This invention relates to gastrin and cholecystokinin (CCK) receptor ligands. (The receptor previously known as the CCKβ/gastrin receptor is now termed the CCK ₂ receptor). The invention further relates to pharmaceutical compositions comprising such ligands and methods for preparing such pharmaceutical compositions.

Gastrin and the cholecystokinins are structurally related neuropeptides which exist in gastrointestinal tissue and the central nervous system (Mutt V., Gastrointestinal Hormones, Glass G.B.J., ed., Raven Press, New York, p. 169; 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 ₂ ) which is reported in the literature to have full pharmacological activity (Tracy HJ. 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-NH ₂ ) 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 mobility, 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 central nervous system.

Compounds which bind to cholecystokinin and/or gastrin receptors are important because of their potential pharmaceutical use as antagonists, inverse agonists or partial agonists of the natural peptides. Such compounds are described herein as ligands. The term ligand as used herein means either an antagonist, partial or full agonist, or an inverse agonist. Usually, the term ligand refers to an antagonist.

A number of gastrin ligands have been proposed for various therapeutic applications, including the prevention of gastrin-related disorders including gastrointestinal ulcers, dyspepsia, reflux oesophagitis (gastroesophageal reflux disease (GERD), both erosive and non-erosive) by reduction in gastric acid secretion and/or improving impaired motor activity at the lower oesophageal sphincter, Zollinger-EUison syndrome, Barrett's oesophagus (specialized intestinal metaplasia of distal oesophagus), ECL cell hyperplasia, rebound hypersecretion (following cessation of anti-secretory therapy), ECL-derived gastric polyps most commonly found in patients with atrophic gastritis both with (pernicious anaemia) or without vitamin Bl 2 deficiency, antral G cell hyperplasia and other conditions in which lower gastrin activity or lower acid secretion is desirable. The hormone has also been shown to have a trophic action on cells and so an antagonist may be expected to be useful in the treatment of cancers, particularly in the GI tract, more particularly in the stomach, oesophagus and colo-rectal areas. Tumours found in other organs such as the pancreas, lung (small cell lung carcinomas) and thyroid (thyroid medullary tumours) may also be treated.

Other possible uses are in the CCK receptor-mediated potentiation of opiate (for example morphine) analgesia. Moreover, ligands for cholecystokinin receptors in the brain (so- called CCK ₂ receptors) have been claimed to possess CCK receptor-mediated anxiolytic activity.

A known antagonist of the CCK ₂ receptor is L-365,260 (Bock et al (1989) J Med Chem 32:13-16), which is based on a benzodiazepine structure. In the rat stomach assay described hereinbelow, L-365,260 was shown to have an affinity of pKβ = 7.61±0.12 for the CCK ₂ receptor (Kalindjian et al (1994) J Med Chem 37:3671-3673).

L-365,260

Following this discovery, another benzodiazepine, YF476, was developed as a potent CCKo antagonist (Nishida et al (1994) Journal of Pharmacology and Experimental Therapeutics 269:725-731). In rat cortical membranes, YF476 was found to have an affinity pKj of 10.17±0.03 for the CCK ₂ receptor.

YF476

L-365,260 and YF476 are structurally closely related. Both compounds are 1,4- benzodiazepine-2-ones.

More recently, l,3,4-benzotriazepine-2-ones have been developed as gastrin and CCK receptor ligands. For example, WO 03/041714 discloses potent and selective gastrin and CCK receptor ligands that have the following general formula:

wherein W is N or N -O ^" .

Similarly, l,3,5-benzotriazepine-2, 4-diones have also been developed as gastrin and CCK receptor ligands. For example, international patent application number

PCT/GB2004/002049 discloses potent and selective gastrin and CCK receptor ligands that have the following general formula:

In another development, l,3,4-benzotriazepine-2-ones have been shown to be gastrin and CCK receptor ligands. For example, international patent application number PCT/GB2004/002027 discloses potent and selective gastrin and CCK receptor ligands that have the following general formula:

wherein W is NZ or NO and Z is H, Cj to C ₆ alkyl, t-butoxycarbonyl, acetyl, benzoyl or benzyl.

However, all of the above-noted benzodiazepinone and benzotriazepinone gastrin and CCK receptor ligands have a nitrogen atom at the 1 -position. The present invention is based on the discovery that this nitrogen atom is not an essential requirement for gastrin and CCK receptor binding in l,3,4-benzotriazepine-2-ones. Indeed, this nitrogen atom may be substituted with a carbon atom without loss of gastrin and CCK receptor binding ability. Accordingly, it is an object of the present invention to provide potent and selective gastrin and CCK receptor ligands. It is a further object of the present invention to provide 2,3-benzodiazepine-4-one gastrin and CCK receptor ligands that have a substituted carbon atom at the 5-position.

2,3-benzodiazepine-4-ones that are unsubstituted at the 5-position (see formula 1 below) are known from Gatta et al (1985) // Farmaco - Ed Sci 40:942-955, where they are shown to bind "benzodiazepine central pharmacological receptors" in membrane preparations prepared from the rat brain cortex. Similar compounds are disclosed in WO 97/28135; Chirri et al (1997) J Med Chem 40:1258-1269; Sarro et al (1999) // Farmaco 54:178-187; Grasso et al (1999) J Med Chem 42:4414-4421 and Grasso et al (2001) Bioorg Med Chem Letts 11 :463-466, where they are said to be AMPA/kainate receptor antagonists and therefore have anticonvulsant and neuroprotective properties.

(D

Similarly, 2,3-benzodiazepine-4-ones that are unsubstituted at the 3 -position (see formula 2 below), are known from WO 02/088096, where they are said to be phosophodiesterase inhibitors, and therefore useful as anti-inflammatory agents.

(2)

In other studies, 2,3-benzodiazepine-4-ones that are substituted at both the 3- and 5-positions (see formula 3 below) have been shown to inhibit β-amyloid formation and therefore be useful in the treatment of Alzheimer's disease (US 6,432,944); act as phosphodiesterase inhibitors (WO 02/098865); AMPA receptor antagonists (WO 97/34878 and US 5,891,871) and have tranquilizing activity (FR 2085645).

(3)

Further examples of 2,3-benzodiazepine-4-ones that are substituted at both the 3- and 5- position (see formulae 4 and 5 below) are described in Bogza et al (1995) Khimiya Geterotsiklicheskikh Soedinenii 12:1691-1692 and Bogza et al (1996) Zhumal Organicheskoi Khimii 32:596-603.

(5)

(4)

Other 2,3-benzodiazepine-4-ones that are substituted at both the 3- and 5-position (see formula 6 below) are described in Flammang et at (1976) Eur J Med Chem 1 1 :83-87 and are said to have anxiolytic activity.

(6)

However, until the present invention, it was not known that any 2,3-benzodiazepine-4-ones could act as gastrin and CCK receptor ligands. Moreover, there has been no disclosure of the specific 2,3-benzodiazepine-4-one gastrin and CCK receptor ligands claimed herein.

According to the present invention, there are provided compounds of formula (I):

(I)

wherein: W is N or N ⁺ -O ^" ;

Ri and R ₅ are independently H, Ci to C ₆ alkyl, (Ci to C ₆ alkyl)oxy, thio, (Ci to C ₆ alkyl)thio, carboxy, carboxy(Ci to C ₆ alkyl), formyl, (Ci to C ₆ alkyl)carbonyl, (Ci to C ₆ alkyl)oxycarbonyl, (C ₁ to C ₆ alkyl)carbonyloxy, nitro, trihalomethyl, hydroxy, hydroxy(Cj to C ₆ alkyl), amino, (Ci to C ₆ alkyl)amino, di(C _! to C ₆ alkyl)amino, aminocarbonyl, halo, halo(Cj to C ₆ alkyl), aminosulfonyl, (Ci to C ₆ alkyl)sulfonylamino, (Ci to C ₆ alkyl)aminocarbonyl, di(Ci to C ₆ alkyl)aminocarbonyl, [N-Z](Ci to C ₆ alkyl)carbonylamino, formyloxy, formamido, (C ₁ to C ₆ alkyl)aminosulfonyl, di(Ci to C ₆ alkyl)aminosulfonyl, [N-Z](Ci to C ₆ alkyl)sulfonylamino or cyano; or Rj and R ₅ together form a methylenedioxy group; R ₂ is of the formula:

wherein: s is 1, 2 or 3; t is 0, 1, 2 or 3;

R ₈ is selected from H, OH; or C ₁ to Cj ₂ alkyl, (C ₁ to C ₁₂ alkyl)oxy, (C ₁ to C ₁₂ alkyl)amino, C ₃ to Cj ₂ cycloalkyl, (C ₃ to C ₁₂ cycloalkyl)oxy, (C ₃ to C ₁₂ cycloalkyl)amino, phenyl, benzyloxy, phenylamino, benzylamino, naphthyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazolyl, furanyl, thienyl, furazanyl, oxazolyl, isoxazolyl, thiazolyl, thiazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl, benzofuranyl, benzothienyl, piperazinyl, piperidinyl, azepanyl, pyrrolidinyl, pyrrolinyl,

dihydropyranyl, tetrahydropyranyl, pyranyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, thiomoφholinyl or thioxanyl (all optionally substituted with 1 , 2 or 3 groups independently selected from Ci to C ₆ alkyl, (Ci to C ₆ alkyl)oxy, thio, (Ci to C ₆ alkyl)thio, carboxy, carboxy(Ci to C ₆ alkyl), formyl, (Cj to C ₆ alkyl)carbonyl, (C ₁ to C ₆ alkyl)oxycarbonyl, (Ci to C ₆ alkyl)carbonyloxy, nitro, trihalomethyl, hydroxy, hydroxy(Ci to C ₆ alkyl), amino, (Cj to C ₆ alkyl)amino, (Ii(C ₁ to C ₆ alkyl)amino, aminocarbonyl, halo, halo(C] to C ₆ alkyl), aminosulfonyl, (Ci to C ₆ alkyl)sulfonylamino or cyano); R ₃ is -(CRi,R ₁₂ ) _m -X-(CRi ₃ R ₁₄ )p-R ₉ ; m is 0, 1, 2, 3 or 4 (preferably 1 or 2); p is 0, 1 or 2;

X is a bond, -CR ₁₅ =CR ₁₆ -, -CsC-, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH, NHC(O)O, OC(O)NH, NH, O, CO, SO ₂ , SO ₂ NH, C(O)NHNH,

R ₉ is H; C ₁ to C ₆ alkyl; or phenyl, naphthyl, pyridyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolinyl, isoindolinyl, indolyl, isoindolyl or 2- pyridonyl, all optionally substituted with 1 , 2 or 3 groups independently selected from -L-Q wherein: L is a bond, or a group of the formula -(CR ₁₇ R _{1 S} ) _V -Y-(CR ₁ ^yR ₁₈ ) _w , wherein v and w are independently O, 1, 2 or 3, and Y is a bond, -CR ₁₅ =CR ₁₆ -, phenyl, furanyl, thiophenyl, pyrrolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, isoxazolonyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridazyl group; and Q is H, (C ₁ to C ₆ alkyl), (C ₁ to C ₆ alkyl)oxy, [TV-Z](C ₁ to C ₆ alkyl)oxy(Ci to C ₆ alkyl)amino, thio, (C ₁ to C ₆ alkyl)thio, carboxy(Ci to C ₆ alkyl)thio, carboxy, CaTbOXy(C ₁ to C ₆ alkyl), carboxy(d to C ₆ alkenyl), [N-Z]CaAoXy(C ₁ to C ₆ alkyl)amino, CaTbOXy(C ₁ to C ₆ alkyl)oxy, foraiyl, (C ₁ to C ₆ alkyl)carbonyl, (C ₁ to C ₆ alkyl)oxycarbonyl, (C ₁ to C ₆ alkyl)oxycarbonyl(d to C ₆ alkyl)thio, (C ₁ to C ₆ alkyl)carbonyloxy, nitro, trihalomethyl, hydroxy, amino, [N-Z](C ₁ to C ₆ alkyl)amino, aminocarbonyl, (C ₁ to C ₆ alkyl)aminocarbonyl, di(Q to C ₆ alkyl)aminocarbonyl, [N-Z](C ₁ to C ₆

alkyl)carbonylamino, C ₅ to Cg cycloalkyl, [N-Z](Ci to C ₆ alkyl)carbonyl(C] to C ₆ alkyl)amino, halo, halo(Ci to C ₆ alkyl), sulfamoyl, [TV-Z](Ci to C ₆ alkyl)sulfonylamino, (Ci to C ₆ alkyl)sulfonylaminocarbonyl, carboxy(Ci to C ₆ alkyl)sulfonyl, carboxy(Cj to C ₆ alkyl)sulfinyl, tetrazolyl, [N-Z]tetrazolylamino, cyano, amidino, amidinothio, SO ₃ H, formyloxy, formamido, C ₃ to C ₈ cycloalkyl, (Ci to C ₆ alkyl)sulphamoyl, (Ii(C ₁ to C ₆ alkyl)sulphamoyl, (Ci to C ₆ .alkyl)carbonylaniinosulfonyl, 5-oxo-2,5- dihydro[l,2,4]oxadiazolyl, carboxy(Cj to C ₆ alkyl)carbonylamino, tetrazolyl(C] to C ₆ alkyl)thio, [N-Z]tetrazolyl(Ci to C ₆ alkyl)amino, 5-oxo-2,5-dihydro[l,2,4]thiadiazolyl, 5- oxo-1, 2-dihydro[l,2,4]triazolyl, [N-Z](Cj to C ₆ alkyl)amino(Ci to C ₆ alkyl)amino, or a group of the formula

wherein P is O, S or ΝR ₁₉ ;

Z is H, Ci to C ₆ alkyl, t-butoxycarbonyl, acetyl, benzoyl or benzyl;

R ₄ is C ₃ to C ₁₂ cycloalkyl (optionally substituted with 1, 2 or 3 groups independently selected from C ₁ to C ₆ alkyl, (C ₁ to C ₆ alkyl)oxy, C ₃ to C ₈ cycloalkyl, (C ₃ to C ₈ cycloalkyl)oxy, thio, (C ₁ to C ₆ alkyl)thio, carboxy, carboxy(Ci to C ₆ alkyl), formyl, (C ₁ to C ₆ alkyl)carbonyl, (C ₁ to C ₆ alkyl)oxycarbonyl, (C ₁ to C ₆ alkyl)carbonyloxy, nitro, trihalomethyl, hydroxy, hydroxy(Ci to C ₆ alkyl), amino, (Cj to C ₆ alkyl)amino, CU(C ₁ to C ₆ alkyl)amino, aminocarbonyl, halo, 1IaIo(C ₁ to C ₆ alkyl), aminosulfonyl, (Ci to C ₆ alkyl)sulfonylamino or cyano) or R ₁₀ ;

R ₁₀ is phenyl, naphthyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazolyl, furanyl, thienyl, furazanyl, oxazolyl, isoxazolyl, thiazolyl, thiazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl, benzofuranyl, benzothienyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, dihydropyranyl, tetrahydropyranyl, pyranyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, thiomorpholinyl or thioxanyl (all optionally substituted with 1, 2 or 3 groups independently selected from Ci to C ₆ alkyl, (C ₁ to C ₆ alkyl)oxy, C ₃ to C ₈ cycloalkyl, (C ₃ to C ₈ cycloalkyl)oxy, thio, (C ₁ to C ₆ alkyl)thio, carboxy, carboxy(Ci to C ₆ alkyl), formyl, (Ci to C ₆ alkyl)carbonyl, (C ₁ to C ₆ alkyl)oxycarbonyl, (C ₁ to C ₆ alkyl)carbonyloxy, nitro, trihalomethyl, hydroxy, hydroxy^

to C ₆ alkyl), amino, (C] to C ₆ alkyl)amino, di(Ci to C ₆ alkyl)amino, arainocarbonyl, halo, halo(Ci to C ₆ alkyl), aminosulfonyl, (C] to C ₆ alkyl)sulfonylamino or cyano); Rn, Ri ₂ , R) ₃ , Ri ₄ , R _I5 , R ₁₇ , Ri ₈ and R ₁₉ are independently H or Cj to C ₃ alkyl; and Ri _ό is H, C) to C ₃ alkyl, or acetylamino; or a pharmaceutically acceptable salt thereof.

Preferably, W is N.

Preferably Ri and R ₅ are both H. However, it will be appreciated the benzo-fused -ring system may have one or two substituents on the benzene ring as indicated hereinabove.

The substituents may have subtle steric and/or electronic effects which modify the activity of the compound at the gastrin receptor. However, the presence or otherwise of certain substituents on the benzene ring is not crucial to the overall pharmacological activity of the present compounds.

With respect to the formula of R ₂ , it is preferred that s is 1 or 2, more preferably 1.

Similarly, it is preferred that t is 0, 1 or 2, more preferably 0 or 1 and even more preferably

0.

R ₈ is preferably C ₁ to C ₁₂ alkyl, (Ci to C ₁₂ alkyl)oxy, (C ₁ to C ₁₂ alkyl)amino, C ₃ to Cj ₂ cycloalkyl, (C ₃ to C ₁₂ cycloalkyl)oxy, (C ₃ to Cj ₂ cycloalkyl)amino, phenyl, benzyloxy, phenylamino, benzylamino, naphthyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazolyl, furanyl, thienyl, furazanyl, oxazolyl, isoxazolyl, thiazolyl, thiazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl, benzofuranyl, benzothienyl, piperazinyl, piperidinyl, azepanyl, pyrrolidinyl, pyrrolinyl, dihydropyranyl, tetrahydropyranyl, pyranyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, thiomorpholinyl or thioxanyl (all optionally substituted with 1, 2 or 3 groups as defined above). More preferably, R ₈ is branched C ₃ to C ₁₂ alkyl, branched (C ₃ to C ₁₂ alkyl)oxy, C ₃ to C ₁₂ cycloalkyl, (C ₃ to C ₁₂ cycloalkyl)oxy, (C ₃ to C ₁₂ cycloalkyl)amino, phenyl, benzyloxy, phenylamino, benzylamino, naphthyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazolyl, furanyl, thienyl, furazanyl, oxazolyl, isoxazolyl, thiazolyl, thiazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl, benzofuranyl, benzothienyl, piperazinyl, piperidinyl, azepanyl, pyrrolidinyl, pyrrolinyl, dihydropyranyl,

tetrahydropyranyl, pyranyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, thiomorpholinyl or thioxanyl (all optionally substituted with 1, 2 or 3 groups as defined above). In further prefered embodiments, Rg is branched C ₃ to Ci ₂ alkyl, C ₃ to Cn cycloalkyl, phenyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazolyl, furanyl, thienyl, furazanyl, oxazolyi, isoxazolyl, thiazolyl, thiazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, dihydropyranyl, tetrahydropyranyl, pyranyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, thiomorpholinyl or thioxanyl (all optionally substituted with 1 , 2 or 3 groups as defined abαve).

In preferred embodiments, R ₈ is not substituted. However, in those embodiments where R ₈ is substituted with 1, 2 or 3 of the groups defined above, it is preferred that R ₈ is substituted with 1 or 2, more preferably 1 of these groups. Particularly preferred substituents are Ci to C ₆ alkyl, (C ₁ to C ₆ alkyl)oxy, thio, (C ₁ to C ₆ alkyl)thio, trihalomethyl, (Cj to C ₆ alkyl)amino, di(C _! to C ₆ alkyl)amino, halo and 1IaIo(C ₁ to C ₆ alkyl). An especially preferred substituent is C ₁ to C ₆ alkyl.

In particularly preferred embodiments, R ₈ is a branched C ₃ to C ₁₂ alkyl group (such as tert- butyl, sec-butyl, isopropyl, isobutyl or isovaleryl); or R ₈ is a C ₃ to C ₁₂ cycloalkyl (such as cyclopentyl, cyclohexyl, cycloheptyl or adamantyl), phenyl, pyridyl, pyrrolidinyl or piperidinyl group (all optionally substituted with 1, 2 or 3 C _1-6 alkyl groups).

In certain specific embodiments of the present invention, R ₈ is tert-buty\. In other specific embodiments, R ₈ iscyclohexyl, 1-methylcyclohexyl, 1 -methyl cyclopentyl or cyclopentyl.

Preferably, R ₁₁ , R12, R-13, RH, RI ₅ , Ri ₆ , R17, Ris and R ₁₉ are all H.

A preferred group of compounds according to the present invention is where R ₃ is of formula: -(CH ₂ )-X-R ₉

wherein:

X is C(O)NH or NHC(O), more preferably X is C(O)NH.

Preferably, R ₉ is phenyl substituted with a Ci to C ₆ alkyl, carboxy, carboxy(Ci to C ₆ alkyl), tetrazolyl, tetrazolyl -N-(C] to C ₆ alkyl)amino, carboxy(Ci to C ₆ alkyl)thio, (Cj to C ₆ alkyl)oxycarbonyl(Cj to C ₆ alkyl)thio, carboxy(Ci to C ₆ alkyl)sulfonyl, furanyl, carboxyfuranyl, (Cj to C ₆ alkyl)amino, thiazolyl, (Ci to C ₆ alkyl)thiazolyl, or 5-oxo-2,5- dihydro[l,2,4]oxadiazolyl group; or R ₉ is a .N-[CaA-OXy(C j to C ₆ alkyl)]indolinyl or N- [carboxy(Ci to C ₆ alkyl)] indolyl group. In some of these embodiments, R ₉ is phenyl further substituted with a Cj to C ₆ alkyl group.

When R ₉ is a substituted phenyl group, the substituent is preferably at the 3 -position of the phenyl group. When R ₉ is a substituted phenyl group carrying two or three substituents, one of the substituents is preferably at the 3-position of the phenyl group.

In some embodiments, R ₃ may take any of the definitions given for this group above, with the proviso that R ₃ is not H.

With respect to the formula of R ₄ , in some preferred embodiments, R ₄ is C ₃ to C ₁₂ cycloalkyl (optionally substituted with 1, 2 or 3 groups as defined above). Preferred C ₃ to C ₁₂ cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and adamantyl (all optionally substituted with 1, 2 or 3 groups as defined above). An especially preferred C ₃ to C ₁₂ cycloalkyl groups is cyclohexyl.

In other preferred embodiments, R ₄ is R ₁₀ . Preferred R ₁₀ groups include phenyl, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrirnidinyl, triazolyl, furanyl, thienyl, furazanyl, oxazolyl, isoxazolyl, thiazolyl, thiazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, isoquinolinyl, quinolinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, dihydropyranyl, tetrahydropyranyl, pyranyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, thiomorpholinyl and thioxanyl (all optionally substituted with 1 , 2 or 3 groups as defined above). Particularly preferred R ₁₀ groups include pyridyl and phenyl (both optionally substituted with 1, 2 or 3 groups as defined above).

In preferred embodiments, R ₄ (or R _1O ) is not substituted. However, in those embodiments where R ₄ (or Rio) is substituted with 1, 2 or 3 of the groups defined above, it is preferred

that R ₄ (or Rio) is substituted with 1 or 2, more preferably 1 of these groups. Particularly preferred substituents are Ci to C ₆ alkyl, (C _t to C ₆ alkyl)oxy, thio, (Ci to C ₆ alkyl)thio, trihalomethyl, (Ci to C ₆ alkyl)amino, di(Cj to C ₆ alkyl)amino, halo and halo(Ci to C ₆ alkyl). Especially preferred substituents are OMe, NMe ₂ , CF ₃ , Me, F, Cl, Br and I.

In . particularly preferred embodiments, R ₄ is selected from- C ₃ -1 ₂ jcy.cioalkyl (such- as cyclopentyl, cyclohexyl, cycloheptyl or adamantyl), pyridyl or phenyl (all of which may be optionally substituted with 1, 2 or 3 groups selected from OMe, NMe ₂ , CF ₃ , Me, F, Cl, Br or I). .

In certain specific embodiments of the present invention, R ₄ is phenyl. In other specific embodiments of the present invention, R ₄ is cyclohexyl.

Certain compounds of the invention exist in various regioisomeric, enantiomeric, tautomeric and diastereomeric forms. It will be understood that the invention comprehends the different regioisomers, enantiomers, tautomers and diastereomers in isolation from each other as well as mixtures. In particular, the substituted carbon atom at the 5 -position of the 2,3-benzodiazepine-4-ones of the present invention is stereogenic and one enantiomeric form of the claimed compounds may show a higher affinity for gastrin and CCK receptors than the other enantiomeric form. Accordingly, any such enantiomeric form showing a higher affinity for gastrin and CCK receptors is preferred.

General Synthesis of 2,3-benzodiazepine-4-ones.

Compounds of the present invention may be prepared by the representative procedure shown in Reaction Scheme 1.

Reaction Scheme 1

1-Indanone (I) is reacted with a Grignard reagent (R ₄ MgCl) or an alkyl lithium (R ₄ Li) to form the tertiary alcohol (II). (II) is converted to indene (III) by acid catalysed dehydration, with for example, para-tolunesulfonic acid or HCl. Alternatively, (III) may be obtained following activation of the alcohol as the corresponding mesylate, tosylate, chloride, bromide or iodide, by base catalysed elimination using, for example, DBU, pyridine, triethylamine or diisopropylethylamine. The 2-carboxymethylphenyl ketone (IV) is obtained from (III) by oxidative cleavage with for example ozone, sodium periodate and ruthenium(III) chloride, or chromium(VI) oxide. The corresponding ester (V) can be obtained from (IV) by using an appropriate alcohol YOH and acid-catalysis, under dehydrating conditions using DCC or EDCI, or by treatment of the corresponding cesium, potassium, sodium or lithium salt of the carboxylic acid with an appropriate alkyl halide. Ketone (V) is reacted with NH ₂ NHP (wherein P represents either a protecting group, R ₃ or a suitable precursor R ₃ ' thereof) to form benzodiazepine (VI). (VII) is obtained from (VI) by base catalysed alkylation using sodium hydride, lithium diisopropyl amide or LiHMDS and a suitable alkyl halide, R ₂ 'Br (wherein R ₂ ' represents either R ₂ or a suitable precursor thereof). Modification of R ₂ ' and/or R ₃ ' affords the desired benzodiazepinone (VIII).

Compounds wherein W is N ⁺ -O ^" may be prepared by treating compound VIII directly or an appropriately protected derivative of compound VII, with an oxidising agent such as MCPBA. Such derivatives of compound VII yield the desired N-oxide following deprotection.

R ₂ ' groups which are suitable precursors of Ra will depend on the particular nature of R ₂ . For example, when R ₂ is -(CH ₂ ) _S -C(O)-Rs, a suitable R ₂ ' group would be -(CH ₂ ) _S -CN or -(CH ₂ ) _s -C(O)NMe(OMe). In this case, the requisite R ₂ groups may be readily accessed via treatment, with the appropriate Gn gnard- reagent R ₈ MgCl or alkyl lithium R ₈ Li, Similarly, when R ₂ is -(CH ₂ ) _S -C(O)-(C] to C ₆ alkyl)amino, a suitable R ₂ ' would be -(CH ₂ ) _S -C(O)-(C ₁ to Cj ₂ alkyl)oxy. In this case, the requisite R ₂ may be readily accessed via an ester hydrolysis followed by an amide coupling reaction. The skilled person will be aware of many other suitable R ₂ > groups, depending on the nature of R ₂ .

In the same way, R ₃ - groups which are suitable precursors of R ₃ will depend on the particular nature of R ₃ . When P represents R ₃ ', then these may be obtained directly by treatment of (V) using the appropriate substituted hydrazine, or indirectly when P represents a protecting group, such as 4-methoxybenzyl or t-butyloxycarbonyl, by first removal of the protecting group with trifluoroacetic acid or hydrochloric acid, followed by base catalysed reaction using sodium hydride and R ₃ 'Br. A suitable R ₃ ' precursor of R ₃ when, for example, R ₃ is -(CH ₂ ) _m C(O)NH-(CH ₂ ) _p -R ₉ would be -(CH ₂ ) _m CO ₂ (C _1-6 alkyl). In this case, the requisite R ₃ groups may be readily accessed via an ester hydrolysis followed by a simple amide coupling reaction. The skilled person will be aware of many other suitable R ₃ > groups, depending on the nature of R ₃ .

For example, a more specific scheme for obtaining compounds according to an embodiment of the present invention is given in Reaction Scheme 2.

Reaction Scheme 2

Hence, the present invention also provides a method of making compounds according to formula (I).

The invention also comprehends derivative compounds ("pro-drugs") which are degraded in vzVo to yield the species of formula (I) Pro-drugs are usually (but not always) of lower potency at the target receptor than the species to which they are degraded. Pro-drugs are particularly useful when the desired species has chemical or physical properties which make its administration difficult or inefficient. For example, the desired species may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an

undesirably short plasma half-life. Further discussion of pro-drugs may be found in Stella, V. J. et al., "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473.

Pro-drug forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (I) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form -COOR ^a , wherein R ^a is Cj to C ₅ alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the following:

Amidated acid groups include groups of the formula -CONR ¹³ R ⁰ , wherein R ^b is H, C ₁ to C ₅ alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and R° is -OH or one of the groups just recited for R ^b .

Compounds of formula (I) having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This will hydrolyse with first order kinetics in aqueous solution.

Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) substantially as described herein before with a pharmaceutically acceptable diluent or carrier.

Another aspect of the present invention is a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) for use in medicine.

Another aspect of the present invention is a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) for use in the preparation of a medicament for the treatment of gastrin related disorders.

Typical gastrin related disorders are gastrointestinal ulcers, dyspepsia, reflux oesophagitis (gastroesophageal reflux disease (GERD), both erosive and non-erosive), Zollinger-EUison

syndrome, Barrett's oesophagus (specialized intestinal metaplasia of distal oesophagus), ECL cell hyperplasia, rebound hypersecretion (following cessation of anti-secretory therapy), ECL-derived gastric polyps, cancer (including cancers of the GI tract, more particularly in the stomach, oesophagus and colo-rectal areas, as well as tumours found in other organs such as the pancreas, lung (small cell lung carcinomas) and thyroid (thyroid medullary tumours)) and CCK receptor-mediated anxiety. The CCK receptor-mediated potentiation of opiate induced analgesia may also provide a role for the gastrin ligands of the present invention.

Yet another aspect of the present invention is a method of making a pharmaceutical composition comprising a compound of formula (I) substantially as described herein before, comprising mixing said compound with a pharmaceutically acceptable diluent or carrier.

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.

Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, zinc, and ammonium, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, arginine, benzathine, diolamine, olamine, procaine, chlorine and tromethamine.

Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide.

It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation.

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-susp-βnsion.

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. Corn starch and alginic acid are suitable, disintegrating agents. Binding agents may include starch and gelatine. 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 gelatine capsules in which the active ingredient is mixed with a solid diluent and soft gelatine 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, polyvinyl¬ pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

Effective doses of the compounds of the present invention may be ascertained be conventional methods. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the

daily dose- (whether administered as a single dose or as divided doses) will be in the range 0.001 to 5000 mg per day, more usually from 1 to 1000 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.01 μg/kg and 50 mg/kg, especially between 10 μg/kg and 10 mg/kg, eg. between 100 μg/kg and 2 mg/kg.

In a further aspect of the present invention there are provided pharmaceutical compositions comprising a compound according to formula (I) and a proton pump inhibitor. Compositions comprising a CCK ₂ /gastrin antagonist and a proton pump inhibitor are described in International patent application WO93/12817, incorporated herein by reference.

In one aspect of the present invention the proton pump inhibitor is omeprazole which is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)- methyl]sulfinyl]-lH-benzimidazole;

BY308;

SK&F 95601 which is 2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]-5- methoxy-(lH)-benzimidazole;

SK & 96067 which is 3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline; 5-trifluoromethyl-2-[4-methoxy-3-methyl-2-pyridyl-methyl]-th io-[lH]- benzimidazole; or pharmaceutically acceptable salts thereof.

These proton pump inhibitors are described and claimed in US Patents 4,472,409 and 4,255,431. These patents are incorporated herein by reference.

In a further aspect of the present invention, the proton pump inhibitor is lansoprazole which is 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole; pantoprazole which is 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfϊnyl]- 1 H-benzimidazole; perprazole;

rabeprazole which - is 2-[[4-(3-methoxypropoxy)-3-methylpyridin-2- yl]methylsulfinyl]-lH-benzimidazole;

[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridyl]- methyl] sulfenamide; (Z)-5-methyl-2-[2-(l-naphthyl)ethenyl]-4- piperidinopyridine HCl; 2- (4-cyclohexyloxy-5-methylpyridin-2- ^" yl) -3- (1- naphthyl) -1-propanol; methyl 2-cyano-3-(ethylthio)-3-(methylthio)-2propenoate; 2-((4-methoxy-2-pyridyl)methylsulphinyl)-5-( 1 , 1 ,2,2-tetrafluoroethoxy)-lH- benzimidazole sodium;

2-[[[4-(2,2,3,3,4,4,4-heptafluorobutoxy)-2-ρyridyl]methy l)sulfinyl]-lH-thieno [3,4- djimidazole;

2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridyl]methyl] sulfmyl]-lH- benzimidazole;

2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2-ρyridyl]methyl ]sulfinyl]-lH- benzimidazole; 2-methyl-8-(phenylmethoxy)=irnidazo(l,2-A)- pyridine-3-acetonitrile;

(2-((2-dimethylaminobenzyl)sulfinyl)-benzimidazole);

4-(N-allyl-N-methylamino)-l-ethyl-8-((5-fluoro-6-methoxy- 2-benzimidazolyl) sulfinylmethyl)- 1 -ethyl 1 ,2,3 ,4-tetrahydroquinolone;

2-[[(2-dimethylaminophenyl)methyl]sulfinyl]-4,7-dimethoxy -lH-benz imidazole; 2-[(2-(2-pyridyl)phenyl)sulfinyl)~ 1 H-benzimidazole;

(2-[(2-amino-4-methylbenzyl)sulfinyl]-5-methoxybenzo[d]im idazole; (4(2-methylpyiτol-3-yl)-2-guanidisothiazole); 4-(4-(3-(imidazole)propoxy)phenyl)-2phenylthiazole; (E)-2-(2-(4-(3-(dipropylamino)butoxy)phenyl)-ethenyl)benzoxa zole; (E)-2-(2-(4-(3-(dipropylamino)propoxy)phenyl)ethenyl)-benzot hiazole;

Benzeneamine, 2-[ [(5-methoxy- 1 H-benzimidazol-2-yl)sulfinyl]methyl)-4-methyl-; Pumilacidin A;

2,3-dihydro-2-methoxycarbonylamino-l,2-benzisothiazol-3-o ne; 2-(2-ethylaminophenylmethylsulfinyl)-5,6-dimethoxybenzimidaz ole; 2-methyl-8-(phenylmethoxy)imidazo[l ,2-a)pyridine-3-acetonitrile;

3-amino-2-methyl-8-phenylmethoxyimidazo[l ,2-a)-pyrazine HCl ; 2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]-sulfinyl)-5-met hoxy-(lH)- benzinidazole;

[3-butyryl-4-(2-methylphenylamino)-8-methoxy-quinoline); 2-indanyl 2-(2-pyridyl)-2-thiocarbamoylacetate HCl; 2,3-dihydro-2-(2-pyridinyl)-thiazolo (3,2-a) - benzimidazole; 3-cyanomethyl-2-methyl-8-(3-methyl-2-butenyloxy)- (l,2-a)imidazopyridine; zinc L-carnosine; or pharmaceutically acceptable salts thereof.

Rabeprazole is described in US patent 5,045,552. Lansoprazole is described in US patent 4,628,098. Pantoprazole is described in US patent 4,758,579— These patents -are incorporated herein by reference.

Preferably, the proton pump inhibitor is selected from (RS)-rabeprazole, (RS)-omeprazole, lansoprazole, pantoprazole, (R)-omeprazole, (S)-omeprazole, perprazole, (R)-rabeprazole, (S)-rabeprazole, or the alkaline salts thereof. The alkaline salts may be, for example, the lithium, sodium, potassium, calcium or magnesium salts.

Compositions of this invention comprising a compound of formula (I) and a proton pump inhibitor may be administered as described above. Preferably the dose of each of the active ingredients in these compositions will be equal to or less than that which is approved or indicated in monotherapy with said active ingredient.

In another aspect of this invention, there is provided a kit comprising a compound of formula (I) and a proton pump inhibitor. The kit is useful as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from gastrointestinal disorders.

In yet a further aspect of the present invention there is provided a method of making a pharmaceutical composition comprising a compound of formula (I) substantially as described herein before and a proton pump inhibitor, comprising mixing said compound and said proton pump inhibitor with a pharmaceutically acceptable carrier or diluent.

The term "alkyl" is used herein to refer to both straight and branched chain forms. Further, the alkyl chain may include multiple bonds. Hence, the term "alkyl" also encompasses

alkenyl and alkynyl groups. Likewise, the term "cycloalkyl" also encompasses cycloalkenyl groups. Preferably, alkyl and cycloalkyl groups as used in the present invention do not contain multiple bonds. Where there are preferred alkenyl groups, these are specified as alkenyl groups. However, specific reference to alkenyl groups is not to be construed as any limitation on the definition of alkyl groups as described above.

Where reference is made to dialkyl groups [e.g. di(Cj to C ₆ alkyl)amino groups], it is understood that the two alkyl groups may be the same or different.

In the interests of simplicity, terms which are normally used to refer to monovalent groups (such as "alkyl" or "phenyl") are also used herein to refer to divalent bridging groups which. are formed from the corresponding monovalent group by the loss of one hydrogen atom. Whether such a term refers to a monovalent group or to a divalent group will be clear from the context. For example, when L is -(CR ₁₇ R ₁₈ )V-Y-(CRnR ₁₈ ) _W -, it is clear that ^{■ ■} Y- must be a divalent group. Thus, when Y is defined as thiazolyl, for example, this refers to a divalent group having the structure

Where, as in this example, a divalent bridging group is formed from a cyclic moiety, the linking bonds may be on any suitable ring atom, subject to the normal rules of valency. Accordingly, by way of further example, the term pyrrolyl in the definition of Y includes all of the following groups:

The term "halogen" or "halo" ^" is used herein to refer to any of fluorine, chlorine, bromine and iodine. Mosl usually, however, halogen substituents in the compounds of the invention are chlorine and fluorine substituents. Groups such as halo(Cj to C ₆ alkyl) includes mono-, di- or tri-halo substituted Ci to C ₆ alkyl groups. Moreover, the halo substitution may be at any position in the alkyl chain.

The prefix [N-Z] refers to possible substitution of an amino group in the following compound or substituent name. For example, [N-Z] alkyl amino refers to groups of the form

Z alkyl — r

Similarly, [N-Z]tetrazolylamino, wherein Z is C ₁ to C ₆ alkyl, includes groups such as tetrazolyl[N-methyl] amino and tetrazolyl[N-ethyl]amino. Of course, when Z is H, no substitution is present.

In case there is any doubt, the group named as 5-oxo-2,5-dihydro[l,2,4]oxadiazolyl has the following formula

and comprehends tautomeric forms.

The invention is now further illustrated by means of the following Examples.

Experimental

All reactions were performed under an atmosphere of dry argon unless otherwise stated. Commercially available dichloromethane (DCM), tetrahydrofuran (THF) and N, N- dimethylformamide (DMF) were used. Flash column chromatography was performed on Merck silica gel 60 (40-63 μm) using the reported solvent systems. ¹ H ΝMR spectra were recorded on a Bruker DRX-300 instrument at 300MHz and the chemical shifts (5 _H ) were recorded relative to an internal standard. 2-Bromo-l-cyclopentyl-ethanone and 2-bromo-l- cyclohexyl-ethanone were prepared by a published method (M. Gaudry, A. Marquet, Org. Synth., (1976), 55, 24). 2-Bromo-l-(lmethyl-cyclopentyl)-ethanone was prepared by a published method (T. S. Sorensen, J. Am. Chem. Soc, (1969), 91, 6398). Substituted anilines were either obtained commercially, synthesised by the literature method indicated where first mentioned, or prepared in the number of steps and from the starting material as indicated, using standard chemical transformations.

Example 1: (+/-)2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihy dro- benzofd] [1 ,2] 'diazepin-3-yl] ' -N-f3-(5-oxo-2,5-dihydro-[J ,2,4] Oxadiazol-3-yl) -phenyl) '- acetamide

Step a. 1-Phenyl-indan-l-ol. A solution of 1.0M phenylmagnesium chloride in dry THF- Et ₂ O (1:1 / 160OmL, 1.6mol), was added drop- wise over 30 mins to a solution of 1- indanone (141g, 1.07mol) in dry Et ₂ O (80OmL) under argon and maintained 25°C with ice- H ₂ O cooling. The mixture was stirred for 16h at room temperature followed by the drop- wise addition, over 30 mins with stirring, of saturated NH ₄ Cl solution (20OmL). The organic layer was separated and the aqueous phase extracted with EtOAc (2x500mL). The combined organic layers were washed successively with saturated NaHCO ₃ solution (20OmL), brine (20OmL), and dried (MgSO ₄ ). Filtration and evaporation of the solvent gave the title compound as a yellow oil (205g, 91%). ¹ H NMR (CDCl ₃ ) 7.34 (9H, m), 3.24-2.91 (2H, m), 2.50 (2H, m), 2.14 (IH, s).

Step b. 3-Phenyl-lB.-indene. To a solution of 1-phenyl-indan-l-ol (205g, 0.97mol) in dry DCM (80OmL) was added j?-toluenesulphonic acid monohydrate (0.2g, lmmol). The

mixture stirred at room temperature for 36h, washed with saturated NaHCO ₃ solution (10OmL) and dried over MgSO ₄ . Filtration and evaporation of the solvent gave the product as an oil which was purified by vacuum distillation. The title compound was obtained as a pale yellow oil (86.6g, 46 %). (b.pt. 120-123 ⁰ C / lmm Hg). ¹ H NMR (CDCl ₃ ) 7.66-7.29 -5 (9H, m), 6.62 (IH, t), 3.55 (2H, d).

Step c. (2-Benzoyl-phenyl)-acetic acid. Sodium periodate (375g, 1.75mol) was added in small portions over Ih to a solution of 3 -phenyl- IH-indene (82.1Og, 0.43 mol) and

- - ruthenium (III) chloride hydrate (1.67g, 7.41mmol) in a mixture of MeCN-hexane-H ₂ O

10 (2:2:3 / 210OmL) at 5°C. The mixture was allowed to warm to room temperature and stirred for 2h and poured into 6N HCl-DCM (1 :2 / 3L). The organic layer was separated and extracted with 2N NaOH (40OmL). The aqueous extract was washed with DCM (30OmL) and acidified to pH 2 by the addition of 6N HCl. The mixture was extracted with DCM (2x200mL), the extracts washed with brine (40OmL) and dried (MgSO ₄ ). Filtration

15 and evaporation of the solvent gave the crude product which was crystallised from hexane to give the title compound as a colourless solid (60.94 g, 59%). ¹ H NMR (CDCl ₃ ) 12.0- 10.0 (IH, bs), 7.85-7.39 (9H, m), 3.83 (2H, s).

Step d. (2-Benzoyϊ-phenyl)-acetic acid methyl ester. A solution of (2-benzoyl-phenyl)- 20 acetic acid (60.94g, 0.25mol) in MeOH (50OmL) was saturated with HCl gas and heated at reflux for 3h. On cooling, the solvent was evaporated and the residue dissolved in toluene and re-evaporated (3x10OmL) followed by DCM (2x10OmL). The title compound was obtained as a yellow oil (61.9Ig, 96%). ¹ H NMR (CDCl ₃ ) 7.84-7.34 (9H, m), 3.90 (2H, s), 3.56 (3H, s). 25

Step e. (4-Oxo-l -phenyl-4,5-dihydro-benzo[d] [1 ,2] diazepin-3-yl)-acetic acid ethyl ester. Pyridine (4OmL, 0.5mol) was added to a mixture of (2-benzoyl-phenyl)-acetic acid methyl ester (62.78g, 0.25mol) and ethyl hydrazinoacetate hydrochloride (76.34g, 0.5mol) in EtOH (50OmL) and heated at reflux for 120 h. On cooling to room temperature, the 30 precipitated solid was removed by filtration and the filtrate evaporated. The residue was taken up in EtOAc (20OmL), washed with H ₂ O (2x10OmL), 2N KHSO ₄ (2x10OmL), brine (10OmL) and dried (MgSO ₄ ). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with EtOAc-DCM (1:25) as

eluant followed by crystalisation from pentane-Et ₂ O (4:1). (4-Oxo-l-phenyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl)-acetic acid ethyl ester was obtained as a colourless solid (5 Ig, 64%). ¹ H NMR (CDCl ₃ ) 7.63-7.25 (9H, m), 4.62 (2H, s), 4.16 (2H, q), 3.67 (2H, bs), 1.21 (3H, t).

Step . JF. (+/-)[5-(3, 3-Dimethyl-2-oxo-butyl)-4-oxo- 1 -phenyl-4, 5-dihydro- benzo[d] [ 1 ,2] dia∑epin-3-yl] -acetic acid ethyl ester. Lithium hexamethyldisilazide (1.0M solution in THF/ 10OmL) was added over 15 mins to a solution of (4-oxo-l-phenyl-4,5- dihydro-benzo[d][l,2]diazepin-3-yl)-acetic acid -ethyl ester (30.62^ 95mmol) in dry THF (50OmL) at — 2D°C under argon. Stirring was continued at — 20°C for 30mins. Followed by the addition of 1 -bromopinacolone (14.12mL, O.lmol). The reaction mixture was allowed to warm to room temperature and stirred for a 16 h. 2N HCl (20OmL) was slowly added followed by EtOAc (50OmL). The organic was separated, washed successively with H ₂ O (20OmL), saturated NaHCO ₃ solution (20OmL), brine (20OmL) and dried (MgSO ₄ ). Filtration and evaporation of the solvent gave the crude product, which was purified by chromatography on silica gel with EtOAc-DCM (3:25) as eluant. [5-(3,3-Dimethyl-2-oxo- butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-acetic acid ethyl ester was obtained as a colourless foam (7.45g, 19%). ¹ H NMR (CDCl ₃ ) 7.66-7.25 (9H, m), 4.83- 4.44 (2H, q), 4.07 (2H, m), 3.97 (IH, m), 3.82-3.10 (2H, m), 1.28 (9H, s), 1.12 (3H, t).

Step g. (+/~)[5-(3, 3-Dimethyl-2-oxo-butyl)-4-oxo-l -phenyl-4, 5-dihydro- benzofdjfl, 2] diazepirι-3-yl] -acetic acid

A solution of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid ethyl ester (7.42g, 17.6mmol) in MeOH (10OmL) was added to IN LiOH (35.3mL, 35.3mmol) and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated (-40 mL) in vacuo, and acidified to pH 2 with 2N HCl. The mixture was extracted with DCM (2x10OmL), the combined extracts washed with brine (10OmL), and dried (MgSO ₄ ). Filtration and evaporation of the solvent and re-evaporation from Et ₂ O-hexane (1 :1 / 5OmL) afforded the product as a pale yellow amorphous solid (6.29g, 91%). ¹ H NMR (CDC13) 7.65-7.25 (9H, m), 4.65 (2H, m), 3.95

(IH, m), 3.90-3.12 (2H, m), 1.28 (9H, s).

Step h. (+/-)2-[5-(3,3-Dimethyl-2-oxo-butyl)- -4-oxo-l~phenyl~4,5-dihydro- benzo[d] [1 ,2] diazepin-3-yl]-N-[3-(5-oxo-2,5-dihydro-[l ,2,4] oxadiazol-3-yl)-phenyl] - acetamide. Oxalyl chloride (45μL, 0.5mmol), and DMF (lOμL) were added to a solution of (+/-)[5-(3, 3 -dimethyl-2-oxo-butyl)-4-oxo-l -phenyl -4,5-dihydro-benzo[d][l,2]diazepin- 3-yl]-acetic acid (lOOmg, 0.26mmol) in DCM (1OmL) and the mixture stirred at room temperature for 2h. Evaporated on a rotary evaporator to dryness and re-evaporated from DCM (3x15mL). The solid obtained was dissolved taken up in DCM (1OmL) and added drop-wise to a stirred solution of 3-(3-Amino-phenyl)-2H-[l,2,4]oxadiazol-5-one (47mg, 0.27mmol) and NEt ₃ (70μL, 0.5mmol) in DCM (2OmL) at- room temperature. Stirred was continued for lόh, the solution, washed with 2N HCl (1OmL) and dried (MgSO ₄ ). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with MeOH-DCM (1 :50) as eluant. 2-[5-(3,3-Dimethyl-2- oxo-butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin- 3-yl]-N-[3-(5-oxo-2,5- dihydro-[l,2,4]oxadiazol-3-yl)-phenyl]-acetamide was obtained as an amorphous colourless solid (104mg, 74%). ¹ H NMR (CDC13) 10.55 (IH, bs), 9.01 (IH, bs), 7.73- 7.05 (13H, m), 4.81-4.56 (2H, m), 4.00-3.06 (3H, m), 1.23 (9H, s). The compound was further characterised as the iV-methyl-D-glucamine salt. Found: C 59.04, H 6.44, N 10.18%; C ₃₁ H ₂₉ N ₅ O ₅ -C ₇ Hi ₇ NO ₅ -1.2H ₂ O»0.6C ₄ H ₈ O ₂ requires: C 59.08, H 6.53, N 10.23%.

Example 2. (+/-)3-{2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-d ihydro- benzofdj '[I ,2] ' diazepin-3-yl) ' -acetylamino) -benzoic acid

Step a. (+/-)3-{2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l -phenyl-4, 5-dihydro- benzofdj [1 ,2] 'diazepin-3-yl] ' -acetylamino) -benzoic acid methyl ester was obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-N-[3-(5-oxo-2 ,5-dihydro- [l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that 3-benzoic acid methyl ester was used in place of 3-(3-amino-phenyl)-2H-[l,2,4]oxadiazol-5-one. ¹ H NMR (CDC13) 8.13-7.34 (14H, m), 4.97-A33 (2H, m), 3.97-3.07 (3H, m), 3.88 (3H, s), 1.32 (9H, s).

--Step b. (+/-)3-{2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-d ihydro- benzo[d] [1 ,2] diazepin-3-yl] -acetylaminoj-benzoic acid was obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid (Example 1, step g), except that (+/-)3-{2-[5-(3,3- dimethyl-2-oxo-butyl)-4-oxo-l -phenyI-4,5-dihydro-benzo[d][l ,2] diazepin-3-yl] - acetylaminoj-benzoic acid methyl ester was used in place of (+/-)[5-(3,3-dimethyl-2-oxo- butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-acetic acid ethyl ester. ¹ H

NMR (CDC13) 8.14-7.21 (15H, m), 4.94-4.42 (2H, m), 3.90-3.13 (3H, m), 1.31 (9H, s).

..Trie-. compound was further characterised as the N-methyl-D-glucamine _: salt. Found: C 60.91, H 6.63, N 7.43%; C ₃₀ H ₂₉ N ₃ O ₅ ^C ₇ H , ₇ NO ₅ »1.4H ₂ O requires: C 60.76, _H 6.71, N

7.66%.

Example 3. (+/-)3-(3-{2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l~phenyl-4, 5-dihydro- benzo [d] [1 ,2) 'diazepin-3-yl] '-acetylamino} -phenyl) -propionic acid

Step a. (+/-)3-(3-{2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4, 5-dihydro- benzofd] [1,2] 'diazepin-3-yl] '-acetylamino} -phenyl) -propionic acid tert-butyl ester was obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo- butyl)-4-oxo-l -ρhenyl-4,5-dihydro-benzo[d][l ,2]diazepin-3-yl]-N-[3-(5-oxo-2,5-dihydro- [l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that 3-aminophenyl propionic acid tert-butyl ester was used in place of 3-(3-amino-phenyl)-2H- [l,2,4]oxadiazol-5-one. ¹ H NMR (CDCl ₃ ) 7.93-6.68 (14H, m), 5.03-4.53 (2H, m), 4.12- 3.23 (5H, m), 3.02-2.61 (4H, m), 1.55 (9H, s), 1.46 (9H, s).

Step b. (+/-)3-(3-{2-[5-(3, 3-Dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4, 5-dihydro- benzo[d] [1,2] diazepin-3-yl] -acetylamino}-phenyl)-propionic acid. (+/-)3-(3- {2-[5-(3,3- Dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l, 2]diazepin-3-yl]- acetylamino}-phenyl)-propionic acid tert-butyl ester (160mg, 0.27mmol) was dissolved in trifluoroacetic acid (5mL) and the mixture stirred at room temperature for Ih. The solution evaporated to dryness, the residue dissolved in DCM (2OmL) washed with H ₂ O (2x1 OmL), brine (1OmL) and dried (MgSO ₄ ). Filtration and evaporation of the solvent afforded the title compound as a beige solid (140mg, 97%). ¹ H NMR (CDCl ₃ ) 9.61 (IH, bs), 7.94-

6.93 (14H, m>, 4.91-4.39 (2H, m), 3.98-3.09 (3H, m), 2.89-2.61 (4H, m), 1.30 (9H, s). The compound was further characterised as the iV-methyl-D-glucamine salt. Found: C 59.15, H 6.55, N 7.03%; C ₃₂ H ₃₃ N ₃ O ₅ -C ₇ H ₁₇ NO ₅ -OJCF ₃ CO ₂ H requires: C 59.40, H 6.25, N 6.85%.

Example 4. (+/-)2-[5-(3,3-Dimethyl-2-oxo-bntyl)-4-oxo-l-phenyl-4,5-dihy dro- benzo[d] [ 1 ,2] diazepin-3-yl] -N-[3-(lH-tetrazol-5-yl)-phenyl] -acetamide

Step a. (+/-)2,2-Dimethyl-propionic acid 5-(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d] [ 1,2] diazepin-3-yl] -acetylamino}-phenyl)-tetrazol-l-ylmethyl ester was obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl- 2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepi n-3-yl]-N-[3-(5-oxo-2,5- .dihydro-[l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that 2,2- dimethyl-propionic acid 5-(3-amino-phenyl)-tetrazol-2-ylmethyl ester was used in place of 3-(3-amino-ρhenyl)~2H-[l,2,4]oxadiazol-5-one. ¹ H NMR ( CDCl ₃ ) 8.37-7.41 (14H, m), 6.64 (2H, s), 5.10-4.55 (2H, m), 4.14-3.26 (3H, m), 1.47 (9H, s), 1.37 (9H, s).

Step b. (+/-)2-[5-(3, 3-Dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4, 5-dihydro- benzo[d] [1 ,2] diazepin-3-yl] -N-[3-(lH-tetrazol-5-yl)-phenyl] -acetamide.

(+/-)2,2-Dimethyl-propionic acid 5-(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl- 4, 5-dihydro-benzo[d] [1 ,2] diazepin-3-yl] -acetylamino}-phenyl)-tetrazol-l-ylmethyl ester (83mg, 0.13mmol) was dissolved in a saturated solution of ammonia in MeOH (1OmL) and the mixture stirred at room temperature for 16h. The reaction mixture was evaporated to dryness, the residue dissolved in DCM (2OmL), washed with IN HCl (1OmL), H ₂ O (1OmL), brine (1OmL) and dried (MgSO ₄ ). Filtration and evaporation of the solvent afforded the product as a colourless solid (65mg, 96%). ¹ H NMR (CDCl ₃ ) 13.5 (IH, bs), 9.31 (IH, bs), 7.71-7.03 (13H, m), 4.77 (2H, m), 3.98-3.04 (3H, m), 1.13 (9H, s). The compound was further characterised as the JV-methyl-D-glucamine salt. Found: C 56.30, H 6.52, N 12.89%; C ₃ OH ₂₉ N ₇ O ₃ -C ₇ H ₁₇ NO ₅ -S-OH ₂ O-OJC ₄ H ₈ O ₂ requires: C 56.47, H 6.86, N 13.23%.

Example 5. (+/-)2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4, 5-dihydro- benzofd] [1 ,2] diazepin-3-yl] -N-[3-(5-oxo-2,5-dihydro-[l ,2,4] oxadiazol-3~yl)-phenyl] - acetamide

Step a. (+/-)[5-(2-Cyclopentyl-2~oxo-eth.yl)-4-oxo-l-phenyl-4, 5-dihydro- benzo[d] [ 1 ,2] dia∑epin-3-yl] -acetic acid ethyl ester was obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimemyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydro - benzo[d][l,2]diazepin-3-yl]-acetic acid ethyl ester (Example 1, step f), except that 2- bromo-1-cyclopentyl-ethanone was used in place of 1-bromopinacolone. ¹ H NMR (CDC13) 7.65-7.14 (9H, m), 4.57 (2H, m), 4.13 (2H, m), 4.10 (IH, m), 4.00 (IH, m), 3.90-3.00 (2H, m), 2.00-1.20 (8H, m), 1.14 (3H, m).

Step b. (+/-)[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihyd ro- benzo[d] [1 ,2] diazepin-3-yl] -acetic acid was obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l -phenyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetic acid (Example 1, step g), except that (+/-)[5-(2- cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d] [l,2]diazepin-3-yl]-acetic acid ethyl ester was used in place of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl- 4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-acetic acid ethyl ester. ¹ H NMR (DMSOd ₆ ) 12.70 (IH, bs) 7.64-7.05 (9H, m), 4.41 (2H, m), 3.80-3.05 (4H, m), 2.00-1.00 (8H, m).

Step c. (+/-)2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dih ydro- benzofdjfl, 2] diazepin-3-yl] -N-[3-(5-oxo-2, 5-dihydro-[l, 2, 4] oxadiazol-3-yl)-phenyl] - acetamide

l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71mg, 0.37mmol) was added to a solution of (+/-)[5-(2-cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihyd ro- benzo[d][l,2]diazepin-3-yl]-acetic acid (lOOmg, 0.25mmol), 3-(3-amino-phenyl)-2/f- [l,2,4]oxadiazol-5-one (46mg, 0.26mmol), 1-hydroxybenzotriazole hydrate (50mg, 0.37mmol) and DMAP (lmg) in DMF (1OmL) and the mixture stirred at room temperature for 16h. H ₂ O (3OmL) was added, and the mixture extracted with DCM (2x30mL). The combined extracts were washed successively with H ₂ O (4OmL), brine (4OmL) and dried

(MgSO ₄ ). Filtration and evaporation of the solvent gave the crude product which was purified chromatography on silica gel with MeOH-DCM (1 :100) as eluant. (+/-)2-[5-(2- Cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d] [l ,2]diazepin-3-yl]-N-[3- (5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl)-phenyl]-acetamide was obtained as an amorphous colourless solid (85mg, 61 ⁰ Zo)- ¹ H NMR (CDCl ₃ ) 11.50-10.50 (IH, bs), 9.35 and 8.86 (IH, m), 7.80-7.25 (13H, m), 5.10-3.00 (6H, m), 2.20-1.05 (8H, m). The compound was further characterised as the TV-methyl-D-glucamine salt. Found: C 58.35, H 6.26, N 10.12%; C ₃₂ H ₂₉ N ₅ O ₅ »C ₇ Hj ₇ NO ₅ β2.6H ₂ 0 requires: C 58.08, H 6.41, N 10.41%.

Example 6. (+/-)3-{2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-J-phenyl-4, 5-dihydro- ben∑ofd] [1, 2) ' diazepin-3~yl] ' -acetylaminoj -benzoic acid

Step a. (+/-)3- {2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-l -phenyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetylamino}-benzoic acid methyl ester was obtained by a similar method used in the preparation of (+/-)2-[5-(2-cyclopentyl-2-oxo-ethyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-N-[3-(5-oxo-2 ,5-dihydro- [l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 5, step c), except that 3-aminobenzoic acid methyl ester was used in place of 3-(3-amino-phenyl)-2H-[l,2,4]oxadiazol-5-one. ¹ H NMR (CDCl ₃ ) 9.10-7.30 (14H, m), 4.93-2.10 (6H, m), 3.86 (3H, m), 2.05-0.95 (8H, m).

Step b. (+/-)3-{2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4, 5-dihydro- benzofd] [1 ,2] ' diazepin-3-yl] ' -acetylamino} -benzoic acid was obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid (Example 1, step g), except that (+/-)3-{2-[5-(2- cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d] [l,2]diazepin-3-yl]- acetylamino} -benzoic acid methyl ester was used in place of (+/-)[5-(3,3-dimethyl-2-oxo- butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-acetic acid ethyl ester. ¹ H NMR ( CDCl ₃ ) 9.50-7.20 (15H, m), 4.91-2.25 (6H, m), 2.20-0.95 (8H, m). The compound was further characterised as the iV-methyl-D-glucamine salt. Found: C 57.54, H 6.71, N 7.12%; C ₃₁ H ₂₉ N ₃ CVC ₇ H ₁₇ NO ₅ ^OH ₂ O requires: C 57.71, H 6.88, N 7.08%.

Example 7.- (+/-)3-(3-{2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4 ,5-dihydro- benzo[d] [ 1 ,2] diazepin-3-yl] -acetylaminoj-phenyty-propionic acid

Step a. (+/-)3-(3- {2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo- 1 -phenyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetylamino}-phenyl)-propionic acid tert-butyl ester was .obtained by. a similar method used in the preparation of (+/-)2-[5-(2-cyclopentyl-2-oxo- ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-N-[3-(5-oxo-2,5-dihydro- [l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 5, step c), except that 3-aminophenyl propionic acid tert-butyl ester . was used in place of 3-(3-amino-phenyl)-2H- [l,2,4]oxadiazol-5-one. ¹ H NMR (CDCl ₃ ) 8.86-6.87 (14H, m), 4.89-2.10 (1OH, m), 2.05-0.90 (8H, m), 1.40 (9H, s).

Step b. (+/-)3-(3-{2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4 , 5-dihydro- benzofdj [1 ,2] ' diazepin-3-yl] '-acetylamino}-phenyl)-propionic acid was obtained by a similar method used in the preparation of (+/-)3-(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4- oxo-1 -phenyl-4,5-dihydro-benzo[d] [ 1 ,2]diazepin-3-yl]-acetylamino} -phenyl)-propionic acid (Example 3, step b), except that (+/-)3-(3-{2-[5-(2-cyclopentyl-2-oxo-ethyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-acetylamino}- phenyl)-propionic acid tert- butyl ester was used in place of (+/-)3-(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-acetylamino}- phenyl)-propionic acid tert- butyl ester. ¹ H NMR (CDCl ₃ ) 9.00-6.90 (15H, m), 4.86-2.25 (1OH, m), 2.05-0.90 (8H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C 59.22, H 6.64, N 6.77%; C ₃₃ H ₃₃ N ₃ O ₅ -C ₇ H ₁₇ NO ₅ .1.4H ₂ O»0.6CH ₂ Cl ₂ requires: C 59.25, H 6.61, N 6.81%.

Example 8. (+/-)2-[5-(2-Cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4, 5-dihydro- benzo[d] [1 ,2] diazepin-3-yl] -N-[3-(lH-tetrazol-5-yl)-phenyl] -acetamide

Step a. (+/-)2,2-Dimethyl-propionic acid 5-(3-{2-[5-(2-cyclopentyl-2-oxo-ethyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-acetylamino}- phenyl)-tetrazol-l-ylm ethyl ester was obtained by a similar method used in the preparation of (+/-)2-[5-(2-cyclopentyl- 2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepi n-3-yl]-N-[3-(5-oxo-2,5-

dihydro-[l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example -5, step c), except that 2,2- dimethyl -propionic acid 5-(3-amino-phenyl)-tetrazol-2-ylmethyl ester was used in place of 3-(3-amino-phenyl)-2H-[l,2,4]oxadiazol-5-one. ¹ H NMR (CDCl ₃ ) 9.05-7.15 (14H, m), 6.47 (2H, s), 4.92-2.10 (6H, m), 2.05-1.00 (8H, m), 1.19 (9H, s). - .

Step b. (+/-)2-[5-(2-CyclopentyU2-oxo-ethyl)--4-oxo-l-phenyl-4, 5-dihydro-. benzo [d] [ 1 ,2] diazepin-3-yl] -N-[3-(l H-tetrazol-5-yl)-phenyl] -acetamide was obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-N-[3-(lH-tetr azol-5-yl)-phenyl]- acetamide (Example 4, step b), except that (+/-)2,2-dimethyl-propionic acid 5-(3-{2-[5-(2- cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d] [l,2]diazepin-3-yl]- acetylamino}-phenyl)-tetrazol-l-ylmethyl ester was used in place of (+/-)2,2-dimethyl- propionic acid 5-(3- {2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l -phenyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetylamino}-phenyl)-tetrazol-l- ylmethyl ester. ¹ H NMR (CDCl ₃ ) 9.45-7.11 (14H, m), 5.00-2.10 (6H, m), 2.05-1.00 (8H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C 57.09, H 6.44, N 13.14%; C ₃₃ H ₂₉ N ₇ O ₃ *C ₇ H ₁₇ Nθ5»3.0H ₂ O«0.5C ₄ H ₈ θ2 requires: C 57.25, H 6.70, N 13.35%.

Example 9. (+/-)2-[5-(2-Cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihy dro- benzo[d] [1 ,2] diazepin-3-yl] -N-[3-(5-oxo-2,5-dihydro-[l ,2,4] oxadiazol-3-yl)-phenyl] - acetamide

Step a. (+/-)[5-(2-Cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d] [1,2] diazepin-3-yl] -acetic acid ethyl ester is obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid ethyl ester (Example 1, step f), except that 2- bromo-1-cyclohexyl-ethanone is used in place of 1-bromopinacolone.

Step b. (+/-)[5-(2-Cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4, 5-dihydro- benzo [d][ 1,2] diazepin-3-yl] -acetic acid is obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l -phenyl-4,5-dihydro- benzo[d][ 1,2] diazepin-3-yl] -acetic acid (Example 1, step g), except that (+/-)[5-(2- cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][ l,2]diazepin-3-yl]-acetic

acid ethyl ester is used in place of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5- dihydro-benzo[d][l,2]diazepin-3-yl]-acetic acid ethyl ester.

Step c. (+/-)2-[5-(2-Cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihy dro- benzofdj [1 ,2] diazepin-3-yl] -N-[3-(5-oxo-2,5-dihydro-[l ,2,4] oxadiazol-3-yl)-phenyl] ^' - acetamide is obtained by a similar method used in the preparation of (+/-)2r[5-(2- cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d] [l,2]diazepin-3-yl]-N-[3- (5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 5, step c), except that (+/-)[5-(2-cyclohexyl-2-oxo-ethyl)-4-oxo-l -phenyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetic acid is used in place of (+/-)[5-(2-cyclopentyl-2-oxo- ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-acetic acid.

Example 10. (+/-)3-{2-[5-(2-Cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-d ihydro- ben∑ofdj [1 ,2] diazepin-3-yl] '-acetylamino}-4-methyl-benzoic acid

Step a. (+/-)3-{2-[5-(2-Cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-d ihydro- benzo[d] [1 ,2] diazepin-3-yl] -acetylamino}-4-methyl-benzoic acid methyl ester is obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo- l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-N-[3-(5-oxo -2,5-dihydro- [l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that (+/-)[5-(2- cyclohexyl-2-oxo-ethyl)-4-oxo- 1 -phenyl-4,5-dihydro-benzo[d] [ 1 ,2]diazepin-3-yl]-acetic acid and 4-methyl -3 -benzoic acid methyl ester are used in place of (+/-)[5-(3,3-dimethyl-2- oxo-butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin- 3-yl]-acetic acid and 3-(3- amino-phenyl)-2H-[l ,2,4]oxadiazol-5-one respectively.

Step b. (+/-)3-{2-[5-(2-Cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4, 5-dihydro- benzofd] f 1,2] diazepin-3-yl] -acetylanιinoj-4-methyl-benzoic acid is obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5- dihydro-benzo[d][l,2]diazepin-3-yl]-acetic acid (Example 1, step g), except that (+/-)3-{2- [5-(2-cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-ben zo[d][l,2]diazepin-3-yl]- acetylamino}-4-methyl-benzoic acid methyl ester is used in place of (+/-)[5-(3,3-dimethyl- 2-oxo-butyl)-4-oxo-l -phenyl-4,5-dihydro-benzo[d] [ 1 ,2] diazepin-3-yl] -acetic acid ethyl ester.

Example 11. (+/-)2-[5-(2-Cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihy dro- benzo[d] [ 1 ,2] diazepin-3-yl] -N-[2-methyl-thiazol-4-yl)phenyl] -acetamide

The- title compound is obtained by a similar method used in the preparation of (+/-)2-[5- (3,3-dimeihyl-Z-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[ d][l,2]diazepin-3-yl]-N-[3-

(5-0X0-2, 5-dihydro-[l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that (+/-)[5-(2-cyclohexyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d].[.l,2]diazepin-3-yl]-acetic acid and 3-(2-methyl-thiazol-4-yl)-phenylamine (prepared in two steps from 2-bromo-3'-nitroacetophenone) are used in place of (+/-)[5-

(3,3-dimethyl-2-oxo-butyl)-4-oxo-l -phenyl-4,5-dihydro-benzo[d][ 1 ,2]diazepin-3-yl]-acetic acid and 3-(3-amino-phenyl)-2H-[l,2,4]oxadiazol-5-one respectively.

Example 12. (+/-)3-{2-[5-(2-(l-Methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l- cyclohexyl-4,5- dihydro-benzofd] [1 , 2] ' diazepin-3-yl) ' -acetylamino) -benzoic acid

Step a. (4-Oxo-l-cyclohexyl-4,5-dihydro-benzo[d] [1 ,2] diazepin-3-yl)-acetic acid ethyl ester is obtained using steps a-e of the preparation of (4-oxo-l-phenyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl)-acetic acid ethyl ester (Example 1, step e), except that cyclohexylmagnesium chloride is used in place of phenylmagnesium chloride in step a.

Step b. (+/-)3-{2-[5-(2-(l-Methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l- cyclohexyl-4,5- dihydro-benzo[d] [1,2] diazepin-3-yl] -acetic acid is obtained from (4-oxo-l-cyclohexyl- 4,5-dihydro-benzo[d][l,2]diazepin-3-yl)-acetic acid ethyl ester using steps f-g of the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-buryl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid (Example 1, step g), except that 2-bromo-l-(l- methyl-cyclopentyl)-ethanone is used in step fin place of 1-bromopinacolone.

Step c. (+/-)3-{2-[5-(2-(l-Methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l- cyclohexyl-4,5- dihydro-benzofd] [1,2] diazepin-3-yl] -acetylamino} -benzoic acid methyl ester is obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo- 1 -phenyl-4,5-dihydro-benzo [d] [ 1 ,2]diazepin-3 -yl]-N-[3 -(5-oxo-2,5-dihydro- [l,2,4]oxadiazol-3-yl)-ρhenyl]-acetamide (Example 1, step h), except that (+/-)3-{2-[5-(2-

(l-raethyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l-cyclohexyl-4,5- dihydro- benzo[d][l,2]diazepin-3-yl]-acetic acid and 3-benzoic acid methyl ester are used in place of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo- 1 -phenyl -4,5-dihydro-benzo[d] [ 1 ,2]diazepin- 3-yl]-acetic acid and 3 -(3 -amino-phenyl)-2H-[l,2,4]oxadiazol-5-one respectively. -

Step d. (+/-)3-{2-[5-(2=(l-Methyl-cyclopentyl)-2^oxo-ethyl)-4-oxo-l- cyclohexyl-4, 5- dihydro-benzo[d] [1 ,2] ' diazepin-3-yl] ' -acetylamino) -benzoic add is obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5- dihydro-benzo[d][l,2]diazepin-3-yl]-acetic acid (Example.!, step g), except that (+/-)3-{2- [5-(2-(l-methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l-cyclohexyl -4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetylamino}-benzoic acid methyl ester is used in place of (+/- )[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydro-be nzo[d][l,2]diazepin-3-yl]- acetic acid ethyl ester.

Example 13. (+/-)(3-{2-[5-(2-(l-Methyl-cyclopentyl)-2^oxo-ethyl)-4-oxo-l -cyclohexyl~4,5- dihydro-benzo [d] ^' / ϊ ,2] ' diazepin-3-yl) ' -acetylamino} -phenyl) -acetic acid

Step a. (+/-)(3-{2-[5-(2-(l-Methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l -cyclohexyl~4,5- dihydro-benzo[d] [1,2] diazepin-3-yl] ^' -acetylammo) -phenyl) -acetic acid methyl ester is obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo- butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-N-[3-(5-oxo-2,5-dihydro- [l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that (+/-)3-{2-[5-(2- (l-methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l-cyclohexyl-4,5-d ihydro- benzo[d][l,2]diazepin-3-yl]-acetic acid and 3-phenylacetic acid methyl ester are used in place of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid and 3-(3-amino-phenyl)-2H-[l,2,4]oxadiazol-5-one respectively.

Step b. (+/-)(3-{2-[5-(2-(l-Methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l -cyclohexyl~4,5- dihydro-benzofd] [1,2] diazepin-3-yl] -acetylamino}-phenyl)-acetic acid is obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-acetic acid (Example 1, step g), except that (+/-)(3-{2-[5-(2-(l-methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l -cyclohexyl-4,5-dihydro-

benzo[d][l,2]diazepin-3-yl]-acetylamino}-phenyl)-acetic acid methyl ester is used in place of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydr o-benzo[d][l,2]diazepin- 3 -yl] -acetic acid ethyl ester.

Example 14. (+/-)(3-{2-[5-(2-(l-Methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l -cyclohexyI-4,5- dihydro-benzo[d][ 1, 2] diazepin-3-yl] -acetylamino}-phenysulfan}d)-acetic acid

Step a. (+/-)(3-{2-[5-(2-(l-Methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l -cyclohexyl-4,5- dihydro-benzo[d] [1 ,2] diazepin-3-yl] -acetylamino}-phenysulfanyl)-acetic acid ethyLesterΛs obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo- butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-N-[3-(5-oxo-2,5-dihydro- [l,2,4}oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that (+/-)3-{2-[5-(2- (l-methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l-cyclohexyl-4,5-d ihydro- benzo[d][l,2]diazepin-3-yl]-acetic acid and (3-amino-phenylsulfanyl)-acetic acid ethyl ester are used in place of (+/-)[5-(3,3-dimemyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydro - benzo[d][l,2]diazepin-3-yl]-acetic acid and 3-(3-amino-phenyl)-2H-[l,2,4]oxadiazol-5-one respectively.

Step b. (+/-)(3-{2~[5-(2-(l-Methyl-cyclopentyl)~2-oxo-ethyl)-4-oxo-l -cyclohexyl-4,5- dihydro-benzo[d] [1 ,2] diazepin-3-yl] -acetylamino}-phenysulfanyl)-acetic acid is obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-acetic acid (Example 1, step g), except that (+/-)(3-{2-[5-(2-(l-methyl-cyclopentyl)-2-oxo-ethyl)-4-oxo-l -cyclohexyl-4,5-dihydro- benzofdjfl^Jdiazepin-S-ylj-acetylaminoj-phenysulfany^-acetic acid ethyl ester is used in place of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid ethyl ester.

Example 15. (+/-)2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l-cyclohexyl~4,5- dihydro- benzo[d] [1 ,2] diazepin-3-yl] -N-[3-(5-oxo-2,5-dihydro~[l ,2,4] oxadiazol-3-yl)-phenyl] - acetamide

Step a. (+/-)3-{2-[5-(2-(3,3-Dimethyl-2-oxo-butyl)-2-oxo-ethyl)-4-ox o-l-cyclohexyl-4,5- dihydro-benzo[d][ 1,2] diazepin-3-yl] -acetic acid is obtained using steps f-g of the

preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l -phenyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetic acid (Example 1 , Step g), except that (4-oxo-l- cyclohexyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl)-acetic acid ethyl ester is used in step f in place of (4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl)-acet ic acid ethyl ester.

Step b. (+/-)2-[5-(3, 3-Dimethyl-2-oxo-butyl)-4-oxo-l -cyclohexyl-4 , 5-dihydro- benzo[d] [1 ,2] diazepin-3-yl] -N-[3-(5-oxo-2,5-dihydro-[l ,2,4] oxadiazol-3-yl)-phenyl] - acetamide As. obtained by a similar method used in the preparation of (+/-)2-[5-(2- cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d] [l ,2]diazepin-3-yl]-N-[3- (5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 5, step c), except that (+/-)3-{2-[5-(2-(3,3-dimethyl-2-oxo-butyl)-2-oxo-ethyl)-4-ox o-l-cyclohexyl-4,5- dihydro-benzo[d][l,2]diazepin-3-yl]-acetic acid is used in place of (+/-)[5-(2-cyclopentyl- 2-oxo-ethyl)-4-oxo-l -phenyl-4,5-dihydro-benzo[d][l ,2]diazepin-3-yl]-acetic acid. ^{~ ■}

Example 16. (+/-)2-[5-(3, 3-Dimethyl-2-oxo-butyl)-4-oxo-l -cyclohexyl-4, 5-dihydro- benzofdj [1,2] 'diazepin-3-yl] ' -N-[3-(lH-tetrazol-5-yl)-phenyl] -acetamide

Step a. (+/-)2,2-Dimethyl-propionic acid 5-(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- cyclohexyl-4, 5-dihydro-benzo [d] [1 ,2] diazepin-3-yl] -acetylamino}-phenyl)-tetrazol-l - ylmethyl ester is obtained by a similar method used in the preparation of (+/-)2-[5-(2- cyclopentyl-2-oxo-ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d] [l,2]diazepin-3-yl]-N-[3- (5-oxo-2,5-dihydro-[l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 5, step c), except that (+/-)3- {2-[5-(2-(3,3-dimethyl-2-oxo-butyl)-2-oxo-ethyl)-4-oxo-l -cyclohexyl-4,5- dihydro-benzo[d][l,2]diazepin-3-yl]-acetic acid and 2,2-dimethyl-propionic acid 5-(3- amino-phenyl)-tetrazol-2 -ylmethyl ester are used in place of (+/-)[5-(2-cyclopentyl-2-oxo- ethyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-acetic acid and 3-(3- amino-phenyl)-2H-[l ,2,4]oxadiazol-5-one respectively.

Step b. (+/-)2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l-cyclohexyl-4,5- dihydro- benzo[d] [1 ,2] diazepin-3-yl] -N-[3-(lH-tetrazol-5-yl)-phenyl] -acetamide is obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-N-[3-(lH-tetr azol-5-yl)-phenyl]-

acetamide (Example 4, step b), except-that (+/-)2,2-<iimethyl-propionic acid 5-(3-{2-[5- (3,3-dimethyl-2-oxo-butyl)-4-oxo-l-cyclohexyl-4,5-dihydro-be nzo[d][l,2]diazepin-3-yl]- acetylamino}-phenyl)-tetrazol-l-ylmethyl ester is used in place of (+/-)2,2-dimethyl- propionic acid 5-(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dih ydro- benzo[d][l,2]diazepin-3-yl]-acetylamino}-phenyl)-tetrazol-l- ylmethyl ester.

Example 17. (+/-)(3-{2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l-cyclohexyl- 4,5-dihydro- benzofd] [J ,2] diazepin-3-yl] -acetylamino}-phenyl)-furan-2-carhoxylic acid

Step a. (+/-)(3-{2-[5-(3,3-Dimethyl-2-oxo-bιιtyl)-4-oxo-l-cyclohex yl-4,5-dihydro- benzofdj [1 ,2] diazepin-3-yl) -acetylaminoj -phenyl) -fur an-2-carboxylic acid methyl ester is obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo- butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-N-[3-(5-oxo-2,5-dihydro- [l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that (+/-)3-{2-[5-(2- (3,3-dimethyl-2-oxo-butyl)-2-oxo-ethyl)-4-oxo-l -cyclohexyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetic acid and 5-(3-amino-phenyl)-furan-2-carboxylic acid methyl ester (prepared in two steps from 5-(3-nitrophenyl)-2-furoic acid) are used in place of (+/-)[5-(3 ,3 -dimethyl-2-oxo-butyl)-4-oxo- 1 -phenyl-4,5-dihydro-benzo[d] [ 1 ,2] diazepin- 3-yl]-acetic acid and 3-(3-amino-phenyl)-2H-[l,2,4]oxadiazol-5-one respectively.

Step b. (+/-)(3~{2-[5-(3, 3-Dimethyl-2-oxo-bntyl)-4-oxo-l -cyclohexyl-4, 5-dihydro- benzo[d] [1 ,2] diazepin-3-yl] -acetylamino}-phenyl)-furan-2-carboxylic acid is obtained by a similar method used in the preparation of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l _:> 2]diazepin-3-yl]-acetic acid (Example 1, step g), except that (+/-)(3 - {2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo- 1 -cyclohexyl-4,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetylamino}-phenyl)-furan-2-car boxylic acid methyl ester is used in place of (+/-)[5-(3,3-dimethyl-2-oxq-butyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid ethyl ester.

Example 18. (+/-)(3-{2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l-cyclohexyl- 4,5-dihydro- benzo[d][l ,2} ' diazepin-3-yl] '-acetylamino}-phenyl)-propionic acid

Step a. (+/-)(3-{2-[5-(3,3-Dimethyl-2-oxo-butyl)-4-oxo-l~cyclohexyl- 4,5-dihydro~ benzo[dJ[l,2Jdiazepin-3-ylJ-acetylamino}-phenyl)-propionic acid tert-butyl ester is obtained by a similar method used in the preparation of (+/-)2-[5-(3,3-dimethyl-2-oxo- butyl)-4-oxo-l-phenyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl ]-N-[3-(5-oxo-2,5-dihydro- [l,2,4]oxadiazol-3-yl)-phenyl]-acetamide (Example 1, step h), except that (+/-)3-{2-[5-(2- (3,3-dimethyl-2-oxo-butyl)-2-oxo-ethyl)-4-oxo-l-cyclohexyl-4 ,5-dihydro- benzo[d][l,2]diazepin-3-yl]-acetic acid and 3-phenylpropionic acid tot-butyl ester are used in place of (+/-)[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l-phenyl-4,5-dihydr o- benzo[d][l,2]diazepin-3-yl]-acetic acid and 3-(3-amino-phenyl)-2H-[l,2,4]oxadiazol-5-one respectively.

Step b. . (+/-)(3-{2-[5-(3,3-Dimethyl-2-oxo-bιιtyl)~4-oxo-l-cyclohex yl-4,5-dihydro- benzofd] ' [1 ,2] ' diazepin-3-yl] '-acetylamino}-phenyl)-propionic acid is obtained by a similar method used in the preparation of (+/-)3-(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l ,2]diazepin-3-yl]-acetylamino}-phenyl)-propionic acid (Example 3, step b), except that (+/-)(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- cyclohexyl-4,5-dihydro-benzo[d][l,2]diazepin-3-yl]-acetylami no}-phenyl)-propionic acid tert-butyl ester is used in place of (+/-)3-(3-{2-[5-(3,3-dimethyl-2-oxo-butyl)-4-oxo-l- phenyl-4,5-dihydro-benzo[d][l ,2]diazepm-3-yl]-acetylamino} -phenyl)-propionic acid tert- butyl ester.

CCK ₂ and CCKjAntagonist Activity

Certain compounds of the examples were tested for gastrin (CCK ₂ ) antagonist activity in an immature rat stomach assay. The procedure was as follows:

The oesophagus of immature rats (33-50 g, ca. 21 days old) was ligated at the level of the cardiac sphincter and the duodenal sphincter was cannulated. The stomach was excised and flushed with ca. 1 ml of unbuffered physiological saline solution. The fundus was punctured and cannulated. A further 4-5 ml of unbuffered solution was flushed through the stomach to ensure the preparation was not leaking. The stomach was lowered into a jacketed organ bath containing 40 ml of buffered solution containing 3 x 10 ^"8 M 5- methylfurmethide, maintained at 37° and gassed vigorously with 95% O ₂ / 5% CO ₂ . The

stomach was continuously perfused at a rate of 1 ml min ^" with unbuffered solution gassed with 100% O ₂ with the perfusate passing over an internally referenced pH-electrode fixed 12 cm above the stomach.

After 120 miri of stabilisation the drugs were added directly to the serosal solution in the organ bath and after a further 60 min cumulative pentagastrin dose-response curves were started. Changes in acid secretion were monitored and the curves analysed according to Black et al, Br. J. Pharmacol, 1985, 86, 581.

The results obtained at the CCK ₂ receptor are set out in the following Table.

In vitro biological activity of 2,3-benzodiazepin-4-ones

The CCK| - activity of the ligands was assessed in a radioligand binding study, looking at the displacement of [ ³ H]-L-364,718 from sites in CHO-Kl cells into which the human CCKi -receptor sequence has been cloned. Where examined, the Examples showed a pKj of less than 6.

It is found that, the compositions and products- of the present invention comprising a compound of formula (I) and a proton pump inhibitor reduce hyperplasia, associated with administration of proton pump inhibitors. This was measured according to the following experimental protocol.

Animals and treatment:

40 male SPF Wistar rats (200 g) were divided into 4 treatment groups and 2 strata. The treatment of the 20 rats in the second stratum started 2 weeks after the treatment of the first stratum. The design of the study was completely randomised double blind with individual blinding; all rats were placed in a separate cage. Animals had continuous access to water and food.

Animals were treated once daily during 14 days:

- Control group: 1 ml gastrin test drug vehicle + 1 ml p.o.(gavage) 0,25% Methocel (Dow Corning)

- PPI group: 1 ml gastrin test drug vehicle +1 ml p.o.(gavage) 25 mg/kg Rabeprazole in

0.25% Methocel.

- GRA group: 1 ml gastrin test drug + 1 ml p.o. (gavage) 0,25% Methocel

- GRA-PPI group: 1 ml gastrin test drug + 1 ml p.o.(gavage) 25 mg/kg Rabeprazole in 0.25% Methocel.

Gastrin test drug made up to an appropriate dose in physiologically compatible solvent.

Preparation of tissue: After removal of the fundus, the stomach were rinsed with phosphate buffered saline prior to fixation with 4% formalin in Millonig buffer. After 4 hours immersion in fixative solutions at room temperature, tissue was rinsed in phosphate buffered saline (PBS), dehydrated and embedded in paraffin using the Leitz paraffin embedding station (Leitz TP

1050; Germany) dehydration module and paraffin embedding module -(Lei-tz EG -1160; Germany).

Cross sections (3 μm thick) of the oxyntic part of the stomach were made at 3 levels, each separated by a distance of 400 μm.

Immunostaining

The following indirect immunofluorescence labeling method was used:

- removal of paraffin and rehydratation of the sections followed by a blocking step - primary antibodies: polyclonal guinea pig anti-histidine decarboxylase, 1/2000 (from Euro-Diagnostica) and monoclonal mouse anti PCNA 1/2500 (Clone PClO from Sigma). All antibodies were diluted in a 0.2% BSA solution. Sections were incubated overnight at 4°C and then washed with a BSA solution.

- secondary antibodies: goat anti guinea pig coupled to CY5 ₅ 1/500 (from Jackson Laboratories) and goat anti-mouse coupled to Cy3, 1/250 (from Jackson Laboratories); incubation for 4 hours at 37°C. After rinsing with BSA and PBS solutions, sections were mounted with slowfade (Molecular Probes Europe BV), and stored at 4 ⁰ C.

Imaging Fluorescence labelling was observed with an epifluorescence microscope or a Zeiss LSM510 (Carl Zeiss Jena GmbH) confocal microscope.

By using CY5- and CY3 -coupled antibodies, the high autofluorescence properties of the oxyntic mucosa were circumvented when sections are illuminated by a 488 nm (FITC channel) light source. Negative controls, by omitting the primary antibodies, and an isotype control staining for PCNA showed complete absence of staining. The specific labelling of PCNA was checked using double staining with TOPRO-3® (Molecular Probes Europe BV), a nuclear stain. Only in the most luminal located epithelial cells, non-specific cytoplasmic labelling was present. In the glandular part of the mucosa, non-specific PCNA-staining was absent.

For determination of the labelling index of ECL cells, at least 80 confocal images per rat

were taken -from the 3 slides at the 3 different levels. The ratio of double labelled cells (HDC + PCNA) and all HDC labelled cells yielded the labelling index of ECL cells.

Proliferation activity of ECL cells in the PPI group is expected to be increased compared with sham, GRA and GRA-PPI groups (Eissele, R., Patberg, H., Koop, H., Krack, W., Lorenz, W., McKnight, A.T., and Arnold, R. Effect of gastrin receptor blockade on endrocine cells in rats during achlorhydria. Gastroenterology, 103, 1596-1601, 1992). Increased proliferation by PPI will be completely blocked by GRA.