl, 
R.sub.5 and R.sub.4 (or each R.sub.5 and R.sub.6 group, when m or n is 2 or 
more) are independently selected from halo, amino, nitro, cyano, 
sulphamoyl, C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3 alkoxy, carboxy, 
esterified carboxy, amidated carboxy or tetrazolyl, 
R.sub.5 and R.sub.6 are independently selected from hydrogen, C.sub.1 to 
C.sub.5 alkyl, phenyl, benzyl, substituted phenyl and substituted benzyl, 
m is from 0 to 4, provided that m is not more than 2 unless R.sub.5 is 
exclusively halo, 
n is from 0 to 4, provided that n is not more than 2 unless R.sub.5 is 
exclusively halo, 
or a pharmaceutically acceptable salt thereof. 
Compounds according to formula (I) above are believed to be novel per se, 
provided that -Z is not absent, -W-Z is not equal to -X-Y, and A or B 
contains at least one aromatic ring, and further provided that the 
compound is not 7-(methyl-aminocarbonyl)-2-diphenylmethylene 
bicyclo2.2.1! hept-4-ene-6-carboxylic acid or endo 
7-(phenethylaminocarbonyl)-2-diphenylmethylene bicyclo2.2.1! 
hept-4-ene-6-carboxylic acid. 
The compounds of the invention exist in various enantiomeric and 
diastereomeric forms as a result of the asymmetric carbon atoms to which W 
and X are attached. It will be understood that the invention comprehends 
the different enantiomers and diastereomers in isolation from each other, 
as well as mixtures of enantiomers. Also, the structural formulae herein 
show the groups W and X arranged cis to each other, but it will be 
appreciated that the invention includes the corresponding trans isomers. 
Similarly, the invention includes the different regioisomers which result 
from W and X being arranged in different configurations relative to A. 
That is to say, the invention comprehends both the exo and the endo 
isomers of the compounds represented by the above formula. In this 
specification, the designation exo and endo is determined by the 
convention described in "Vocabulary of Organic Chemistry", Orchin et al 
(eds.), Wiley, New York (1980) p141. For example, in the benzo-fused 
compounds of the invention, the exo isomer has the 7 and 8 substituents on 
the opposite side of the molecule to this aromatic ring. 
The term "hydrocarbyl", as used herein, refers to monovalent groups 
consisting of carbon and hydrogen. Hydrocarbyl groups thus include alkyl, 
alkenyl, and alkynyl groups (in both straight and branched chain forms), 
cycloalkyl (including polycycloalkyl), cycloalkenyl, and aryl groups, and 
combinations of the foregoing, such as alkylaryl, alkenylaryl, 
alkynylaryl, cycloalkylaryl, and cycloalkenylaryl groups, 
A "carbocyclic" group, as the term is used herein, comprises one or more 
closed chains or rings, which consist entirely of carbon atoms. Included 
in such groups are alicyclic groups (such as cyclopropyl, cyclobutyl, 
cyclopentyl, cyclohexyl and adamantyl), groups containing both alkyl and 
cycloalkyl moieties (such as methyl adamantyl), and aromatic groups (such 
as phenyl, naphthyl, indanyl, fluorenyl, (1,2,3,4)-tetrahydronaphthyl, 
indenyl and isoindenyl). 
The term "aryl" is used herein to refer to aromatic carbocyclic groups, 
including those mentioned above. 
A "heterocyclic" group comprises one or more closed chains or rings which 
have at least one atom other than carbon in the closed chain or ring. 
Examples include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, 
thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, 
imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, 
pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, 
morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, 
oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, 
benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, 
naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, 
quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl. 
The term "halogen", as used herein, refers to any of fluorine, chlorine, 
bromine and iodine. Most usually, however, halogen substituents in the 
compounds of the invention are chlorine or fluorine substituents. 
When reference is made herein to a "substituted" aromatic group, the 
substituents will generally be from 1 to 3 in number (and more usually 1 
or 2 in number), and selected from the groups recited above for R.sub.5. 
Preferably, m and n are both 0. However, when m and n are not both 0, 
R.sub.5 and R.sub.6 are preferably selected from halo, amino, nitro, 
cyano, sulphamoyl, C.sub.1 to C.sub.3 alkyl and C.sub.1 to C.sub.3 alkoxy. 
As mentioned above, when m or n is 2 or more, each R.sub.5 and R.sub.6 
group is independent of the others. For example, the compounds of the 
invention may include two different R.sub.5 groups. 
Particularly preferred groups for R.sub.3 and R.sub.4 are hydrogen and the 
groups just recited for R.sub.5, and especially hydrogen, methyl and 
fluoro. 
An "esterified" carboxy group, as the term is used herein, is preferably of 
the form --COOR.sub.20, wherein R.sub.20 is C.sub.1 to C.sub.5 alkyl, 
phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the 
following: 
##STR12## 
Most commonly, R.sub.20 is C.sub.1 to C.sub.5 alkyl, benzyl or substituted 
benzyl, and particularly C.sub.1 to C.sub.5 alkyl. Similarly, an 
"amidated" carboxy group is preferably of the form --CONR.sub.21 R.sub.22 
wherein R.sub.21 and R.sub.22 are independently H, C.sub.1 to C.sub.5 
alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl. 
In the case of the group T, preferred amidated carboxy groups take the form 
--CONR.sub.21 R.sub.22 (wherein R.sub.21 and R.sub.22 are as defined 
above) or 
##STR13## 
wherein R.sub.21 is as defined above, R.sub.23 and R.sub.24 are 
independently H or methyl, or R.sub.23 and R.sub.24 (together with the 
carbon atom to which they are attached) form a 3- to 7-membered 
carbocyclic group, J is --OH, --O--R.sub.20 or --NHR.sub.22, wherein 
R.sub.20 and R.sub.24 are as defined above, and x is 0 to 3. 
When R.sub.13 and R.sub.14 are linked to form a ring, such ring will 
generally be saturated, and usually also carbocyclic. Similarly, when Q' 
and R.sub.14 are linked to form a ring, this will also usually be 
saturated and carbocyclic. 
Exemplary carbocyclic and heterocyclic groups which may form the group U 
include: 
##STR14## 
wherein R.sub.25 is as defined above for R.sub.5, and h is from 0 to 3, 
and 
##STR15## 
wherein P is H or --COOR.sub.26, in which R.sub.26 is as defined above for 
R.sub.21. 
Z is preferably --NH.sub.2, --O--R.sub.11 or 
##STR16## 
wherein i is from 0 to 4, j is from 0 to 3, R.sub.27 and R.sub.28 are 
independently H or methyl, or R.sub.27 and R.sub.28 together form a group 
of the formula --(CH.sub.2).sub.k --V'--CH.sub.2 -- (wherein V' is 
--CH.sub.2 --, --CHOH-- or --C(O)--, and k is 0 to 2). Most commonly, i is 
0 or 1 and j is 0 to 2. 
When W is sulphinyl, Y is preferably R.sub.9 --NH--. 
Preferably, R.sub.9 is C.sub.6 to C.sub.8 straight or branched chain alkyl, 
or R.sub.29 --(CH.sub.2).sub.p --, wherein R.sub.29 is selected from 
phenyl, 1-naphthyl, 2-naphthyl, indolyl, norbornyl, adamantyl or 
cyclohexyl, and p is from 0 to 3. 
Compounds according to the present invention in which W is a carbonyl 
group, X is carbonyl or sulphonyl, and Z is OH may conveniently be made by 
the process depicted in Reaction Scheme A. 
##STR17## 
In this scheme, and in Reaction Schemes B, C and D below, A' is selected 
from 
##STR18## 
and B' is selected from 
##STR19## 
(provided that A' is not 
##STR20## 
when B' is 
##STR21## 
In Reaction Scheme A, compound (1)(e.g. naphthalene or 
2,3-dimethylnaphthalene) is reacted with the acid anhydride (2) in a 
Diels-Alder reaction. The reactants are conveniently refluxed together in 
a suitable solvent such as toluene to form the adduct (3). In some cases, 
it may be appropriate to conduct the reaction at elevated pressure and/or 
in the presence of a Lewis acid catalyst. The adduct (3) is then reacted 
with a compound of the formula YH (ie. either an alcohol or an amine) to 
form the acid compound (4). If YH is an amine, the reaction is suitably 
carried out in a solvent such as THF in the presence of a catalytic amount 
of DMAP. If YH is an alcohol, the reaction may be conducted in pyridine at 
elevated temperature. 
The invention therefore also provides a method of making compounds wherein 
W is carbonyl and X is carbonyl or sulphonyl, said method including the 
step of reacting a compound of the formula 
##STR22## 
with a compound of formula YH. 
The equivalent trans adducts can be prepared using a suitably 
differentiated fumaric acid (eg. the mono methyl mono benzyl diester), 
which, after addition to compound (1), allows independent elaboration of 
the two side chains. 
In those cases in which the Diels Alder reaction leads to a bicyclooctene 
or a bicycloheptene, the corresponding bicyclooctane or bicycloheptane can 
be obtained, if desired, by catalytic hydrogenation under appropriate 
conditions (preferably using a platinum catalyst), usually as the final 
step in the procedure. 
Compounds in which Z is other than OH may of course be made from the acid 
compound (4) by conventional esterification or amidation reactions. 
Suitable amidation methods are described in detail in "The Peptides, Vol. 
1", Gross and Meinenhofer, Eds., Academic Press, N.Y., 1979. These include 
the carbodiimide method (using, for example, 1,3-dicyclohexylcarbodiimide 
DCC! or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 
EDCI!, and optionally an additive such as 1-hydroxybenzotriazole HOBT! 
to prevent racemization), the azide method, the mixed anhydride method, 
the symmetrical anhydride method, the acid chloride method, the acid 
bromide method, the use of bis (2-oxo-3-oxazolidinyl) phosphinic chloride 
BOP-Cl!, the use of PyBOP, the use of the isopropenylsuccinimido 
carbonate method and the active ester method (using, for example, 
N-hydroxysuccinimide esters, 4-nitrophenyl esters or 2,4,5-trichlorophenol 
esters). 
The coupling reactions are generally conducted under an inert atmosphere, 
such as an atmosphere of nitrogen or argon. Suitable solvents for the 
reactants include methylene chloride, tetrahydrofuran THF!, 
dimethoxyethane DME! and dimethylformamide DMF!. 
A procedure analogous to that shown in reaction scheme A may also be used 
as the basis for preparing the compounds of the invention in which W is 
sulphonyl and Y is R.sub.9 --O--, as depicted in reaction scheme B below: 
##STR23## 
In this case, the Diels-Alder adduct (6) is opened with an alcohol such as 
benzyl alcohol (represented as QOH), so that product (7) is the 
corresponding sulphonyl ester. The free carboxylic acid group of this 
sulphonyl ester may then be esterified by conventional methods, followed 
by hydrogenolysis of the product (8) to yield the desired sulphonic acid 
carboxylic ester (9); 
The compounds of the invention in which W is sulphonyl and Y is R.sub.9 
--NH-- may be prepared by analogous means, in which compound (7) is 
amidated (rather than esterified) prior to hydrogenolysis. Alternatively, 
a process such as is depicted in reaction scheme C may be employed: 
##STR24## 
In this scheme, compound (1) is reacted with the N-protected compound (10) 
in a Diels-Alder reaction analogous to that of the first step in reaction 
scheme A. The deprotected product Diels-Alder adduct (11) is then reacted 
with a compound of the formula R.sub.9 -Hal (wherein Hal represents a 
halogen atom) to form compound (12). The N-containing ring may then be 
opened using an alkoxide (eg. sodium methoxide in methanol) to produce the 
target compound (13). 
The invention therefore also provides a method of making compounds wherein 
W is sulphonyl and Y is R.sub.9 --NH--, said method comprising the step of 
reacting a compound of the formula 
##STR25## 
with a compound of the formula R.sub.9 -Hal, and then reacting the product 
with an alkoxide. 
Compounds of the invention wherein W or X is a sulphoxide group may 
conveniently be prepared by the route shown in reaction scheme D: 
##STR26## 
Reaction scheme D is analogous to reaction scheme C, except that the 
sulphoxide analogue of compound (10) is used in the Diels-Alder reaction, 
to yield the sulphoxide analogue of adduct (12). This can then be opened 
both ways to give on the one hand the sulphinamide acid alkyl ester (17), 
and on the other the sulphinic acid amide (18). The free sulphinamide acid 
can of course be obtained from the alkyl ester (12) by conventional 
methods. 
Accordingly, the invention also provides a method of making compounds 
wherein W or X is sulphoxide, said method comprising the step of reacting 
a compound of the formula: 
##STR27## 
with a compound of the formula R.sub.9 -Hal, and then reacting the product 
with an alkoxide. 
While reaction schemes C and D above lead to the free sulphonic or 
sulphinic acid compounds, it will be appreciated that the corresponding 
ester or amide derivatives can be prepared from the free acid compounds by 
conventional methods. Most usually, coupling of the sulphonic or sulphinic 
acid compounds will be via the corresponding sulphonic or sulphinic acid 
chlorides. 
Pharmaceutically acceptable salts of the acidic or basic compounds of the 
invention can of course be made by conventional procedures, such as by 
reacting the free base or acid with at least a stoichiometric amount of 
the desired salt-forming acid or base. 
The compounds of the invention can be administered by oral or parenteral 
routes, including intravenous, intramuscular, intraperitoneal, 
subcutaneous, rectal and topical administration. 
For oral administration, the compounds of the invention will generally be 
provided in the form of tablets or capsules or as an aqueous solution or 
suspension. 
Tablets for oral use may include the active ingredient mixed with 
pharmaceutically acceptable excipients such as inert diluents, 
disintegrating agents, binding agents, lubricating agents, sweetening 
agents, flavouring agents, colouring agents and preservatives. Suitable 
inert diluents include sodium and calcium carbonate, sodium and calcium 
phosphate, and lactose, while corn starch and alginic acid are suitable 
disintegrating agents. Binding agents may include starch and gelatin, 
while the lubricating agent, if present, will generally be magnesium 
stearate, stearic acid or talc. If desired, the tablets may be coated With 
a material such as glyceryl monostearate or glyceryl distearate, to delay 
absorption in the gastrointestinal tract. 
Capsules for oral use include hard gelatin capsules in which the active 
ingredient is mixed with a solid diluent, and soft gelatin capsules 
wherein the active ingredient is mixed with water or an oil such as peanut 
oil, liquid paraffin or olive oil. 
For intramuscular, intraperitoneal, subcutaneous and intravenous use, the 
compounds of the invention will generally be provided in sterile aqueous 
solutions or suspensions, buffered to an appropriate pH and isotonicity. 
Suitable aqueous vehicles include Ringer's solution and isotonic sodium 
chloride. Aqueous suspensions according to the invention may include 
suspending agents such as cellulose derivatives, sodium alginate, 
polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as 
lecithin. Suitable preservatives for aqueous suspensions include ethyl and 
n-propyl p-hydroxybenzoate.