BENZODIAZEPINE DERIVATIVES

Abstract: Compounds of formula (I), and salts and prodrugs thereof, wherein R<1> represents H, optionally substituted C1-6alkyl or C3-7cycloalkyl; R<2> is NHR<12> or (CH2)sR<13> where s is 0, 1 or 2; R<3> represents C1-6alkyl, halo or NR<6>R<7>; R<4> and R<5> are H , C1-12alkyl optionally substituted by NR<9>R<9'> or an azacyclic or azabicyclic group, optionally substituted C4-9cycloalkyl, C4-9cycloalkylC1-4alkyl, aryl, arylC1-6alkyl or azacyclic or azabicyclic groups, or R<4> and R<5> together form the residue of an optionally substituted azacyclic or azabicyclic ring system; x is 0, 1, 2 or 3; R<12> is optionally substituted phenyl or pyridyl; R<13> represents a group (A) wherein R<14> is H or C1-6alkyl; R<15> is H, C1-6alkyl, halo or NR<6>R<7>; and the dotted line is an optional covalent bond; are CCK and/or gastrin antagonists useful in therapy.

Description: BENZODIAZEPI E DERIVATIVES This invention relates to benzodiazepine compounds which are useful as antagonists of cholecystokinin and gastrin receptors. Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system (see, V. Mutt, Gastrointestinal Hormones. G.B.J. Green, Ed., Raven Press, N.Y., p.169 and G. Nission, ibid. p.127) . Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form (see. Mutt and Jorpes, Biochem. J. 125. 678 (1971)), its carboxylterminal octapeptide, CCK-8 (also a naturally-occurring neuropeptide and the minimum fully active sequence) , and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14-amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH2, which is the common structural element shared by both CCK and gastrin. CCKs are believed to be physiological satiety hormones, thereby possibly playing an important role in appetite regulation (G. P. Smith, Eatinσ and Its Disorders. A. J. Stunkard and E. Stellar, Eds, Raven Press, New York, 1984, p. 67), as well as stimulating colonic motility, gall bladder contraction, pancreatic enzyme secretion and inhibiting gastric emptying. They reportedly co-exist with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of dopaminergic systems in the brain, in addition to serving as neurotransmitters in their own right (see A. J. Prange et al. , "Peptides in the Central Nervous System", Ann. Reots. Med. Chem 17. 31, 33 [1982] and references cited therein? J. A. Williams, Biomed Res. 3 107 [1982]; and J.E. Morley, Life Sci. 30. 479 [1982]). The primary role of gastrin, on the other hand, appears to be stimulation of the secretion of water and electrolytes from the stomach and, as such, is involved in control of gastric acid and pepsin secretion. Other physiological effects of gastrin then include increased mucosal blood flow and increased antral motility. Rat studies have shown that gastrin has a positive trophic effect on the gastric mucosa, as evidenced by increased DNA, RNA and protein synthesis. There are at least two subtypes of cholecystokinin receptors termed CCK-A and CCK-B (T.H. Moran et al. , "Two brain cholecystokinin receptors: implications for behavioural actions", Brain Res.. 362. 175-79 [1986]). Both subtypes are found both in the periphery and in the central nervous system. CCK and gastrin receptor antagonists have been disclosed for preventing and treating CCK-related and/or gastrin related disorders of the gastrointestinal (GI) and central nervous (CNS) systems of animals, especially mammals, and more especially those of humans. Just as there is some overlap in the biological activities of CCK and gastrin, antagonists also tend to have affinity for both CCK-B receptors and gastrin receptors. Other antagonists have activity at the CCK-A subtype. Selective CCK antagonists are themselves useful in treating CCK-related disorders of appetite regulatory systems of animals as well as in potentiating and prolonging opiate-mediated analgesia [see P. L. Faris et al. , Science 226. 1215 (1984)], thus having utility in the treatment of pain. CCK-B and CCK-A antagonists have also been shown to have a direct analgesic effect [M.F. O'Neill et al.. Brain Research. 534.287 (1990)]. Selective CCK and gastrin antagonists are useful in the modulation of behaviour mediated by dopaminergic and serotonergic neuronal systems and thus have utility in the treatment of schizophrenia and depression (Rasmussen et. al. , 1991, Eur. J. Pharmacol.. 209, 135-138; Woodruff et. al.. 1991, Neuropeptides. 19, 45-46; Cervo et. al. , 1988, Eur. J. Pharmacol.. 158, 53-59), as a palliative for gastrointestinal neoplasms, and in the treatment and prevention of gastrin-related disorders of the gastrointestinal system in humans and animals, such as peptic ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which reduced gastrin activity is of therapeutic value, see e.g. U.S. Patent 4,820,834. Certain CCK antagonists are useful anxiolytic agents and can be used in the treatment of panic and anxiety disorders. CCK has been reported to evoke the release of stress hormones such as adrenocorticotrophic hormone, β- endorphin, vasopressin and oxytocin, CCK may function as a mediator of responses to stress and as part of the arousal system. CCK-A receptors are now known to be present in a number of areas of the CNS and may be involved in modulating all of the above. CCK may be involved in the regulation of stress and its relationship with drug abuse e.g. alleviation of the benzodiazepine withdrawal syndrome (Singh et. al.. 1992, Br. J. Pharmacol.. 105. 8-10) and neuroadaptive processes. Since CCK and gastrin also have trophic effects on certain tumours [K. Okyama, Hokkaido J. Med. Sci. r 206-216 (1985)], antagonists of CCK and gastrin are useful in treating these tumours [see, R.D. Beauchamp et al. , Ann. Surσ. f 202, 203 (1985)]. In the light of discussion in C. Xu et al. , Peptides. 8, 1987, 769-772, CCK antagonists may also be effective in neuroprotection. CCK receptor antagonists have been found to inhibit the contractile effects of CCK on iris sphincter and ciliary muscles of monkey and human eyes (Eur. J. Pharmacol., 111(2), 183-187; A. Bill et al.. Acta Physiol. Scand., 138, 479-485 [1990]), thus having utility in inducing miosis for therapeutic purposes. A class of benzodiazepine antagonist compounds has been reported which binds selectively to brain CCK (CCK-B and CCK-A) and gastrin receptors [see M. Bock et al. , J. Med Chem.. 12., 13-16 (1989)]. European patent application no. 0 167 919 discloses benzodiazepine CCK and gastrin antagonists substituted in the 3-position by, inter alia, a phenyl urea or an indole amide and at the 5-position by an optionally substituted phenyl or pyridyl group. United States Patent no. 3,414,563 discloses benzodiazepine derivatives optionally substituted at the 3-position by C- j ^alkyl or phenyl and substituted at the 5-position by an amino, alkylamino or dialkylamino group or a 3 to 8-membered azacycle, bound through nitrogen, which azacycle may optionally contain a further O, S or N atom. The compounds are said to have CNS activity. There is no suggestion of a nitrogen-containing substitutuent at the 3-position. Nor is there any suggestion that the disclosed compounds are antagonists at CCK or gastrin receptors. The present invention provides benzodiazepine compounds of formula (I) : (I) wherein: R 1 represents H, Ci-βalkyl optionally substituted by one or more halo, C 3 _7cycloalkyl, cyclopropylmethyl, (CH2) r imidazolyl, (CH2) r triazolyl, ( H2)r te trazolyl (where r is l, 2 or 3), CH2CO2R 11 (where R 11 is C 1 _ 4 alkyl) or CH 2 C0NR 6 R 7 (where R 6 and R 7 each independently represents H or Cι._4alkyl, or R 6 and R 7 together form a chain (CH2) P where p is 4 or 5) ; R 2 represents NHR 12 or (CH 2 ) S *R 13 where s is 0, 1 or 2; R 3 represents Ci-galkyl , halo or NR 6 R 7 , where R 6 and R 7 are as previously defined; R 4 and R 5 each independently represents H, c l -12 alkvl optionally substituted by NR 9 R 9 (where R 9 and R are as previously defined) or an azacyclic or azabicyclic group, C4_gcycloalkyl optionally substituted by one or more Cι_ 4 alkyl groups, C4_ 9 cycloalkylCι_ 4 alkyl optionally substituted in the cycloalkyl ring by one or more groups, optionally substituted aryl, optionally substituted arylC^.galkyl or azacyclic or azabicyclic groups, or R 4 and R 5 together form the residue of an optionally substituted azacyclic or azabicyclic ring system; x is 0, 1, 2 or 3; R 12 represents a phenyl or pyridyl group optionally substituted by one or more substituents selected from Cx-galkyl, halo, hydroxy, C 1 _ 4 alkoxy, (CH )q-tetrazolyl optionally substituted in the tetrazole ring by C 1 _ 4 alkyl, (CH 2 )q-imidazolyl, (CH 2 ) q -triazolyl (where q is 0, 1, 2 or 3) , 5-hydroxy- -pyrone, NR 6 R 7 , NR 9 COR 1:L , NR 9 CONR 9 *R 11 (where R 9 and R 9 ' are each independently H or C* ] ^alkyl and R 11 is as previously defined) , CONR 6 R 7 (where R 6 and R 7 are as previously defined), SO(C 1 _ 6 alkyl) , S0 2 (C 1 -_ 6 alkyl) , trifluoromethyl, CONHS0 R 8 , S0 2 NHCOR 8 (where R 8 is Ci-galkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl) , SO2NHR 10 (where R 10 is a nitrogen containing heterocycle), B(OH)2, (CH2)qC0 2 H, where q is as previously defined; or R 12 represents a group where X 1 represents CH or N; W represents CH2 or NR 9 , where R 9 is as previously defined, and W 1 represents CH2, or W and W 1 each represent 0; or R 12 represents phenyl substituted by a group Z-(CH 2 ) wherein X 2 is 0, S or NR 9 , where R 9 is as previously defined; Z is a bond, O or S; m is 1, 2 or 3; n is 1, 2 or 3; and y is 0, 1, 2 or 3; R 13 represents a group wherein R 14 represents H or Cx-gal yl; R 15 represents H, Cx-βalkyl, halo or NR 6 R 7 , where R 6 and R 7 are a previously defined; and the dotted line represents an optional covalent bond; and pharmaceutically acceptable salts or prodrugs thereof, with the proviso that, when NR 4 R 5 represents an unsubstituted azacyclic ring system, R 2 does not represent NHR 12 where R 12 is optionally substituted phenyl or It will be appreciated that formula (I) is intended to embrace all possible isomers, including optical isomers, and mixtures thereof, including racemateε. As used herein, the definition of each expression, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I) . Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bungaard, Elsevier, 1985. Halo includes fluoro, chloro, bromo and iodo. Preferably halo will be fluoro or chloro. As used herein, unless otherwise indicated, alkyl means straight or branched chain saturated hydrocarbon. As used herein, azacyclic means non-aromatic nitrogen-containing monocyclic, and azabicyclic means non-aromatic nitrogen-containing bicyclic. Unless otherwise stated, aryl means optionally substituted carbocyclic or heterocyclic aromatic groups, especially phenyl. Heteroaryl means aromatic rings preferably having 5 or 6 ring atoms and containing at least one atom selected from O, S and N. A first subgroup of compounds according to the invention is represented by compounds of formula (I) , and salts and prodrugs thereof, wherein R 1 represents Ci-galkyl, C 3 -»7cycloalkyl, cyclopropylmethyl, CH2CO2R 11 or CH2CON 6 R 7 ; R 2 represents NHR 12 where R 12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-ealkyl, halo, hydroxy, Cι_4alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by (CH2)q-imidazolyl, (CH 2 ) q -triazolyl, 5-hy^roxy-4-pyrone, NR 6 R 7 , NR 9 COR ι:L , NR 9 CONR 9 'R I:L , CONR 6 R 7 , SϋfCx-galkyl) , S0 2 (C 1 __ 6 alkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(OH) 2 and (CH 2 )t C0 2 H ' where t is zero, 1 or 2; or R 12 represents a group and NR 4 R 5 represents a group wherein each R 16 independently represents Ci-galkyl, C C 11 __ 66 aallkkoo3xy, hydroxy, oxo, SR 11 , NR 6 R 7 , NR 9 C 1 _ alkylR 17 1 =NOR 9 or / ( C H 2, ) l d where R 11 , R 6 , R 7 and R 9 are as previously defined, R 17 is halo or trifluoromethyl, and d is 2 or 3; v is 1, 2, 3, 4, 5, 6, 7 or 8; and w is 4, 5, 6, 7, 8, 9, 10 or 11. Within the abovementioned subgroup of compounds according to the invention there may be identified a subclass of compounds of formula (I) , and salts and prodrugs thereof, wherein R 12 represents a phenyl group optionally substituted by one or more substituents selected from Cx-galkyl, halo, hydroxy, ^-4alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by C T ^alkyl, (CH 2 ) q -imidazolyl, (CH 2 )qtriazolyl, 5- hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR ι:L , NR 9 COR 9 'R 1:L , CONR 6 R 7 , SO Ci-βal yl) , S0 2 (Ci-ealkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(OH) 2 and (CH 2 )t C0 2 H ' or R 12 represents a group where W represents CH2 or NR 9 ; R 16 represents Ci-galkyl, Ci-galkoxy, hydroxy, oxo, SR 11 , NR 6 R 7 , NR 9 C 1 _ 4 alkylR 17 , =NOR 9 or OR 18 OR 19 , where R 18 and R 19 each independently represent C^_ 4 alkyl or R 18 and R 19 together form a chain CH2CH2 or CH 2 CH 2 CH2; and v is 1. A second subgroup of compounds according to the invention is represented by compounds of formula (I) , and salts and prodrugs thereof, wherein R 1 represents H, Ci-galkyl, C 3 -7cycloalkyl, cyclopropylmethyl, (CH ) r imidazolyl, (CH2) r triazol y 1 ' (CH2)r tetrazolvl , CH2CO2R 11 or CH 2 CONR 6 R 7 ; R 2 is NHR 12 where R 12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-galkyl, halo, hydroxy, Cι_4alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Cι_4alkyl, (CH2)q-imidazolyl, (CH ) q -triazolyl, 5-hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR 1:L , NR 9 CONR 9 'R I:L , CONR 6 R 7 , SO(C 1 _ 6 alkyl) , S0 2 (C 1 « 6 alkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHC0R 8 , S0 2 NHR 10 , B(0H) 2 and (CH2)qC02H; or R 12 represents a group and R 4 and R 5 together form the residue of a bridged azabicyclic ring system. Within the abovementioned second subgroup of compounds according to the invention there may be identified a subclass of compounds of formula (I) , and salts and prodrugs thereof, wherein R 1 represents Ci-g lkyl, C 3 _7cycloalkyl, cyclopropylmethyl, or CH2CONR 6 R 7 ; and R 12 represents a phenyl group optionally substituted by one or more substituents selected from C^-galkyl, halo, hydroxy, Cι_4 lko y, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Cι_ 4 alkyl, (CH2)q-imidazolyl, (CH2)qtriazolyl, 5- hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR 1:L , NR 9 COR 9 'R 11 , CONR 6 R 7 , SO(C 1 _ 6 alkyl) , S0 2 (Ci-ealkyl) , trifluoromethyl, C0NHSO 2 R > 8°, S0 2 NHCOR > 8°, S0 2 NHR 10 , B(0H) 2 and (CH 2 )tC0 2 H, where t is zero, 1 or 2; or R 12 represents a group where W represents CH2 or NR . A third subgroup of compounds according to the invention is represented by compounds of formula (I) , and salts and prodrugs thereof, wherein R 1 represents H, Ci-galkyl, C 3 _7cycloalkyl, cyclopropylmethyl, CH2CO2R 11 or CH2CONR 6 R 7 ; R 12 represents a phenyl group optionally substituted by one or more substituents selected from Cx-ealkyl, halo, hydroxy, (CH 2 )q-tetrazolyl optionally substituted in the tetrazole ring by C 1 _ alkyl, (CH 2 )q-imidazolyl, (CH 2 )q-triazolyl, 5- hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR ι:L , NR 9 CONR 9 'R 11 , CONR 6 R 7 , SO(C 1 _ 6 alkyl) , S0 2 (Ci-βalkyl) , trifluoromethyl, CONHS0 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(OH) 2 a nd (CH 2 ) q C0 2 H; or R 12 represents a group and R 4 and R 5 are independently selected from H, Cι_ i2 a l k Y 1 ' C _gcycloalkyl(CH2)]c optionally substituted by one or more groups, bridged C 6 _ιobicycloalkyl ■ (CH2)kR 20 (where R 20 is NR 6 R 7 as previously defined, or an azacyclic or azabicyclic group and k is 0, 1, 2, 3 or 4) , optionally substituted aryl, and optionally substituted arylCi-galkyl. Within this third subgroup of compounds according to the invention there may be identified a subclass of compounds of formula (I) , and salts and prodrugs thereof, wherein R 1 represents Ci-galkyl, C 3 _7cycloalkyl, cyclopropylmethyl, CH2CO2R 11 or CH2CONR 6 R 7 ; and R 12 represents a phenyl group optionally substituted by one or more substituents selected from Cι_ 6 alkyl, halo, hydroxy, C 1 _ 4 alkoxy, (CH 2 )q-tetrazolyl optionally substituted in the tetrazole ring by C ! __.4alkyl, (CH2)q-imidazolyl, (CH 2 )qtriazolyl, 5-hydroxy- 4-pyrone, NR 6 R 7 , NR 9 C0R i:L , NR 9 COR 9 'R 11 , CONR 6 R 7 , SO(C 1 _ 6 alkyl) , S0 (Cx-galkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHCOR 8 , S0 NHR 10 , B(0H) 2 n (CH 2 )tC0 2 H, where t is zero, 1 or 2; or R 12 represents a group where W represents CH2 or NR 9 ; and R 4 and R are independently selected from H, Cι-_i2alkyl, C _ 9 cycloalkyl, optionally substituted aryl, optionally substituted arylCi-galkyl, and azacyclic and azabicyclic groups. A fourth subgroup of compounds according to the invention is represented by compounds of formula (I) , and salts and prodrugs thereof, wher in R 1 represents Cι_ 6 alkyl, C 3 _7cycloal yl, cyclopropylmethyl, CH2CO2R 11 or CH2CONR 6 7 ; R 2 represents NHR 12 where R 12 represents phenyl substituted by a group and R 4 and R 5 each independently represents H, c l -12 allc y 1 , C4_9cycloalkyl, optionally substituted aryl, optionally substituted arylCι_galkyl or an azacyclic or azabicyclic group, or R 4 and R 5 together form the residue of an azacyclic or a bridged azabicyclic ring system. A fifth subgroup of compounds according to the invention is represented by compounds of formula (I) , and salts and prodrugs thereof, wherein R 1 represents H, Ci-galkyl, C 3 _7cycloalkyl, cyclopropylmethyl, (CH 2 ) r imidazolyl, (CH ) r triazoly1, (CH 2 ) r tetrazolyl, CH2CO2R 11 or CH2CON 6 R 7 ; R 2 represents NHR 12 where R 12 represents a pyridyl group optionally substituted by one or more substituents selected from Ci-galkyl, halo, hydroxy, C 1 _4alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by ^. 4 alkyl, (CH 2 )q-imidazolyl, (CH 2 )q-triazolyl, 5-hydroxy-4-pyrone, NR 6 R 7 , NR 9 C0R 1:L , NR 9 CONR 9 'R 1:L , CONR 6 R 7 , SO(C 1 -_ 6 alkyl) , S0 2 (C 1 _ 6 alkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(OH) 2 and (CH 2 )qC0 H; or R 12 represents a group and R 4 and R 5 each independently represents H, C*-L_*-L2alkyl, C4_ 9 cycloalkyl optionally substituted by one or more Cι_ 4 alkyl groups, C 4 _ 9 cycloal ylCι_ 4 alkyl, optionally substituted aryl, optionally substituted arylCi-galkyl or an azacyclic or azabicyclic group, or R 4 and R 5 together form the residue of an optionally substituted azacyclic or a bridged azabicyclic ring system. A sixth subgroup of compounds according to the invention is represented by compounds of formula (I) , and salts and prodrugs thereof, wherein R 1 represents H, Ci-gal yl, C 3 _7cycloalkyl, cyclopropylmethyl, ( CH2) r i miciazol y 1 , (CH2)r triazol y 1 ' (C H2 ) r tetrazol y 1 , CH2CO2R 11 or CH 2 CONR 6 R 7 ; R 2 represents (CH 2 ) S R 13 ; and R 4 and R 5 together form the residue of an azacyclic or azabicyclic ring system. A seventh subgroup of compounds according to the invention is represented by compounds of formula (I) , and salts and prodrugs thereof, wherein R 1 represents H, Ci-ealkyl, C 3 _ 7 cycloalkyl, cyclopropylmethyl, (CH 2 ) r imidazolyl, (CH 2 ) r triazolyl, (CH 2 )r tetr zol y 1 ' CH2CO2 11 or CH2CONR 6 R 7 ; R 2 is NHR 12 where R 12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-galkyl, halo, hydroxy, C 1 . alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by C 1 _ alkyl, (CH 2 )q-imidazolyl, (CH 2 ) q -triazolyl, 5-hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR lα -, NR 9 C0NR 9 'R 1:L , CONR 6 R 7 , SO Ci.gal yl) , S0 2 (C 1 _ 6 alkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(OH) 2 and (CH2)qC02H; or R 12 represents a group and R 4 and R 5 together form the residue of a fused or spiro azabicycic ring system. When R 1 is C 3 _7cycloalkyl, suitable cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl groups, preferably cyclopropyl. Preferably R 1 represents Ci-galkyl optionally substituted by one or more halo, such as optionally substituted by one, two or three fluoro. Preferred values for R 1 include methyl, ethyl, n-propyl, i-butyl and 2,2,2-trifluroethyl. When R 2 represents NHR 12 and R 12 represents phenyl or pyridyl substituted by CONHS0 2 R 8 or S0 2 NHCOR 8 , suitable values for R 8 include C*- L _ 6 alkyl, optionally substituted aryl and trifluoromethyl. When R 8 is optionally substituted aryl, this will preferably ' be optionally substituted phenyl. Suitable substituents include Cι_4alkyl, Cι_4alkoxy, halo and trifluoromethyl. Preferred is unsubstituted phenyl or phenyl substituted by Cι_galkyl, such as methyl, for example, phenyl substituted by Ci-gal yl in the ortho position. When R 8 is Ci-galkyl, it will preferably represent C 1 -^alkyl. Particularly preferred are methyl and iso-propyl, especially iso-propyl. When R 12 is phenyl or pyridyl substituted by S0 2 NHR 10 , suitable values of R 10 include, for example, thiazole, thiadiazole and pyrazine. Preferably q is zero. When R 2 represents NHR 12 , and R 12 represents optionally substituted phenyl or pyridyl, the substituents will preferably be selected from C^-galkyl, such as methyl and ethyl, halo, such as chloro, bromo, fluoro and iodo, and trifluoromethyl. When R 12 represents monosubstituted phenyl, the substituent will preferably be located at the 3- or 4- position of the phenyl ring, more preferably at the 3- posi •ti • on. When R ±* l Λ 7 represents disubstituted phenyl the substituents will preferably be located at the 3- and 4- positions of the phenyl ring. When R 12 represents optionally substituted pyridyl it will preferably represent optionally substituted 3-pyridyl. When R 12 represents monosubstituted 3-pyridyl, the substituent will preferably be located at the 5-position of the pyridyl ring. When R 12 represents a group where X 1 is CH the fused 5-membered ring will preferably be fused across the 3- and 4-positions of the phenyl ring and where X 1 is N the 5-membered ring will preferably be fused across the 4- and 5-positions of the phenyl ring. Preferably W and W 1 are CH2. When R 12 represents phenyl substituted by a group the substituent will preferably be located at the 3- or 4- position of the phenyl ring, more preferably at the 3- position. Preferably is 1 or 2 , more preferably 1. Preferably n is 1 or 2 , more preferably 1. Preferably y is 0 or l, more preferably 0. Suitable values for X 2 include 0, S, NH and NCH 3 . Preferably Z represents a bond. When R 2 represents (C^Js-R 13 * - s i s preferably 0 or 1, more preferably 0, R 14 is preferably H and R 15 is preferably H. The optional covalent bond may suitably be either present or absent, preferably present. Particularly preferred are compounds of formula (I) wherein R 2 represents NHR 12 and R 12 represents phenyl substituted by one or two substituents selected from Cx-ealkyl, halo and trifloromethyl; or R 12 represents Suitable values for R" 3 include methyl and dimethylamino. Preferably x is 0 or 1, more preferably 0. When R 4 or R 5 represents optionally substituted aryl or optionally substituted arylCi-galkyl, suitable aryl groups include phenyl, thienyl, furyl, pyrrolyl and pyridyl, preferably phenyl. Suitable aryl substituents include, for example, Cι_ 4 alkyl, Cι_ 4 alkoxy, halo and trifluoromethyl. When R 4 or R 5 represents an azacyclic or azabicyclic group, or C^-gal yl substituted by an azacyclic or azabicyclic group, the azacyclic or azabicyclic group may contain, in addition to the nitrogen atom, a further heteroatom selected from 0 and S, or a group NR 21 , where R 21 is H or Cι_ 4 alkyl. When R 4 or R represents an azacyclic group or Cι_galkyl substituted by an azacyclic group, the azacyclic group will suitably contain from 5 to 10 ring atoms. When R 4 or R 5 represents an azabicyclic group or Cι_galkyl substituted by an azabicyclic group, the azabicyclic group will suitably contain from 7 to 10 ring atoms. When R 4 or R 5 represents C4_ 9 cycloalkyl substituted by one or more Cι_4alkyl groups or C4_ 9 cycloalkylCι_4alkyl substituted in the cycloalkyl ring by one or more Cι_4alkyl groups, the Cι_4alkyl groups may be located on any available ring carbon atom. In particular, geminal disubstitution is provied for. The C 1 _ alkyl groups will preferably be methyl groups. Suitably R 4 and R 5 are selected from H, Cι_ 6 alkyl, such as methyl, ethyl and n-propyl, C4_ 9 cycloalkyl, such as cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, optionally substituted by one or more methyl groups, C4- 9 cycloalkylCι_ 4 alkyl, such as cyclohexylmethyl, arylCi-galkyl, such as benzyl, Ci-ealkyl substituted by NR 9 R 9 ' , such as CH 2 CH 2 N(CH3) 2 , Cι«galkyl substituted by an azacyclic group, such as Cι_4 lkyl substituted by morpholinyl, and azacyclic groups, such as N-methylpiperidine. When R 4 and R 5 together form the residue of an azacyclic or azabicyclic ring system, the azacyclic or azabicyclic ring system may contain, in addition to the nitrogen atom to which R 4 and R 5 are attached, a second heteroatom selected from O, S or a group NR 22 , where R 22 is H, Ci_ 4 alkyl, C0 2 R a , COR a or S0 2 R a where R a is Ci_ galkyl, optionally substituted phenyl or benzyl optionally substituted in the phenyl ring by one or more substituents, where the phenyl substituents are selected from Cι_4alkyl, Cι_4alkoxy, halo and trifluoromethyl. When R 4 and R 5 together form the residue of an azacyclic ring system, the ring system may be substituted by one or more groups selected from Ci-galkyl, Ci-galkoxy, hydroxy, halo, trifluoromethyl, oxo, SR 11 , NR 6 R 7 , NR 9 C 1 _ 4 alkylR 23 , =NOR 9 or where R 6 , R 7 , R 9 and R 11 are as previously defined, R 23 is halo or trifluoromethyl, and b is 2 or 3. The substituents may be located on any available carbon atom. In particular, geminal disubstitution is provided for where appropriate. Particularly suitable substituents include oxo, ketyl, Ci-galkyl, Ci-galko y, trifluoromethyl and NHCι_ 4 alkylCF 3 groups. Preferred are Ci-galkyl groups, especially methyl. When R 4 and R 5 form the residue of an azacyclic ring system, the ring system suitably contains from 5 to 10 ring atoms, preferably 6, 7 or 8 ring atoms, more preferably 7 ring atoms. When R 4 and R 5 together form the residue of an azabicyclic ring system, the azabicyclic ring system may be fused, spiro or bridged, preferably fused or bridged, more preferably bridged. The azabicyclic ring system may optionally be substituted by one or more Cι_4alkyl, such as methyl, groups. The alkyl substituents may be located on any available carbon atoms of the azabicyclic ring system. In particular, geminal disubstitution is provided for. Preferably the azabicyclic ring system is unsubstituted. Suitably the azabicyclic ring system contains from 7 to 10 ring atoms, preferably 7, 8 or 9 ring atoms. Particularly preferred are compounds of formula (I) wherein R 4 and R 5 together form the residue of an azacyclic ring system substituted by one or more methyl groups, or R 4 and R 5 together form the residue of a bridged azabicyclic ring system, especially 3- azabicyclo[3.2.2]nonan-3-yl. Preferably the salts of the compounds of formula (I) are pharmaceutically acceptable, but non- phar aceutically acceptable salts may be used for the preparation of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compounds of formula (I) include the conventional non-toxic salts or the quaternary ammonium salts of the compounds from formula (I) formed, e.g., from non-toxic inorganic or organic acids or bases. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, steric, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulphanilic, 2-acetoxy benzoic, fumaric, toluenesulphonic, methanesulphonic, ethane disulphonic, oxalic and isothionic. The salts of the present invention can be synthesized from the compound of formula (I) which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents. The present invention also encompasses a pharmaceutical composition comprising a compound of formula (I) , or a salt or prodrug thereof and a pharmaceutically acceptable carrier. The compounds of formula (I) and their salts and prodrugs, may be administered to animals, preferably to mammals, and most especially to a human subject either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical co postion, according to standard pharmaceutical practice. The compounds can be administered orally, parenterally, including by intravenous, intramuscular, intraperitoneal or subcutaneous administration, or topically. For oral use of an antagonist of CCK, according to this invention, the selected compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. For topical administration, a compound of formula (I) may be formulated as, for example, a suspension, lotion, cream or ointment. For topical administration, pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetraacetic acid, and the like. The compounds of formula (I) antagonise CCK and/or gastrin and are useful for the treatment and prevention of disorders including central nervous system disorders wherein CCK and/or gastrin may be involved. Examples of such disease states include gastrointestinal diseases, including gastrointestinal ulcers, such as peptic and duodenal ulcers, irritable bowel syndrome, gastroesophagenal reflux disease or excess pancreatic or gastrin secretion, acute pancreatitis, or motility disorders; central nervous system disorders, including central nervous system disorders caused by CCK interaction with dopamine, serotonin and other monoamine neurotransmitters, such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis or Gilles de la Tourette syndrome; depression such as depression resulting from organic disease, secondary to stress associated with personal loss, or idiopathic depression; schizophrenia; disorders of appetite regulatory systems; Zollinger-Ellison syndrome, antral and cell hyperplasia, or pain. The compounds of formula (I) are particularly useful in the treatment or prevention of neurological disorders involving anxiety disorders and panic disorders, wherein CCK and/or gastrin is involved. Examples of such disorders include panic disorders, anxiety disorders, panic syndrome, anticipatory anxiety, phobic anxiety, panic anxiety, chronic anxiety and endogenous anxiety. The compounds of formula (I) are also useful for directly inducing analgesia, opiate or non-opiate mediated, as well as anesthesia or loss of the sensation of pain. The compounds of formula (I) may further be useful for preventing or treating the withdrawal response produced by chronic treatment or abuse of drugs or alcohol. Such drugs include, but are not limited to benzodiazepines, cocaine, alcohol and nicotine. The compounds of formula (I) may further by useful in the treatment of stress and its relationship with drug abuse. The compounds of formula (I) may further be useful in the treatment of oncologic disorders wherein CCK may be involved. Examples of such oncologic disorders include small cell adenocarcino as and primary tumours of the central nervous system glial and neuronal cells. Examples of such adenocarcinomas and tumours include, but are not limited to, tumours of the lower oesophagus, stomach, intestine, colon and lung, including small cell lung carcinoma. The compounds of formula (I) may also be useful as neuroprotective agents, for example, in the treatment and/or prevention of neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntingdon's chorea, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Olivo-ponto-cerebellar atrophy, anoxia such as from drowning, spinal cord and head injury, and poisoning by neurotoxins, including environmental neurotoxins. The compounds of formula (I) may further be used to induce miosis for therapeutic purposes after certain types of examination and intraocular surgery. An example of intraocular surgery would include cateract surgery with implantation of an artificial lens. The CCK antagonist compounds of this invention can be used to prevent miosis occuring in association with iritis, ureitis and trauma. The present invention therefore provides a compound of formula (I) or a salt or prodrug thereof for use in the preparation of a medicament. The present invention also provides a compound of formula (I) for use in therapy. In a further or alternative embodiment the present invention provides a method for the treatment or prevention of a physiological disorder involving CCK and/or gastrin which method comprises administration to a patient in need thereof of a CCK and/or gastrin antagonising amount of a compound of formula (I) . When a compound according to formula (I) is used as an antagonist of CCK or gastrin in a human subject, the daily dosage will normally be determined by the prescibing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. However, in most instances, an effective daily dosage wll be in the range from about 0.005mg/kg to about lOOmg/kg of body weight, and preferably, of from 0.05mg/kg to about 50mg/kg, such as from about 0.5mg/kg to about 20mg/kg of body weight, administered in single or divided doses. In some cases, however, it may be necessary to use dosages outside these limits. For example, animal experiments have indicated that doses as low as lng may be effective. In effective treatment of panic syndrome, panic disorder, anxiety disorder and the like, preferably about 0.05 mg/kg to about 0.5 mg/kg of CCK antagonist may be administered orally (p.o.), administered in single or divided doses per day (b.i.d.). Other routes of administration are also suitable. For directly inducing analgesia, anaesthesia or loss of pain sensation, the effective dosage preferably ranges from about 100 ng/kg to about lmg/kg by systemic administration. Oral administration is an alternative route, as well as others. In the treatment or irritable bowel syndrome, preferably about 0.1 to 10 mg/kg of CCK antagonist is administered orally (p.o.), administered in single or divided doses per day (b.i.d.). Other routes of administration are also suitable. The use of a gastrin antagonist as a tumour palliative for gastrointestinal neoplasma with gastrin receptors, as a modulator of central nervous activity, treatment of Zollinger-Ellison syndrome, or in the treatment of peptic ulcer disease, an effective dosage of preferably about 0.1 to about 10 mg/kg administered one- to-four times daily is indicated. For use as neuroprotective agents the effective dosage preferably ranges from about 0.5mg/kg to about 20mg/kg. Because these compounds antagonise the function of CCK in animals, they may also be used as feed additives to increase the food intake of animals in daily dosage of preferably about 0.05mg/kg to about 50mg/kg of body weight. The compounds of formula (I) wherein R 2 is NHR 12 may be prepared by reaction of intermediates of formula (II) with compounds of formula (III) ( I I) ( I I I ) wherein R 1 , R 3 , R 4 , R 5 , R 12 and x are as defined for formula (I) above, one of R 30 and R 31 represents NH 2 and the other of R 30 and R 31 represents -N=C=0. The reaction is conveniently effected in a suitable organic solvent, such as an ether, for example, tetrahydrofura . The compounds of formula (I) wherein R 2 is (CH2) S R 13 may be prepared by reaction of intermediates of formula (II) wherein R 30 is NH 2 (hereinafter intermediates (IIA) ) with compounds of formula HOC(=0) (CH2) S R13 wherein s and R 13 are as previously defined, in the presence of a base and a coupling reagent. Suitable bases of use in the reaction include tertiary amines such as, for example, triethylamine. A preferred coupling agent for use in the reaction is l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (EDC) , preferably in the presence of l-hydroxybenzotriazole. The reaction is conveniently effected in a suitable organic solvent, such as, for example, dimethylformamide. Intermediates of formula (IIA) may be prepared from compounds of formula (IV) : ( IV) wherein R 1 , R 2 , R 3 , R 4 , R 5 and x are as defined for formula (I) above, by reduction, for example, by catalytic hydrogenation or reduction using a suitable metal under acidic conditions. Suitable hydrogenation catalysts include, for example, nobel metal catalysts, e.g. ruthenium, or rhodium which may be supported, for example, on carbon. The reaction is preferably conducted in a suitable organic solvent, such as an alcohol, for example, methanol, at elevated temperature, e.g. about 60'C. Suitable reduction methods using metals include, for example, the use of zinc and trifluoroacetic acid in a suitable solvent, such as acetic acid, preferably at elevated temperature, e.g. at about 40*C. Preferably, intermediates of formula (IIA) may be prepared from compounds of formula (V) (V) wherein R 1 , R 2 , R 3 , R 4 , R 5 and x are as defined for formula (I) and R 50 represents C1-.4alkyl, by reduction, for example, by catalytic hydrogenation. Suitable hydrogenation catalysts include, for example, nobel metal catalysts, such as palladium, which may be supported, for example, on carbon. The reaction is conveniently conducted in a suitable organic solvent, such as an alcohol, for example, methanol, suitably at ambient temperature. Intermediates of formula (II) wherein R 30 is -N=C=0 (hereinafter intermediates (IIB) ) may be prepared from amines of formula (IIA) by reaction with triphosgene in the presence of a base, such as a tertiary amine, for example, triethylamine. The reaction is conveniently effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran, suitably at low temperature, such as about O'C. Intermediates of formula (V) may be prepared from intermediates of formula (IV) by reaction with a compound of formula R 50 N=C=0, wherein R 50 is as previously defined. The reaction is conveniently effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran, suitably at elevated temperature, for example, about 6O'C. Intermediates of formula (IV) may be prepared from compounds of formula (VI) (VI ) wherein R 1 , R 2 , R 3 , R , R 5 and x are as defined for formula (I) , by reaction with isoamyl nitrite in the presence of a base. Suitable bases of use in the reaction include alkali metal alkoxides, such as potassium t-butoxide. Compounds of formula (VI) may be prepared from compounds of formula (VII) (VI I) wherein R 1 , R 3 and x are as defined for formula (I) and Hal represents halo, such as chloro, by reaction with an amine of formula HNR 4 R 5 . Compounds of formula (VII) may be prepared as described in Uinted Kingdom Patent Specification no. 1,145,471. Compounds of formula (III) wherein R 31 is -N=C=0 (IIIB) may be prepared from the corresponding compounds of formula (III) wherein R 31 is NH (IIIA) analogously to the preparation of compounds of formula (IIB) from compounds of formula (IIA) . Compounds of formula (IIIA) and H0C(=0) (CH2) S R 13 are commerically available or may be prepared from commerically available starting materials by known methods. Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers these isomers may, if desired, be separated, suitably by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-L- tartaric acid and/or (- )-di-p-toluoyl-D-tartaric acid followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, enantiomers of the novel compounds may be separated by HPLC using a chiral column. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The following non-limiting examples are provided to assist in a further understanding of the invention. EXAMP E 1 : N-r3ffi.5?)-2.3-Dihvdro-5-(1.4-dioxa-8-azaspiro r4.51decan-8-v1V2-oxo-l-propvl-lH-1.4-benzodiazepin-3-vl1 a) 5-(1.4-Dioxa-8-azaspiror4.51decan-8-vl1-2-oxo-l-propvl- 1.4-benzodiazepine To a solution of l-propyl-l,2,3,4-tetrahydro-3H- l,4-benzodiazepin-2,5-dione (13.5g) (prepared in the same way as described in Example 4a and b except using N-propylanthranilic acid methyl ester as starting material) in dichloromethane (250ml) was added phosphorus pentachloride (15.9g) in dichloromethane (100ml) over 30 min. The reaction mixture was stirred at room temperature for 2h then concentrated under high vacuum. The residue obtained was redissolved in dichloromethane (200ml), cooled to 0°C and l,4-dioxa-8-azaspiro[4.5]decane (24.2ml) in dichloromethane (100ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and left to stir for 14h, washed with saturated sodium carbonate solution (2 x 15ml), dried (MgS0 4 ), filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and filtered through a short plug of silica using 20% ethyl acetate in dichloromethane as eluant, then triturated with diethyl ether to give the required compound (18.2g). mp 142°C. 1H NMR (360MHz, D 6 -DMSO) δ 0.68 (3H, t, J=7.4Hz), 1.24 (IH, m), 1.38 (IH, m), 1.51 (2H, m), 1.72 (2H, m), 3.25 (4H, m), 3.35 (IH, d, J=11.4Hz), 3.55 (IH, m), 3.88 (4H, s), 3.94 (IH, d, J=11.4Hz), 4.20 (IH, m), 7.31 (IH, m), 7.54 (3H, m). MS (CI) m/e 344 [MH] + . b) 5-(1.4-Dioxa-8-azaspiror4.51decan-8-vlV3-oximido- 2-oxo-l-propvl-1.4-benzodiazepine The product from step a) (18g) was dissolved in dry toluene and cooled to -20°C under an atmosphere of nitrogen. Potassium tert-butoxide (16.3g) was added and after 20 min isoamyl nitrite (7.72ml) was added dropwise. The reaction mixture was stirred at -20°C for 14h then allowed to warm to room temperature and quenched with dilute hydrochloric acid to pH 7. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 200ml). The orgamc layers were combined, dried (MgS0 4 ), filtered and concentrated under vacuum. The residue was triturated with diethyl ether to give the required compound (5.27g). mp 197°C. 1H NMR (360MHz, D 6 -DMSO) δ 0.71 (3H, 2 x t, J=7.3Hz), 1.24-1.54 (6H, m), 3.04-3.80 (5H, m), 3.91 (4H, s), 4.23 (IH, m), 7.18-7.62 (4H, m), 9.95 and 10.17 (IH, 2 x s). MS (CD m/e 373 [MH] + . c) N-r3(i!gV2.3-Dihvdro-5-(1.4-dioxa-8-azaspiror4.51 decan-8-vlV2-oxo-l-propvl-lH-1.4-benzodiazepin-3-vll N -r3-methvlphenvl1 urea The product from step b) (1.5g) was dissolved in methanol (40ml) and 5% rhodium on carbon catalyst (1.5g) was added to the solution. The reaction mixture was heated at 60°C under 50 psi of hydrogen on a Parr apparatus for 6h then cooled, filtered and concentrated under vacuum. The residue was dissolved in dry dichloromethane (40ml) and -tolyl isocyanate (0.5ml) was added in one portion. The reaction mixture was stirred at room temperature for 2h then concentrated under vacuum. The residue was purified by chromatography on silica gel using 65% ethyl acetate in hexane as eluant to give the title compound (0.14g). mp 238-240°C. 1H NMR (360MHz, D 6 -DMSO) δ 0.70 (3H, t, J=7.5Hz), 1.26 (IH, m), 1.39 (IH, m), 1.54 (2H, m), 1.73 (2H, m), 2.21 (3H, s), 3.25 (4H, m), 3.64 (IH, m), 3.88 (4H, s), 4.23 (IH, m), 4.92 (IH, d, J=8.4Hz), 6.70 (IH, d, J=6.8Hz), 7.01-7.65 (8H, m), 8.82 (IH, s). MS (CD m/e 492 [MHf. Anal. Found C, 65.92; H, 6.61; N, 14.27. requires C, 65.97; H, 6.77; N, 14.25%. EXAMPLE 2: N.r3fftS)-2.3-Dihvdro-2-oxo-5-(4-oxopiperidin- l-vD-l-propyl-1H-1.4-benzodiazepm-3-vn H3-roethγlphenYl1 urea To a solution of the product from Example lc) (O.lg) in 1,4-dioxan (30ml) was added perchloric arid (3ml). The reaction mixture was stirred at room temperature for 14h then concentrated under high vacuum. The residue was partitioned between ethyl acetate (50ml) and saturated sodium hydrogen carbonate solution (30ml) then the organic layer was dried (Na 2 S0 4 ), filtered and concentrated under vacuum. The crude product was purified by chromatography on silica gel using 65% ethyl acetate in hexane as eluant to give the title compound (0.06g). mp 150-152°C. 1H NMR (360MHz, D 6 -DMSO) δ 0.70 (3H, t, J=7.3Hz), 1.27 (IH, m), 1.41 (IH, m), 2.22 (3H, s), 2.26 (2H, m), 2.49 (2H, m), 3.52 (4H, m), 3.64 (IH, m), 4.23 (IH, m), 4.97 (IH, d, J=8.4Hz), 6.71 (IH, d, J=7.2Hz), 7.10 (3H, m), 7.17 (IH, s), 7.42 (IH, m), 7.68 (3H, m), 8.83 (IH, s). MS (CD m e 448 [MH] + . Anal. Found C, 65.45; H, 6.49; N, 15.09. C 25 H 29 N 5 0 3 . 0.6H 2 O requires C, 65.51; H, 6.64; N, 15.28%. EXAMPLE 3: N-r3( r!,ςV2.3-Dihvdro-2-oxo-l-propv1-5-(4-π .l.l- trifluoroethylaminelpiperidin-l-vlVlH-1.4-benzodiazenin-3-vl] N'-r3-methvlphenvl1 urea The product from Example 2 (0.5g) was dissolved in methanol (50ml) with trifluoroethylamine hydrochloride (0.272g). Crushed 3A sieves (lOg) were added to the mixture, followed by sodium cyanoborohydride (0.087g). Methanolic hydrogen chloride was added dropwise until a pH of 5 was attained and stirring was continued at room temperature for 4 days. The reaction mixture was filtered and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and washed with saturated sodium hydrogen carbonate solution. The organic layer was dried (Na 2 S0 4 ), filtered and concentrated in vacuo. The solid obtained was recrystallised from ethyl acetate/hexane to give the title compound (0.16g). mp 209-210°C. 1H NMR (360MHz, D 6 -DMSO) δ 0.70 (3H, t, J=7.3Hz), 1.14-1.45 (4H, m), 1.73-1.85 (2H, m), 2.21 (3H, s), 2.35 (IH, m, disappears on D 2 0 shake), 2.65-2.83 (3H, m), 3.22 (2H, m), 3.60-3.67 (3H, m), 4.23 (IH, m), 4.92 (IH, d, J=8.4Hz), 6.70 (IH, d, J=6.8Hz), 6.99-7.12 (4H, m), 7.38 (IH, m), 7.54 (IH, d, J=7.6Hz), 7.64 (2H, m), 8.81 (IH, s). MS (CD m/e 531 [MHf. Anal. Found C, 61.48; H, 6.18; N, 15.82. C 27 H 33 F 3 0 2 requires C, 61.12; H, 6.27; N, 15.84%. EXAMPLE 4: N-r3ffl.SV2.3-Dihvdro-5-(4.4-dimethylpiperidin- l-yl)-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-yl1 N'-rindan-5-yl1 urea Intermediate 1: 4.4-Dimethvlpiperidine To a solution of lithium aluminium hydride in diethyl ether (430ml of a 1.0M solution) under nitrogen, at reflux, was added a suspension of 3,3-dimethylglutarimide (20g) in anhydrous diethyl ether (570ml), dropwise over a period of lh. The mixture was then heated at reflux for a further 8h then cooled to 0°C. Water (16ml) was added dropwise, followed by aqueous sodium hydroxide (16ml of a 4N solution) and water (48ml). The resultant solid was removed by filtration, the filtrate dried (Na 2 S0 4 ) and evaporated. The pale yellow oil was distilled under reduced pressure to afford the title piperidine (12.3g). bp 44°C/25mmHg. 1H NMR (360MHz, CDC1 3 ) δ 0.93 (6H, s), 1.29-1.32 (4H, m), 2.78-2.81 (4H, m). a) Methyl 2-(N-bromoacetyl-N-methylamino)benzoate A solution of bromoacetyl bromide (209g) in dichloromethane (200ml) was added dropwise to a cooled (ice bath) solution of methyl N-methylanthranilate (168g) in dichloromethane (1.41). A solution of sodium hydroxide (59g) in water (400ml) was added dropwise and the reaction mixture was stirred at room temperature for 20h. The organic phase was separated and washed with IM hydrochloric arid (500ml), brine (300ml), saturated sodium hydrogen carbonate solution (400ml), dried (Na 2 S0 4 ) then evaporated to afford the required product (255g). X H NMR (360MHz, CDC1 3 ) δ 3.23 (3H, s), 3.54 (IH, d, J=llHz), 3.60 (IH, d, J=llHz), 3.90 (3H, s), 7.40 (IH, d, J=8Hz), 7.51 (IH, dd, J j = J 2 = 8Hz), 7.65 (IH, dd, J t = J 2 = 8Hz), 8.04 (IH, d, J=8Hz). b) !-Me hyl-1.2.3.4-tetrahvdro-3H-1.4-beι vtia7^nin-2.5-(tione Ammonia gas was bubbled through an ice-cooled solution of methyl 2-(N-bιt)moacetyl-N-memylamino)benzoate (255g) in methanol (1600ml) until saturated. The cooling bath was removed and the reaction mixture left standing at room temperature for 18h. The precipitate was collected to afford the required product (79g). mp 190-193°C. 1H NMR (360MHz, CDClg) δ 3.42 (3H, s), 3.80 (2H, brs), 6.80 (IH, s), 7.24 (IH, d, J=8Hz), 7.32 (IH, dd, J x = J 2 = 8Hz), 7.57 (IH, dd, J x = J 2 = 8Hz), 7.90 (IH, d, J=8Hz). Found: C, 63.20; H, 5.25; N, 14.77. C 10 H 10 N 2 O 2 requires C, 63.15; H, 5.30; N, 14.73%. c) 1.2-Dihvdro-5-(4.4-dimethylpiperidin-l-yl)-l-methyl- 3H- 1.4-benzodiazepin-2-one To a solution of the product of part b) (10g) in anhydrous dichloromethane (700ml) was added phosphorus pentachloride (13.17g) in anhydrous dichloromethane (500ml) over a period of 30 min. The reaction mixture was stirred at ambient temperature for 2.5h. The solvent was evaporated in vacuo and the residue redissolved in anhydrous dichloromethane (400ml). After cooling to 0°C, a solution of 4,4-dimethylpiperidine (Intermediate 1) (5.95g) and triethylamine (18.3ml) in anhydrous dichloromethane (100ml) was added dropwise. The reaction mixture was allowed to warm to ambient temperature with stirring for 19h, washed with saturated potassium carbonate solution (500ml), water (200ml) and brine (150ml). The organic layer was dried (KgCOg) and treated with decolourising charcoal and silica gel. After filtering, the solvent was evaporated in vacuo. The residue was redissolved in dichloromethane (300ml) and extracted with citric arid solution (10%, 3 x 50ml). The combined aqueous layers were basified (4M NaOH solution) and extracted with dichloromethane (6 x 125ml). These organic extracts were combined, dried (K->C0 3 ) and evaporated in vacuo to give the title compound (7.5g). mp 143-145°C. l Η. NMR (360MHz, CDC1 3 ) δ 0.98 (6H, s), 1.26-1.36 (2H, m), 1.46-1.53 (2H, m), 3.13-3.32 (4H, m), 3.36 (3H, s), 3.50 (IH, d, J=12.0Hz), 4.24 (IH, d, J=12.0Hz), 7.21 (IH, t, J=8.3Hz), 7.27 (IH, d, J=8.3Hz), 7.46-7.53 (2H, m). MS (CD m/e 286 [MH] + . d) 1.2-Dihvdro-5-(4.4-dimethvlpiperidin-l-vl)-l-methvl- 3-oximido-3H-1.4-benzodiazepin-2-one A solution of the product of part c) (7g) in anhydrous toluene (200ml) was cooled to -20°C under an atmosphere of nitrogen, and potassium tert-butoxide (7.5g) was added portionwise over 5 min. After stirring at -20°C for 30 min, isopentyl nitrite (3.9ml) was added dropwise. The reaction mixture was stirred at -20°C for 5h 30 min and then allowed to warm to ambient temperature. The mixture was poured onto a rapidly stirred mixture of ethyl acetate (300ml) and water (50ml) containing citric arid (4.68g), stirred vigorously for 5 min and then neutralised to pH 7 using saturated potassium carbonate solution. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 x 100ml). The combined organic phases were dried (Na 2 S0 4 ) and evaporated in vacuo to give an orange solid. This was triturated with diethyl ether to give the title compound (6.92g). mp 215°C (dec). 1H NMR (360MHz, D 6 -DMSO) δ 0.97 (6H, s), 1.23-1.36 (2H, m), 1.40-1.50 (2H, m), 3.22-3.50 (7H, m), 7.26-7.32 (IH, m), 7.44 (IH, d, J=7.9Hz), 7.48-7.60 (2H, m), 10.10 (IH, brs). MS (CD m/e 315 [MH] + . e) 1.2-Dihvdro-5-(4.4-dimethvlpiperidin-l-vl)-l-methvl-3- (0-ethvlam ocarbonv oximido-3H-1.4-benzodiazepin-2-one To a suspension of the product of part d) (3.64g) in anhydrous tetrahydrofuran (60ml) was added triethylamine (1.6ml) followed by ethyl isocyanate (1.4ml) dropwise. This mixture was heated at 60°C under an atmosphere of nitrogen for 3h. The solvent was evaporated in vacuo and the residue chromatographed on silica gel using a gradient of 0% to 3% methanol in dichloromethane as eluant to give the title compound (4.5g). 1H. NMR (360MHz, CDC1 3 ) δ 1.02 (6H, brs), 1.13 (3H, t, J=7.3Hz), 1.20-1.84 (4H, m), 3.20-3.30 (3H, m), 3.35-3.42 (4H, m), 3.60-3.78 (IH, m), 3.80-4.00 (IH, m), 6.36-6.42 (IH, m), 7.20-7.35 (3H, m), 7.46-7.52 (IH, m). MS (CD m/e 386 [MHT. f) N 3(*R.g)-g,3 ihγdrQ-5-(4,4'di ethγ ipgri in-l-γD- 1- mgthγl-g- ??o-lH-l,4-bepsodia*ggpin-3-yϊl N'-findan-S-yll urea To a solution of the product of part e) (4.5g) in methanol (250ml) was added 10% palladium on carbon (lg). The mixture was hydrogenated at 40 psi for 3h and then the catalyst was filtered off and washed with methanol. The solvent was evaporated in vacuo to give the amine (3.5g) which was used without further purification. To a solution of 5-aminoindane (2.32g) in anhydrous tetrahydrofuran (150ml) cooled to 0°C under an atmosphere of nitrogen was added triphosgene (1.72g) in one portion. Triethylamine (7.2ml) was added dropwise. After stirring at 0°C for 30 min a solution of the amine (3.5g) in anhydrous tetrahydrofuran (20ml) was added dropwise. The mixture was stirred at 0°C for 5 min and then was allowed to warm to ambient temperature and stirred for 10 min. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (150ml) and water (75ml). The undissolved solid was collected by filtration to afford the title product (3.17g). mp 132°C (dec). 1H NMR (360MHz, CDC1 3 ) δ 0.96 (6H, s), 1.30-1.39 (2H, m), 1.44-1.56 (2H, m), 2.04 (2H, quin, J=7.4Hz), 2.84 (4H, q, J=7.0Hz), 3.16-3.26 (2H, m), 3.28-3.38 (2H, m), 3.42 (3H, s), 5.32 (IH, d, J=8.0Hz), 6.59-6.66 (IH, m), 6.95-7.13 (3H, m), 7.24-7.36 (3H, m), 7.51-7.58 (2H, m). MS (CD m/e 460 [MH] + . Anal. Found C, 67.85; H, 7.11; N, 14.60. C 27 H 33 N ε 0 2 .H 2 0 requires C, 67.90; H, 7.39; N, 14.66%. An alternative procedure can be used for preparation of N-[3(_R,_S)-2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-l-methyl-2- oxo-lH-l,4-benzodiazepin-3-yl] N'-indan-5-yl] urea: Step 1: Indan-5-vl isocvanate To a solution of 5-aminoindane (25g) in anhydrous diethyl ether (1250ml), under an atmosphere of nitrogen, at 0°C was added triphosgene (18.3g). The mixture was stirred at 0°C for 2 min then triethylamine (64.7ml) was added until pH8. The mixture was stirred at 0°C for 10 min then at 10°C for 10 min. The undissolved solids were filtered off and the filtrate evaporated in vacuo. The residue was distilled at 100°C/lmbar to afford the title compound (20g). 1H NMR (360MHz, CDC1 3 ) δ 2.07 (2H, quin, J=7.5Hz), 2.86 (4H, m), 6.84 (IH, dd, J=7.9 and 2.0Hz), 6.94 (IH, s), 7.13 (IH, d, J=7.9Hz). Step 2: N-r3(fl.S)-2.3-Dihvdro-5-(4.4-dimethylpiperidin-l- vI)-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-yl1N'-fιndan-5-yl1 urea To a solution of l,2-dihydro-5-(4,4-dimethylpiperidin-l-yl)- l-methyl-3-(0-ethylaminocarbonyl)oximido-3H-l,4- benzodiazepin-2-one (10.3g) in methanol (400ml) was added 10% palladium on carbon (2.24g, 21% (w/w)). The mixture was hydrogenated at 40 psi for 4h then the catalyst was filtered off and washed with methanol. The solvent was evaporated in vacuo to give the crude amine (8.3g). To a stirred solution of the crude amine (8.3g) in anhydrous diethyl ether (50ml) under an atmosphere of nitrogen, at room temperature, was added a solution of indan-5-yl isocyanate (4.2g) in anhydrous diethyl ether (7ml). After stirring at room temperature for 10 min the title compound (8.9g) was collected by filtration. EXAMPLE R: Chiral Separation of N-r3(fl.S)-2.3-dihvdro-5-(4.4- dimethvlpiperidin-l-vl)-l-methvl-2-oxo-lH-1.4-benzodiazepin-3- yll N'-rindan-5-yll urea N-[3(β,S)-2,3-Dmydro-5-(4,4-dimethylpiperidin-l-yl)-l- methyl-2-oxo-lH-l,4-benzodiazepm-3-yl] N'-[indan-5-yl] urea (0.17g) was dissolved in 1:1 chloroform:methanol (4ml). 440μl of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., 5μm) per run using 95:5:1 l-chlorobutane:methanol:acetic acid as the mobile phase. Using a flow rate of 20ml/min and UV detection at 330nm, the two enantiomers were efficiently separated. The fractions containing each separate enantiomer were combined and evaporated in vacuo. Separately each enantiomer was partitioned between ethyl acetate (25ml) and potassium carbonate solution (0.5M, 10ml). The organic phases were dried (Na 2 S0 4 ) and evaporated in vacuo. The residues obtained were redissolved in dichloromethane and saturated ethereal hydrogen chloride (~ 2ml) was added. The solvents were evaporated in vacuo and the residues obtained were triturated with diethyl ether and the resulting solids collected by filtration to give: Peak A (69mg). mp 180°C (dec). 1H NMR (360MHz, D 6 -DMSO) δ 0.92-1.06 (6H, m), 1.22-1.62 (4H, m), 1.97 (2H, quin, J=7.3Hz), 2.77 (4H, q, J=7.3Hz), 3.23-3.70 (7H, m), 5.30-5.38 (IH, m), 7.05-7.13 (2H, m), 7.29 (2H, brs), 7.56 (IH, t, J=7.5Hz), 7.71 (IH, d, J=8.2Hz), 7.83-7.92 (2H, m), 9.93 (IH, brs), 10.56 (IH, brs). MS (CD m/e 460 [MH] + . Anal. Found C, 61.67; H, 6.81; N, 13.67. C 27 H 33 N 5 0 2 .HC1.1.5(H 2 0) requires C, 62.00; H, 7.13; N, 13.39%. [α] 2 ^ -241.1° (c=0.54, MeOH). Purity A:B s > 99.5:0.5. Peak B (67mg). mp 180°C (dec). 1H NMR (360MHz, D 6 -DMSO) δ 0.92-1.06 (6H, m), 1.22-1.62 (4H, m), 1.97 (2H, quin, J=7.3Hz), 2.77 (4H, q, J=7.3Hz), 3.23-3.70 (7H, m), 5.30-5.38 (IH, m), 7.05-7.13 (2H, m), 7.28 (2H, brs), 7.56 (IH, t, J*=7.5Hz), 7.71 (IH, d, J=8.2Hz), 7.83-7.92 (2H, m), 9.33 (IH, brs), 10.46 (IH, brs). MS (CD m/e 460 [MH] + . Anal. Found C, Purity A:B = 1.7:98.3. EXAMPLE β- N-r3(fi., )-2.3-Dibvdro- -(^.< ? -2.β-dimethvl- piperidin-l-yl)-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-vll N -r3-methvlphenvn urea a) 1.2-Dihvdro-5-(cis-2.6-dimethvlpiperidin-l-vl)-l- methvl-3-oximido-3H-1.4-benzodiazepin-2-one Prepared as in Example 4, steps c) and d), from 1-methyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (5g) and cis- 2,6-dimethylpiperidine (3.5ml). mp 240°C (dec). X H NMR (360MHz, D 6 -DMSO) δ 0.85-0.96 (3H, m), 1.20-1.92 (9H, m), 3.31 (3H, s), 3.97-4.09 (IH, m), 4.36-4.56 (IH, m), 7.25-7.34 (IH, m), 7.40 (IH, d, J=7.7Hz), 7.49-7.60 (2H, m), 9.88-10.16 (IH, m). MS (CD m e 315 [MH] + . b) N-r3(_R._gV2.3-Dihvdro-5-( s-2.6-dimethylpiperidin-l- vIVl-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn 3- methylphenyll urea To a suspension of the product of part a) (1.5g) in methanol (150ml) was added 5% rhodium on carbon (1.5g, 100% (w/w)). The mixture was hydrogenated at 40 psi at 60°C for 6h 30min and, after cooling, the catalyst was filtered off and washed with methanol. The solvent was evaporated in vacuo to give the amine (1.43g). The amine was redissolved in anhydrous tetrahydrofuran (20ml) and cooled to 0°C under an atmosphere of nitrogen. -Tolyl isocyanate (0.62ml) was added dropwise. After stirring for 10 min the mixture was left standing in the fridge overnight. The reaction mixture was evaporated in vacuo and the residue partitioned between ethyl acetate (50ml) and water (30ml). The aqueous layer was separated and extracted with ethyl acetate (25ml). The combined organic phases were dried (Na 2 S0 4 ) and evaporated in vacuo. The residue was chromatographed on silica gel using a gradient of 0% to 50% ethyl acetate in dichloromethane as the eluant to afford a gum. This was further purified by chromatographing on silica gel using 20% ethyl acetate in dichloromethane as the eluant to afford a solid. This was triturated with diethyl ether to give the title compound (0.32g). mp 248°C (dec). 1H NMR (360MHz, CDC1 3 ) δ 0.88-1.03 (3H, m), 1.33 (3H, d, J=6.9Hz), 1.42-1.90 (6H, m), 2.28 (3H, s), 3.42 (3H, s), 3.90-4.32 (2H, m), 5.27 (IH, d, J=8.0Hz), 6.42-6.50 (IH, m), 6.81 (IH, d, J=7.0Hz), 6.91 (IH, brs), 7.06-7.16 (2H, m), 7.21-7.28 (2H, m), 7.32 (IH, d, J=7.8Hz), 7.42-7.52 (2H, m). MS (CD m e 434 [MH] + . Anal. Found C, 68.07; H, 7.12; N, 15.98. C 23 H 31 N 5 O 2 .0.35(H 2 O) requires C, 68.27; H, 7.26; N, 15.92%. EXAMPLE 7: N-r3(R.SV2.3-Dihvdro-l-methv1-5-(4- methvlpiperidin-l-vD-2-oxo-lH-1.4-benzodiazepin-3-vn N 3-methvlphenvll urea a) 1.2-Dihvdro-l-methvl-5-(4-methvlpiperidin-l-vD-3- QxmridQ-3*ff-l,4-bensQdiagepjn-2-ope Prepared as in Example 4, steps c) and d) from 1-methyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (5g) and 4- methylpiperidine (10.9ml). mp 225-228°C. 1H NMR (360MHz, D 6 -DMSO) δ 0.90-1.15 (4H, m), 1.20-1.36 (IH, m), 1.54-1.76 (3H, m), 2.77-3.01 (2H, m), 3.26 (3H, s), 3.69-4.24 (2H, m), 7.24-7.32 (1H, m), 7.38-7.43 (IH, m), 7.46-7.58 (2H, m), 9.93 and 10.16 (IH, 2 x s). MS (CD m/e 301 [MH] + . b) N-r3fR- ?)-2.3-Dihvdro-1 -methv1-5-(4- methvlpiperidin-l-vD-2-oxo-lH-1.4-benzodiazepin-3-vn N'-r3-methvlphenvll urea In the same way as in Example 6b) from 1,2-dihydro- l-methyl-5-(4-methylpiperidin- l-yl)-3-oximido-3H- l,4-benzodiazepin-2-one (0.6g), the amine (0.57g) was obtained. The title compound was then prepared from the crude amine and m-tolyl isocyanate (0.26ml) as described in Example 6b) and recrystallised from methanol. mp 142°C (dec). 1H NMR (360MHz, CDC1 3 ) δ 0.95 (3H, d, J*=6.3Hz), 1.06-1.19 (IH, m), 1.24-1.36 (IH, m), 1.46-1.60 (2H, m), 1.65-1.76 (IH, m), 2.28 (3H, s), 2.62-2.82 (2H, m), 3.41 (3H, s), 3.48-3.58 (IH, m), 3.90-3.98 (IH, m), 5.28 (IH, d, J=8.6Hz), 6.54 (IH, d, J=7.9Hz), 6.82 (IH, d, J=7.3Hz), 6.95 (IH, s), 7.04-7.16 (2H, m), 7.21-7.32 (3H, m), 7.45-7.56 (2H, m). MS (CD m/e 420 [MH]\ Anal. Found C, 65.09; H, 6.79; N, 15.94. C 24 H 29 N 5 0 2 .1.25(H 2 0) requires C, 65.21; H, 7.18; N, 15.84%. EXAMPLE fi; Chiral separation of N-r3(fl.g)-2,3-dihγdro- l-methvl-5-(4-methvlpiperidin-l-vl)-2-oxo-lH-1.4-benzodiazepin- 3-yll N'-r3-methylphenyll urea N-[3(_R,S)-2,3-Dihydro-l-methyl-5-(4-methylpiperidin-l-yl) -2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea (0.6g) was dissolved in 1:24 methano dichloromethane (6ml). The enantiomers were separated as described in Example 5. Peak A (250mg). mp 178°C (dec). 1H NMR (360MHz, CDC1 3 ) δ 0.96-1.08 (3H, m), 1.30-1.44 and 1.64-1.86 (4H, 2 x m), 1.95-2.06 (IH, m), 2.28 (3H, s), 3.14-3.60 (5H, m), 3.62-3.76 (IH, m), 4.32-4.42 and 4.64-4.70 (IH, 2 x m), 5.67-5.76 (IH, m), 6.80 (IH, d, J=7.4Hz), 7.11 (IH, t, J=7.8Hz), 7.16-7.34 (3H, m), 7.38-7.64 (3H, m), 7.72-7.82 (IH, m) 8.07 and 8.50 (IH, 2 x brs), 11.85 and 11.96 (IH, 2 x brs). MS (C m/e 420 [MH] + . [α] 23 D -247.7° (c=0.50, MeOH). Purity A:B = > 99.5:0.5. Peak B (270mg). mp 180°C (dec). l H NMR (360MHz, CDC1 3 ) δ 0.96-1.08 (3H, m), 1.30-1.44 and 1.64-1.86 (4H, 2 x m), 1.95-2.06 (IH, m), 2.28 (3H, s), 3.14-3.60 (5H, m), 3.62-3.76 {IH, m), 4.32-4.42 and 4.64-4.70 (IH, 2 x m), 5.67-5.76 (IH, ), 6.80 (IH, d, J=7.4Hz), 7.11 (IH, t, J=7.8Hz), 7.16-7.34 (3H, ), 7.38-7.64 (3H, m), 7.72-7.82 (IH, ), 8.07 and 8.50 (IH, 2 x brs), 11.85 and 11.96 (IH, 2 x brs). MS (CD m/e 420 [MH] + . [ O +244.3° (c=0.50, MeOH). Purity A:B = 2.3:97.7. EXAMPLE 9: N-r3(RS 2.3-Dihvdro-5-(4.4-dimethvlpiperidin- l-vl)-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1 '-r3-metfrγlpheιyyπ urea The amine was prepared as in Example 6b), from l,2-dihydro-5-(4,4-dimethylpiperidin- 1-yD- l-methyl-3-oxinιido- 3H-l,4-benzodiazepin-2-one (7.5g). The title compound was prepared from the crude amine and m-tolyl isocyanate (3.1ml) as described in Example 6b). mp 135°C (dec). 1H NMR (360MHz, CDC1 3 ) δ 0.95 (6H, s), 1.28-1.38 (2H, m), 1.44-1.51 (2H, m), 2.26 (3H, s), 3.15-3.24 (2H, m), 3.26-3.39 (2H, m), 3.43 (3H, s), 5.33 (IH, d, J=8.0Hz), 6.65-6.72 (IH, m), 6.82 (IH, d, J=7.0Hz), 7.06-7.19 (3H, m), 7.22-7.35 (3H, m), 7.50-7.57 (2H, m). MS (CD m/e 434 [MH] + . Anal. Found C, 66.76; H, 7.03; N, 15.60. C--B 31 l<i s O 2 .0.9(Ii 2 O) requires C, 66.76; H, 7.03; N, 15.57%. EXAMPLE 10: Chiral Separation of N-r3(_R.S)-2.3-dihvdro- 5-(4.4-dimethvlpiperidin-l-vl)-l-methvl-2-oxo-lH-1.4-benzodiaze pin-3- yll N'-r3-methylphenvH urea N-[3(i2,S)-2,3-Dihydro-5-(4,4-dimethylpiperidin-l-yl)-l- methyl-2-oxo- IH- 1 ,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea (0.27g) was dissolved in 2:3 methanoLdichloromethane (5ml). The enantiomers were separated as described in Example 5. Peak A (103mg). mp 170°C (dec). 1H NMR (360MHz, D 6 -DMSO) δ 0.92-1.07 (6H, m), 1.27-1.40 (IH, m), 1.49-1.65 (3H, m), 2.23 (3H, s), 3.30-3.77 (7H, m), 5.30-5.38 (IH, m), 6.76 (IH, d, J=7.3Hz), 7.08-7.19 (2H, m), 7.23 (IH, s), 7.32-7.39 (IH, m), 7.56 (IH, t, J=7.6Hz), 7.71 (IH, d, J=8.1Hz), 7.82-7.92 (2H, ), 9.50 (IH, brs), 10.57 (IH, brs). MS (CD m/e 434 [MH] + . Anal. Found C, 62.00; H, 7.09; N, 14.11. C 25 H 31 N B O 2 ΗCr0.8(H 2 O) requires C, 61.99; H, 6.99; N, 14.46%. [α] 22 D -264.9° (c=0.61, MeOH). Purity A:B = > 99.5:0.5. Peak B (89mg). mp 172°C (dec). 1H NMR (360MHz, D 6 -DMSO) δ 0.92-1.05 (6H, m), 1.25-1.40 (IH, m), 1.45-1.65 (3H, m), 2.23 (3H, s), 3.16-3.76 (7H, m), 5.26-5.37 (IH, m), 6.76 (IH, d, J=7.2Hz), 7.06-7.36 (4H, m), 7.50-7.60 (IH, m), 7.67-7.74 (IH, m), 7.78-7.94 (2H, m), 9.40 (IH, brs), 10.46 (IH, brs). MS (CD m/e 434 [MH] + . Anal. Found C, 61.83; H, 7.07; N, 14.03. C, 61.53; H, 7.02; N, 14.35%. Purity A:B = 3.0:97.0. EXAMPLE 11 : N-r3fRS 2.3-Dihvdro-5-(4-methoxvpiperidin- l-vD-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn r-r3-roethylphenγl1 urea a) 1.2-Dihvdro-5-(4-methoxvpiperidin-l-vD-3H- l-methvl-1.4-benzodiazepin-2-one Prepared as described in Example 4c), from l-methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (4.5g) and 4-methoxypiperidine hydrochloride (3.6g). H NMR (360MHz, CDC1 3 ) δ 1.43-1.86 (3H, m), 1.98-2.08 (IH, m), 2.91-3.18 (2H, m), 3.33-3.60 (9H, m), 3.63-3.75 (IH, m), 4.25-4.31 (IH, m), 7.20-7.32 (2H, m), 7.47-7.53 (2H, m). MS (CD m/e 288 [MHT. b) 1.2-Dihvdro-5-(4-methnxvpiperidin-l-vlVl-methvl-3- oximido-3H-1.4-henzodiazepin-2-one Prepared as Example 4d), from 1,2-dihydro- 5-(4-methoxypiperidin-l-yl)-methyl-3H-l,4-benzodiazepin-2-one (2.3g) mp 176°C (dec). 1H NMR (360MHz, Dβ-DMSO) δ 1.29-1.50 (IH, m), 1.53-1.65 (IH, m) 1.76-1.88 (IH, m), 1.90-2.04 (IH, m), 3.05-3.95 (11H, m), 7.25-7.32 (IH, m), 7.41-7.63 (3H, m), 9.97 and 10.21 (IH, 2 x brs). MS (CD m/e 317 [MH] + . c) N-r3fB.g)-2.3-Dihvdro-5-(4-methoxvpiperidin-l-vD- V et γl-g-o??Q-lH-l,4-ben2odiazepi^-θ-γIl N -r3-πιethylphenyl1 urea By the method of Example 6b), from 1,2- dihydro-5-(4-methoxypiperidin-l-yl)-l-methyl-3-oximido-3H-l,4- benzodiazepin-2-one (1.4g) was obtained the amine. The title compound was prepared from the crude amine and m-tolyl isocyanate (0.57ml) as described in Example 6b). mp 145-148°C. NMR (360MHz, CDC1 3 ), δ 1.45-1.58 (IH, m), 1.60-1.72 (IH, m), 1.74-1.80 (IH, m), 1.92-2.05 (IH, m), 2.28 (3H, s), 2.97-3.10 (2H, m), 3.30-3.55 (8H, m), 3.64-3.78 (IH, m), 5.33 (IH, d, J=8.0Hz), 6.65-6.75 (IH, m), 6.82 (IH, d, J=6.7Hz), 7.03-7.36 (6H, m), 7.49-7.58 (2H, m). MS (CD m/e 436 [MH] + . Anal. Found C, 62.94; H, 6.63; N, 15.40. requires C, 62.93; N, 6.93; N, 15.29%. EXAMPLE 12: (- N-r2.3-Dihvdro-l-methyl-5-(4- methvlpjperidin-l-vlV2-oxo-lH-1.4-benzodiazepin-3-vll ϊ£ rindan-5-vll urea hydrochloride The amine was prepared by the method of Example 6b), using l,2-dihydro-l-methyl-5-(4-methylpiperidin-l-yl)-3- oximido-3H-l,4-benzodiazepin-2-one (5.7g). To a solution of 5-aminoindane (2.53g) in anhydrous tetrahydrofuran (120ml), cooled to 0°C under an atmosphere of nitrogen, was added triphosgene (1.88g) in one portion. Triethylamine (5.3ml) was added dropwise. After stirring at 0°C for 20 min, a solution of the amine (5.4g) in anydrous tetrahydrofuran (20ml) was added dropwise. The mixture was stirred at 0°C for 10 min and then left to stand in the fridge overnight. The reaction mixture was evaporated in vacuo and the residue partitioned between ethyl acetate (100ml) and water (50ml). The aqueous layer was separated and extracted with ethyl acetate (50ml). The combined organic phases were dried (Na 2 S0 4 ) and evaporated in vacuo. The residue was triturated with dichloromethane to give N-[3(i2,S)-2,3-dihydro-l-methyl-5-(4-methylpiperidin-l-yl)- 2-oxo- lH-l,4-benzodiazepin-3-yl] N'-[indan-5-yl] urea (2.44g). The title compound was separated following the procedure of Example 5. mp 185°C (dec). Η NMR (360MHz, D e -DMSO) δ 0.87-1.04 (3H, m), 1.20-1.88 (5H, m), 1.97 (2H, quin, J=7.4Hz), 2.77 (4H, q, J=7.3Hz), 3.08-3.62 (6H, m), 3.87-4.20 (IH, m), 5.26-5.38 (IH, m), 7.02-7.11 (2H, m), 7.20-7.33 (2H, m), 7.50-7.58 (IH, m), 7.65-7.72 (IH, m), 7.75-7.93 (2H, m), 9.40 (IH, brs), 10.52 (IH, brs). MS (CD m/e 446 [MH] + . Anal. Found C, 62.51; H, 6.93; N, 13.91. C 26 H 31 N 5 0 2 ΗC1Η 2 0 requires C, 62.45; H, 6.85; N, 14.01%. [αF D -245.4° (c=0.62, MeOH). Purity A:B = 99.0:1.0. EXAMPLE 13: N-r3(fl,g)-g,3-Pihγdro-5-(«g-2,6- dimethvlpiperidin-l-vlVl-methvl-2-oxo-lH-1.4-benzodiazepin-3- yll N -lϊndan-5-γll wea a) 1.2-Dihvdro-5-(cig-2.6-dimethvlpiperidin-l-vl)-l-methvl- 3-(0-ethylaminocarbonv oximido-3H-1.4-benzodiazepin-2-one Prepared as described in Example 4e), from l,2-d ydro-5-(cis-2,6-dimethylpiperidin-l-yl l-methyl-3-oxirmdo- 3H-l,4-benzodiazepin-2-one (l.lδg) and ethyl isocyanate (0.43ml). Η NMR (360MHz, CDC1 3 ) δ 1.01 (3H, d, J=7.1Hz), 1.12 (3H, t, J=7.2Hz), 1.36 (3H, d, J=7.0Hz), 1.37-1.94 (6H, m), 3.20-3.31 (2H, m), 3.44 and 3.46 (3H, 2 x s), 4.14-4.23 (IH, m), 4.58-4.67 and 4.72-4.80 (IH, 2 x m), 6.12-6.19 and 6.38-6.46 (IH, 2 x m), 7.20-7.38 (3H, m), 7.43-7.50 (IH, m). MS (CD m/e 386 (MH) + . b) N-r3(J?.S)-2.3-Dihvdro-5-( i.< ; -2.β-dimethvlpiperidin- l-ylVl-methyl-2-oxo-lH-1.4-benzodiazepin-3-vn N'-lmdan-S-vll urea The amine was prepared as in Example 4 f), from l,2-dmydro-5-(cis-2,6-dimethylpiperidin-l-yl)-l-methyl-3- (0-ethylanήnocarbonyl)oximido-3H-l,4-benzodiazepin-2-one (1.41g). The title compound was then prepared from the crude amine (l.lg) and 5-aminoindane (0.73g) as described in Example 4f). mp 240°C (dec). Η NMR (360MHz, CDC1 3 ) δ 0.84-0.94 (3H, m), 1.2δ (3H, d, J=6.8Hz), 1.40-1.84 (6H, m), 1.96 (2H, quin, J=7.4Hz), 2.75 (4H, q, J*=7.0Hz), 3.33 (3H, s), 3.80-4.14 (2H, m), 4.93 (IH, d, J=8.6Hz), 6.88 (IH, d, J=8.5Hz), 7.03 (2H, s), 7.29 (IH, s), 7.33-7.39 (IH, m), 7.48 (IH, d, J=8.0Hz), 7.54-7.64 (2H, m), 8.74 (IH, s). MS (CD m/e 460 [MH] + . Anal. Found C, 69.83; H, 7.15; N, 14.82. C--ll∞N-0 2 .Q.25(lϊ~0) requires C, 69.88; H, 7.28; N, 15.09%. EXAMPLE 14: Chiral Separation of N-r3(fl.S)-2.3-dihvdro-5- (4-methoxvpiperidin-l-vl)-l-methvl-2-oxo-lH-1.4-benzodiazepin- 3-vll N--r3-methvlphenvn urea. N-[3(.R,S)-2,3-Dihydro-5-(4-methoxypiperidin-l- yl)-l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea (Example 11) (0.32g) was dissolved in 4:1 chloroform:methanol (4ml). The enantiomers were separated as described in Example 5. Peak A (135mg). mp 165°C (dec). Η NMR (360MHz, D 6 -DMSO) δ 1.42-1.60 (IH, m), 1.63-1.87 (2H, m), 1.94-2.08 (IH, m), 2.23 (3H, s), 3.14-3.86 (11H, m), 5.26-5.38 (IH, m), 6.76 (IH, d, J=7.0Hz), 7.08-7.17 (2H, m), 7.22 (IH, brs), 7.28-7.38 (IH, m), 7.60-7.59 (IH, m), 7.70 (IH, d, J=8.5Hz), 7.78-7.83 (IH, m), 9.39 (IH, brs), 10.54 (IH, brs). MS (CD m/e 436 [MH] + . [αr 25 D )- ' 265.2° (c=0.16, MeOH). Purity A:B = > 99.5:0.5 Peak B (125mg). mp 165°C (dec). Η NMR (360MHz, D 6 -DMSO) δ 1.42 -1.60 (IH, m), 1.63-1.87 (2H, m), 1.94-2.08 (IH, m), 2.23 (3H, s), 3.14-3.86 (11H, m), 5.26-5.38 (IH, m), 6.76 (IH, d, J=7.0Hz), 7.08-7.17 (2H, m), 7.22 (IH, brs), 7.28-7.38 (IH, m), 7.50-7.69 (IH, m), 7.70 (IH, d, J=8.5Hz), 7.78-7.83 (IH, m), 9.41 (IH, brs), 10.54 (IH, brs). MS (CD m/e 436 [MH] + . [α] 5 D +244.2° (c=0.18, MeOH). Purity A:B = 1:99. EXAMPLE 15: Chiral Separation of N-r3(i?.S)-2.3-dihvdro- 5-(ct.ς-2.β-dimethvlpiperidin-l-vlVl-methvl-2-oxo-lH-1.4-benzodi azepin-3-vll N'-rindan-S-vll urea. N-[3(R^)-2,3-D ydro-5-(cis-2,6-dimethylpiperidin-l-yl)-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[indan-5-yl] urea (Example 13) (0.95g) was dissolved in 3:1 chlorofornrmethanol (20ml). The enantiomers were separated as described in Example 5. Peak A (0.44g). mp 160°C (dec). Η NMR (360MHz, D 6 -DMSO) δ 0.93-1.10 (3H, m), 1.28-2.08 (11H, m), 2.70-2.85 (4H, m), 3.34-3.54 (3H, m), 3.78-4.68 (2H, m), 5.28-5.44 (IH, m), 7.02-7.30 (4H, m), 7.64-7.96 (4H, m), 9.30 (IH, brs), 10.18 and 10.30 (IH, 2 x brs). MS (CD m/e 460 [MH] + . Anal. Found C, 65.32; H, 7.14; N, 13.73. HCI requires C, 65.38; H, 6.91; N, 14.12%. [α] 2δ D -194.4° (c=0.50, MeOH). Purity A:B > 99.5:0.5. Peak B (0.45g). mp 159°C (dec). Η NMR (360MHz, D 6 -DMSO) δ 0.93-1.10 (3H, m), 1.28-2.08 (11H, m), 2.70-2.85 (4H, m), 3.34-3.54 (3H, m), 3.78-4.68 (2H, m), 5.28-5.44 (IH, m), 7.02-7.30 (4H, m), 7.64-7.96 (4H, m), 9.39 (IH, brs), 10.20 and 10.35 (IH, 2 x brs). MS (CD m/e 460 [MH] + . Anal. Found C, 65.14; H, 7.41; N, 13.52. C^HgaNgOa-HCl-O^δiE jO-O.lδ^aO) requires C, 66.01; H, 7.17; N, 13.54%. [αl^+lδS.δ 0 (c=0.δO, MeOH). Purity A:B = 0.7:99.3. EXAMPLE 16: N-r3fRS 2.3-Dihvdro-5-( -2.6- dimethvlmnrpholin-4-ylV1-methvl-2-oxo-lH-1.4-benzodiazepin- 3-vll N'-rø-Tnethvlphenvll urea a) 1.2-Dihvdro-5-(M.9-2.6-dimethvlmorpholin-4-vl)-l- methvl-3H-1.4-benzodiazepin-2-one Prepared as described in Example 4c), from 1-methyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (lOg) and cis- 2,6-dimethylmorpholine (6.5ml). Η NMR (250MHz, CDC1 3 ) δ 1.10 (3H, d, J=7Hz), 1.24 (3H, d, J=7Hz), 2.40-2.76 (2H, m), 3.20- 3.88 (8H, m), 4.29 (IH, d, J=12Hz), 7.19-7.39 (2H, m), 7.47-7.60 (2H, m).. b) l,2-DihydrQ-&-(«s-2,6-dimethγlmQπ?hol -4-γl)-l- methγl-3-oxiιmdo-3H-l,4-benzodiazgpin-2-one Prepared as described in Example 4), from l,2-dihydro-5- (cis-2,6-dm ethymιorpholin-4-yl)-l-methyl-3H-l,4- benzodiazepin-2-one (4.8g). -Η. NMR (360MHz, D 6 -DMSO) δ 1.80 (6H, brs), 2.42-2.64 (2H, ), 3.80-4.20 (7H, brm), 7.30 (IH, dd, J=7.0 and 7.0Hz), 7.46-7.60 (3H, m), 10.10-10.42 (IH, 2 x brs). MS (CD m/e 317 [MH]+. c) 1.2-Dihvdro-5-(cts-2.6-dimethvlmorpholin-4-vI)-l- methvl-3-(0-ethvlaminocarbonvl)oximido-3H-1.4-benzodiazepin- 2-one Prepared as described in Example 4e), from l,2-dihydro-5- (cis-2,6-dimethymιorpholm-4-yl)-l-methyl-3-oximido-3H-l,4- benzodiazepin-2-one (1.5g). -H NMR (360MHz, CDC1 3 ) δ 1.09- 1.26 (9H, m), 2.52-3.40 (2H, brm), 3.22-3.92 (8H, m), 4.36-4.44 and 4.70-4.92 (IH, brm), 6.39 (IH, m), 7.24-7.34 (3H, m), 7.53 (IH, dd, J=7.0 and 7.0Hz). MS (CD m/e 388 [MH1+. d) N-r3(_R.S)-2.3-Dihvdro-5-(cis-2.β-dimethylmorDholin-4- vlVl-methvl-2-oxo-lH-l_4-benzodiazepin-3-vl1 N * -r3- methvlphenvll urea To a solution of the product of part c) (1.52g) in methanol δ (80ml) was added 10% palladium on carbon (400mg, 26% (w/w)). The mixture was hydrogenated at 40 psi for 2h and then the catalyst was filtered off and washed with methanol. The solvent was evaporated in vacuo to give the amine (1.06g). To a stirred solution of the amine (1.06g) in anhydrous 10 tetrahydrofuran (10ml) under an atmosphere of nitrogen, at 0°C, was added m-tolyl isocyanate (0.4δml) dropwise. After stirring at 0°C for 5 min the desired compound (1.45g) was collected by filtration and recrystallised from petro ethyl acetate (1:1). mp 253-25δ°C. Η NMR (360MHz, CDC1 3 ) δ 1.11 (3H, d, J=6.2Hz), lδ 1.17 (3H, d, J=6.2Hz), 2.29 (3H, s), 2.41-2.47 (IH, m), 2.69-2.66 (IH, m), 3.41-3.45 (4H, m), 3.62-3.80 (3H, m), 5.34 (IH, d, J=8.0Hz), 6.69-6.73 (IH, m), 6.83 (IH, d, J=7.1Hz), 7.08-7.16 (3H, m), 7.24-7.35 (3H, m), 7.52-7.57 (2H, m). MS (CD m/e 436 [MH]+. 20 EXAMPLE 17; N-r3(*R.g)-2,3-Pihydro-5-(4-methylpiperidin- v -2-oxo-l-propvl-lH-1.4-benzodiazepin-3-vll N"-r3- metfrylpfrenyll urea a) N-Propylisatoic anhydride 5 To a stirred solution of isatoic anhydride (lOOg) and propyl iodide (66ml) in dimethylformamide (600ml) at 0°C, under nitrogen, was added sodium hydride (28g of a 56% dispersion in mineral oil) portionwise. The mixture was allowed to warm to room temperature and stirred for 18h. The solvent 0 was then removed in vacuo and the residue partitioned between ethyl acetate (1000ml) and water (500ml). The organic phase was separated, washed with brine (2 x 500ml), dried (MgS0 4 ) and evaporated. The residue was triturated with anhydrous diethyl ether to give the title compound (δ7g). Η NMR (360MHz, CDC1 3 ) δ 1.06 (3H, t, J=7.5Hz), 1.76-1.86 (2H, m), 4.01-4.05 (2H, m), 7.17 (IH, d, J=8.5Hz), 7.26-7.32 (IH, m), 7.73-7.78 (IH, m), 8.17 (IH, dd, J=7.9 and 1.7Hz). MS (CD m/e 20δ [M]+. b) l-Propyl-1.2.3.4-tetrahvdro-3H-1.4-benzodiazepin- 2,5-dione N-Propylisatoic anhydride (56g) and glycine (20.5g) were heated at reflux in glacial acetic acid (375ml), under nitrogen, for 5h. The solution was concentrated in vacuo and the residue partitioned between dichloromethane (1500ml) and saturated sodium bicarbonate solution (1000ml). The organic phase was separated, dried (MgS0 4 ) and evaporated to afford an orange gum. The gum was cooled to 0°C then triturated with anhydrous diethyl ether to give the bis-lactam (47g) as colourless needles. Η NMR (360MHz, CDC1 3 ) δ 0.84 (3H, t, J=7.3Hz), 1.46-1.66 (2H, m), 3.52-3.64 (IH, m), 3.70-3.85 (2H, m), 4.18-4.28 (IH, m), 7.22- 7.36 (3H, m), 7.55 (IH, d of t, J=7.5 and 1.7Hz), 7.90 (IH, dd, J=7.8 and 1.7Hz). MS (C m/e 219 [MH]+. c) N-r3(J!. ?V2.3-Dihvdro-5-(4-methvlpiperidin-l-vD-2- oxo-l-propvl-lH-1.4-benzodiazepin-3-vll N -r3-methvlphenvH urea Prepared as described in Example 4, steps c)-f), from l-propyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (30g) and 4-methylpiperidine (16.3ml). mp 133-136°C. Η NMR (360MHz, CDC1 3 ) δ 0.79 (3H, t, J=7.4Hz), 0.96 (3H, d, J=6.4Hz), 1.10-1.75 (7H, m), 2.28 (3H, s), 2.76-3.02 (2H, m), 3.55-3.86 (2H, m), 3.91-4.04 (IH, m), 4.23-4.36 (IH, m), 5.35 (IH, d, J=8.2Hz), 6.79-6.84 (2H, m), 7.11-7.14 (2H, m), 7.24-7.40 (4H, m), 7.51-7.59 (2H, m). MS (CD m/e 448 [MH]+. EXAMPLE 18: Chiral separation of N-r3(fi.,9 -2.3-dihvdro-5-(4- methylpiperidin-l-ylV2-oxo-l-propyl-lH-1.4-benzodiazepin-3-yll N'-r3-methylphenvH urea N-[3(i2,S)-2,3-Dihydro-5-(4-methylpiperidin-l-yl)-2-oxo-l- propyl-H-l,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea (1.74g) was dissolved in 9:1 chloroform:methanol (11ml). 440μl of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., 5μm) per min using 95:δ:l l-chlorobutane:methanol:acetic arid as the mobile phase. Using a flow rate of 20ml/min and u.v. detection at 330nm, the two enantiomers were efficiently separated and isolated as described in Example 5. Peak A: (0.68g). mp 167-170°C. Η NMR (360MHz, D 6 - DMSO) δ 0.66-1.96 (13H, m), 2.22 (3H, s), 3.00-4.20 (9H, m), 5.30-5.34 (IH, m), 6.74-6.76 (IH, m), 7.08-7.22 (2H, m), 7.22 (IH, s), 7.24-7.40 (IH, m), 7.56-7.62 (IH, m), 7.78-7.98 (3H, m), 9.46- 9.δ8 (IH, m), 10.52-10.64 (IH, m). MS (CD m/e 448 [MH+]. [αP D -211.3° (c=0.56, MeOH). Purity A:B = >99.δ:0.δ. Peak B: (0.71g) mp 164-167°C. *H NMR (360MHz, D e - DMSO) δ 0.66-1.96 (13H, m), 2.22 (3H, s), 3.00-4.20 (9H, m), δ.30-δ.34 (IH, m), 6.74-6.76 (IH, m), 7.08-7.22 (2H, m), 7.22 (IH, s), 7.24-7.40 (IH, m), 7.66-7.62 (IH, m), 7.78-7.98 (3H, m), 9.46- 9.68 (IH, m), 10.52-10.64 (IH, m). MS (CD m/e 448 [MH+]. [αP D +201.8° (c=0.57, MeOH). Purity A:B = 2:98. EXAMPLE 1 : N-r3rJϋ..<?V2.3-Dihvdro-l-methyl-2-oxo-5-(4- trifluoromethvlpiperidin-l-vD-lH-1.4-benzodiazepin-3-vll N -r3- m thyl hehyll vrea a) 4-Trifluoromethylpiperidine hydrochloride A solution of 2-chloro-4-trifluoromethylpyridine (11.6g) in glacial acetic acid (70ml), containing 10% palladium on carbon (2.4g, 21% (w/w)) was hydrogenated at 40 psi for 4h. Concentrated hydrochloric acid (20ml) was added and hydrogenation continued for a further lh. The catalyst was filtered off and the filtrate evaporated in vacuo to afford 4- triiluoromethylpyridinium hydrochloride. The pyridium hydrochloride was dissolved in ethanol (70ml) and water (5ml), and hydrogenated at 40 psi at 60°C in the presence of 5% rhodium on carbon (4.8g, 41% (w/w)). After 4h the catalyst was filtered off and the filtrate evaporated in vacuo. The residue was azeotroped with toluene (30ml) and then triturated with anhydrous diethyl ether. Η NMR (250MHz, D6- DMSO) δ 1.62-2.01 (4H, m), 2.56-3.00 (3H, m), 3.18-3.39 (2H, m), 9.00-9.60 (2H, 2 x brs). MS (CD m/e 154 [MH]+. b) l-2-Dihvdro-l-methvl-3-(Q-ethvlaminocarbonvl) oximido-5-(4-trifluoromethvlpiperidin- 1-vP- 3H-1.4- benzodiazepin-2-one Prepared as described in Example 4 steps c)-e), from from l-methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (ll.lg) and 4-trifluoromethylpiperidine hydrochloride (10.63g). VB. NMR (360MHz, CDC1 3 ) δ 1.13 (3H, t, J=7.1Hz), 1.70-.240 (5H, m), 2.80-3.04 (2H, br m), 3.22-3.30 (2H, m), 3.45 (3H, s), 3.50- 4.94 (2H, br m), 6.00-6.10 and 6.35-6.39 (IH, 2 x br s), 7.24-7.38 (3H, m), 7.53 (IH, d of t, J=7.2 and 1.5Hz). MS (CD m/e 426 [MH]+. c) N-r3( S)-2.3-Dihvdro-1-mβthvl-2-oxo-5-(4- trifluoromethvlpiperidin-l-vlVlH-1.4-benzodiazepin-3-vl1 N'-r3- methvlphenvll urea The amine was prepared as in Example 40, from the product of part b). The title compound was then prepared from the amine and m-tolyl isocyanate (490μl) as described in Example 16d). mp 248-250°C. Η NMR (360MHz, D 6 -DMSO) δ 1.30-2.24 (8H, m), 2.40-3.00 (2H, brm), 3.04-4.20 (5H, brm), 5.22- 5.40 (IH, brs), 6.75 (IH, d, J=7.2Hz), 7.08-7.17 (2H, m), 7.22 (IH, s), 7.24-7.46 (IH, brm), 7.50-7.60 (IH, m), 7.68-7.72 (IH, m), 7.80-8.00 (2H, m), 9.46 (IH, brs), 10.72 (IH, brs). MS (CD m/e 474 [MH]+. EXAMPLE 20: Chiral separation of N-r3(fl.S)-2.3-dihvdro-l- methvl-2-oxo-5-(4-trifluoromethvlpiperidin-l-vl)-lH-1.4- benzodiazepin-3-vll N'-rø-methvlphenvll urea N-[3(_R,S)-2,3-Dihydro-l-methyl-2-oxo-5-(4-trifluoro methylpiperidin-l-yl)-lH-l,4-benzodiazepin-3-yll N'-[3- methylphenyl] urea (1.44g) was dissolved in 9:1 chloroform:methanol (20ml). 1.5ml of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., 5μm) per run using 95:5:1 l-chlorobutane:methanol:acetic acid as the mobile phase. The two enantiomers were efficiently separated and isolated as described in Example 5. Peak A (704mg) mp 185-188°. Η NMR (360MHz, D6- DMSO) δ 1.30-2.24 (8H, m), 2.40-3.00 (2H, m), 3.04-4.20 (5H, brm), 5.22-5.40 (IH, brs), 6.75 (IH, d, J=7.2Hz), 7.08-7.17 (2H, m), 7.22 (IH, s), 7.24-7.46 (IH, brm), 7.50-7.60 (IH, m), 7.68-7.72 (IH, m), 7.80-8.00 (2H, m), 9.46 (IH, brs), 10.72 (IH, brs). MS (CD / e 474 [MH]+. [α]*» D -227.7° (c=0.53, MeOH). Purity A:B = >99.5:0.5. Peak B (0.71g) mp 185-188°C. Η NMR (360MHz, CDC1 3 ) δ 1.44-1.62 (IH, m), 1.66-1.98 (3H, m), 2.08-2.22 (IH, m), 2.29 (3H, s), 2.58-3.40 (2H, m), 3.43 (3H, s), 3.58-3.68 (IH, m), 4.01-4.09 (IH, m), 5.30 (IH, d, J=7.9Hz), 6.59 (IH, d, J=7.8Hz), 6.95 (IH, brs), 7.05-7.08 (IH, m), 7.14 (IH, dd, J=7.8 and 7.8Hz), 7.23-7.34 (3H, m), 7.52-7.56 (2H, m). MS (CD m/e 474 [MH]+. [αP D +211° (c=0.52, MeOH). Purity A:B = 2:98. EXAMPLE 21: N-r3(RS)-2.3-Dihvdro-5-(2.2-dimethylpiperidin- l-viyi-methyl-2-oxo-lH-1.4-benzodiazepin-3-vH N -r3- methvlphenvll urea a) 6.6-Dimethyipiperidin-2-one To a solution of 2-2-dimethylcyclopentanone (2g) in formic acid (97%, 27ml) was added portionwise hydroxylamine-O- sulphonic acid (3.02g) over a period of 10 min. The mixture was heated at reflux for 5h. After cooling, ice was added and the mixture neutralised with sodium hydroxide solution (4M, ~200ml) and then extracted with dichloromethane (4 x 50ml). The combined organic layers were dried (Na 2 S0 4 ) and the solvent evaporated in vacuo. The residue was chromatographed on silica gel using a gradient of 0 to 20% ethyl acetate in dichloromethane, followed by 10% methanol in dichloromethane as eluant, to obtain a colourless solid. This was triturated with hexane to afford the title compound (0.43g). mp 128-131°C. Η NMR (360MHz, CDC1 3 ) δ 1.25 (6H, s), 1.64-1.68 (2H, m), 1.80-1.88 (2H, m), 2.31 (2H, t, J=6.6Hz), 5.82 (IH, br s). MS (CD m/e 128 [MH]+. b) 2.2-Dimethylpiperidine To a solution of lithium aluminium hydride in diethyl ether (66ml of a 1.0m solution) under nitrogen at reflux, was added a suspension of 6,6-dimethylpiperidin-2-one (4.2g) in anhydrous diethyl ether (120ml) portionwise over a period of 15 min. The mixture was heated at reflux under nitrogen for 5h, then cooled to 0°C. Water (2.5ml) was added dropwise, followed by aqueous sodium hydroxide (2.5ml of a 4N solution) and water (7.5ml). The resultant granular solid was removed by filtration, the filtrate dried (Na 2 S0 4 ) and evaporated. The pale yellow oil was distilled under reduced pressure to afford the title piperidine (2.7g). bp 70°C/60mmHg. Η NMR (360MHz, CDC1 3 ) δ 1.13 (6H, s), 1.36-1.50 (4H, m), 1.53-1.62 (2H, m), 2.83-2.87 (2H, m). MS (CD m/e 114 (MH)+. c) 1.2-Dihvdro-5-(2.2-dimethylpiperidin-l-ylVl-methyl-3-(0- ethylaminocarbonyl)oximido-3H-1.4-benzodiazepin-2-one Prepared as described in Example 4 steps c) to e), from l-methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (4.54g), and 2,2-dimethylpiperidine (2.7g). Η NMR (360MHz, CDC1 3 ) δ 1.20 and 1.25 (3H, 2 x t, J=7.3Hz), 1.43-1.44 (3H, ), 1.55-1.82 (9H, m), 2.93-3.04 (IH, m), 3.19-3.30 (3H, m), 3.43-3.46 (3H, m), 6.02-6.08 and 6.26-6.32 (IH, m), 7.18-7.34 (2H, m), 7.44- 7.52 (2H, m). MS (CD m/e 386 [MH]+. d) N-r3(J L Z._S. , )-2.3-Dihvdro-5-(2.2-dimethylpiperidin-l-ylVl - methyl-2-oxo-1H-1.4-benzodiazepin-3-yll N'-r3-methylphenyll urea The amine was prepared as in Example 4f), from the product of part c) (2.3g). The title compound was then prepared from the crude amine and m-tolyl isocyanate (0.78ml) as described in Example 6b). mp 235°C (dec). Η NMR (360MHz, CDClg) δ 1.42-1.66 (9H, m), 2.29 (3H, s), 2.80-2.98 (2H, m), 3.42 (3H, s), 5.20 (IH, d, J=7.9Hz), 6.42-6.50 (IH, m), 6.70-6.86 (2H, m), 7.06-7.16 (2H, m), 7.18-7.28 (3H, m), 7.45-7.52 (IH, m), 7.69 (IH, dd, J=7.8 and 1.6Hz). MS (C m/e 434 [MH]+. Anal. Found: C, 69.13; H, 7.23; N, 16.08. C 25 H 31 N 5 0 2 requires: C, 69.26; H, 7.21; N, 16.15% EXAMPLE 22: Chiral separation of N-r3(RS)-2.3-dihvdro-5- (2.2-dimethylpiperidm-l-yl)-l-methyl-2-oxo-lH-1.4- benzodiazepin-3-vn N'-rS-methvlphenvll urea N-[3(i2,S)-2,3-dihydro-5-(2,2-dimethylpiperidin-l-yl)-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea (1.8g) was dissolved in 9:1 chloroform:methanol (12ml). 400μl of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., 5μm) per run using 90:10:1 1- chlorobutane:methanol:acetic acid as the mobile phase. The two enantiomers were efficiently separated and isolated as described in Example 5. Peak A (0.8g). mp 150°C (dec). -Η. NMR (360MHz, d 6 - DMSO) δ 1.17-1.80 (12H, m), 2.23 (3H, s), 2.72-3.82 (5H, m), 5.10-5.28 (IH, m), 6.74 (IH, d, J = 7.0Hz), 7.06-7.36 (4H, m), 7.42-7.58 (IH, m), 7.61-7.98 (3H, m), 9.42 (IH, brs). MS (CD m/e 434 [M+l] + . [αP D -423.1° (c=0.68, MeOH). Purity A:B = > 99.5:0.5. Peak B (0.8g). mp 150°C (dec). *H NMR (360MHz, d 6 - DMSO) δ 1.12-1.83 (121:. i), 2.23 (3H, s), 2.83-3.70 (5H, m), 5.08-5.30 (IH, m), 6.74 (i._ d, J = 6.9Hz), 7.04-7.31 (4H, m), 7.40-7.57 (IH, m), 7.62-7.96 CόH, m), 9.37 (IH, brs). MS (CD m/e 434 [MH] + . [αP D +420.5° (c=0.67, MeOH). Purity A:B = 1.3:98.7. EXAMPLE 23: N-r3(RS)-2.3-Dihvdro-l-methvl-2-oxo-5-(cts- 2.4.6-trimethvlpiperidin-l-v -lH-1.4-benzodiazepin-3-vll N'-f3- methvlphenvll urea a) 1.2-Dihvdro-l-methvl-3-(0-ethvlaminocarbonvl)oximido- 5-(ct.s-2.4.6-trimethvlpjperidin-l-vl>-3H-1.4-benzodiazepin-2-one Prepared as described in Example 4 steps c)-e) from 1- methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (5g) and cis-2,4,6-trimethylpiperidine (11.7g). -Η. NMR (360MHz, CDC1 3 ) δ 0.92-1.50 (14H, m), 1.68-2.23 (3H, m), 3.16-3.30 (2H, m), 3.41-3.47 (3H, m), 3.82-3.88 and 4.07-4.18 (IH, m), 4.54-4.76 (IH, m), 6.13-6.20 and 6.32-6.45 (IH, m), 7.18-7.38 (3H, m), 7.42- 7.δ0 (IH, m). MS (CD m/e 400 [MH] + . b) N-r3(_R._S , )-2.3-Dihvdro-l-methvI-2-oxo-5-(cts-2.4.6- ri ethylpiperidin- yl)-3-H-ι,4-bengodia?epin-3-yll N'-f3- methylphenyll urea The amine was prepared as in Example 4f) from the product of part a). The title compound was then prepared from the crude amine and m-tolyl isocyanate (0.8ml) as described in Example 6b) and recrystallised from ethyl acetate: dichloromethane (9:1). mp 223-225°C. -B NMR (360MHz, CDC1 3 ) δ 0.76-1.18 (11H, m), 1.55-1.90 (3H, m), 2.22 (3H, s), 3.29-3.38 (4H, m), 3.56-3.72 (IH, m), 4.97 (IH, d, J = 8.3Hz), 6.71 (IH, d, J = 7.0Hz), 7.05-7.13 (3H, m), 7.16 (IH, s), 7.35 (IH, t, J = 7.0Hz), 7.55 (IH, d, J = 7.9Hz), 7.61-7.65 (2H, m), 8.85 (IH, s). MS (CD m/e 448 [MH] + . Anal. Found: C, 70.00; H, 7.49; N, 15.4δ. C 26 H 33 N 5 θ 2 requires: C, 69.77; H, 7.43; N, 15.65%. EXAMPLE 24: Chiral separation of N-r3(fl.SV2.3-dihvdro-l- methvl-2-oxo-5-( s-2.4.6-trimethvlpiperidin-l-vl)-lH-l,4- benzodiazepin-3-vn N'-(3-methvlphenvll urea N-[3(B,S)-2,3-Dihydro-l-methyl-2-oxo-5-(cis-2,4,6-trimethyl piperidin-l-yl)-lH-l,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea (1.25g) was dissolved in 9:1 chloroform:methanol (20ml). The enantiomers were separated as described in Example δ. Peak A (0.δ9g). mp 170°C (dec). -Η NMR (360MHz, D 6 - DMSO) δ 0.84-1.74 (11H, m), 1.80-2.32 (6H, m), 3.28-3.84 (4H, m), 4.14-4.48 (IH, m), δ.2δ-δ.44 (IH, m), 6.7δ (IH, d, J = 7.1Hz), 7.08-7.36 (4H, m), 7.50-7.62 (IH, m), 7.66-7.94 (3H, m), 9.4δ (IH, brs), 10.16 (IH, brs). MS (CD m/e 448 [MH] + . Anal. Found: C, 60.42; H, 7.02; N, 13.35. C 26 H 33 N 5 0 2 .HC1.1.75 (H 2 0) requires C, 60.57; H, 7.33; N, 13.58%. [α] 22 D -138.8° (c=0.64, MeOH). Purity A:B = > 99.5:0.δ. Peak B (0.δ3g). mp 170°C (dec). Η NMR (360MHz, D 6 - DMSO) δ 0.84-1.73 (11H, m), 1.80-2.30 (6H, m), 3.32-3.84 (4H, m), 4.16-4.46 (IH, m), δ.24-δ.46 (IH, m), 6.7δ (IH, d, J = 7.1Hz), 7.07-7.18 (2H, m), 7.20-7.34 (2H, m), 7.δ0-7.63 (IH, m), 7.66-7.94 (3H, m), 9.45 (IH, brs), 10.14 (IH, brs). MS (CD m/e 448 [MH] + . Anal. Found: C, 62.14; H, 7.10; N, 13.60. C 26 H 33 N 5 0 2 .HC1.H 2 0 requires C, 62.20; H, 7.23; N, 13.95%. [αP D +138.3° (c=0.65, MeOH). Purity A:B = < 0.5:99.5. EXAMPLE 25: N-r3(RSV2.3-Dihvdro-5-(3.3-dimethylpiperidin- l-vlVl-methyl-2-oxo-lH-1.4-benzodiazepin-3-vl1 N'-r3-methvl phenyll urea a) 1.2-Dihydro-5-(3.3-dimethylpiperidin-l-yl)-l-methyl-3- oximido-3H-1.4-benzodiazepin-2-one Prepared as described in Example 4, steps c) and d) from 1- methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,δ-dione (16.7g) and 3,3-dimethylpiperidine (lO.Og). -B NMR (360MHz, D 6 -DMSO) δ 0.69 (3H, s), 0.82 (3H, s), 1.28-1.46 (3H, m), 1.62- 1.80 (IH, m), 2.75-3.00 (3H, m), 3.30 (3H, s), 3.50-3.60 (IH, m), 7.25-7.30 (IH, m), 7.40-7.60 (3H, m), 9.95 (IH, br s), 10.20 (IH, br s). TLC (10% MeOH/dicbloromethane: silica) Rf = 0.40. b) N-r3f7?.,9V2.3-Dihvdro-5-(3.3-dimethvlpiperidin-l-vlVl- methvl-2-oxo-lH-1.4-benzodiazepin-3-vll N'-F3-metfrγ)phenγll urea l,2-Dihydro-5-(3,3-dimethylpiperidin-l-yl)-l-methyl-3-(0- ethylam_uaocarbonyl)oximido-3H-l,4-benzodiazepin-2-one (11.4g) was prepared as described in Example 4e) from the product of part a). The amine was prepared as in Example 4f) from 1,2- d ydro-5-(3,3-dimethylpiperidin-l-yl)-l-methyl-3-(0- ethylamino-carbonyl)oximido-3H-l,4-benzodiazepin-2-one (11.4g). The title compound was then prepared from the crude amine (8.5g) and m-tolyl isocyanate (4ml) as described in Example 6b). mp 213-215°C. Η NMR (360MHz, CDC1 3 ) δ 0.71 (3H, s), 0.85 (3H, s), 1.30-1.47 (3H, m), 1.64-1.80 (IH, m), 2.22 (3H, s), 2.75-2.82 (IH, m), 2.84-3.00 (2H, m), 3.31 (3H, s), 3.50- 3.60 (IH, m), 4.95 (IH, d, J = 8.4Hz), 6.70 (IH, d, J = 6.9Hz), 6.99-7.00 (IH, m), 7.02-7.20 (3H, m), 7.34-7.40 (IH, m), 7.50-7.70 (3H, m), 8.80 (IH, m). EXAMPLE 26: Chiral separation of N-r3(fl._S)-2.3-dihvdro-5- (3.3-dimethvlpiperidin-l-vl)-l-methvl-2-oxo-lH-1.4- benzodiazepin-3-vll N'-rø-methvlphenvH urea (-)-N-[2,3-dihydro-(3,3-dimethylpiperidin-l-yl)-l-methyl-2- oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea was prepared from the racemate analogously to Example 5. Η NMR (360MHz, D 6 -DMSO) δ 0.56 (3H, s), 0.81 (3H, s), 1.40-1.90 (4H, m), 2.24 (3H, s), 3.17 (IH, d, J = 11.8Hz), 3.22-3.60 (2H, m), 3.41 (3H, s), 4.00-4.10 (IH, m), 5.41 (IH, d, J = 6.7Hz), 6.77 (IH, d, J = 8.2Hz), 7.08-7.18 (3H, m), 7.23 (IH, s), 7.34 (IH, d, J = 6.7Hz), 7.58 (IH, t, J = 7.3Hz), 7.79 (IH, d, J = 7.6Hz), 7.78-7.95 (2H, m), 9.26 (IH, s), lO.δO (IH, m). MS (CD m/e 434 [MH] + . Purity A:B 99.δ:0.δ. [αP D -86.3° (c=0.7δ, CH 2 C1 2 ). EXAMPLE 27: N-r3(J?. L SV2.3-Dihvdro-5-(4.4-dimethvlpiperidin- δ l-vlV2-oxo-1-(2.2.2-trifluoroethvD-lH-1.4-benzodiazepin-3-yl1 N'- (3-methvlphenvl) urea a) Methyl 2-rN-(2-bromoacetyl N-(2.2.2-trifiuoroethvP1 aminohenanate A solution of methyl anthranilate (98.3g) and trifluoroethyl 10 trichloromethanesulphonate Ol.δg) in m-xylene (200ml) was heated at reflux for 3h under nitrogen. The reaction mixture was allowed to cool overnight, then filtered from a white solid, washing well with diethyl ether. The combined filtrates were evaporated in vacuo and the residual oil purified by flash lδ chromatography (silica gel, 10% diethyl ether/hexane) to give methyl 2-[ T-(2,2,2-trifluoroethyl)]aminobenzoate, contaminated with trifluoroethyl trichloromethanesulphonate. To a solution of this mixture (3δ.8g) in dichloromethane (lδOml), cooled to 1°C under nitrogen, was added dropwise bromoacetyl bromide 0 (10.1ml), keeping the temperature below +3°C. The reaction mixture was stirred at 0 ± 3°C for 12 min, then 4N NaOH solution (33.4ml) was added dropwise over 18 min. The cooling bath was removed and the reaction mixture was stirred at room temperature for 4h. More bromoacetyl bromide (1.6ml) was δ added dropwise and the mixture was stirred for a further 6h. After leaving to stand overnight, the organic layer was separated, washed with 10% citric acid (30ml), brine (30ml), saturated potassium carbonate solution (30ml) and brine (30ml), dried (Na 2 S0 4 ) and evaporated in vacuo to leave a yellow oil. 0 This was purified by flash chromatography (silica gel, 20-2δ% EtOAc/petroleum ether) to afford the title compound (27.4g). -B. NMR (CDC1 3 ) δ 3.δ8 (IH, d, J = 11.4Hz), 3.64 (IH, d, J = 11.3Hz), 3.83 (IH, m), 3.90 (3H, s), 4.79 (IH, m), 7.49 (IH, d, J = 7.8Hz), 7.δ7 (IH, t of d, J = 7.6 and 1.3Hz), 7.68 (IH, t of d, J = 7.6 and 1.7Hz), 8.09 (IH, dd, J = 7.8 and 1.6Hz). MS (CI+, NH 3 ) m/e 373/371 (M+NH 4 ) + . b) l-2.3.4-Tetrahvdro-l-(2.2.2-trifluoroethyl)-3H-1.4- δ benzodiazepin-2.5-dione Ammonia gas was bubbled into a solution of the product of part a) (27.3g) in anhydrous methanol (lδOml) for 4h, keeping the temperature at +4 ± 9°C. The reaction mixture was allowed to stand open overnight then nitrogen was bubbled through the 10 solution for lh. The solvent was removed in vacuo and the residue stirred with δ% MeOH/CH 2 Cl 2 . The solid was filtered off, washed well with more δ% MeOH/CH 2 Cl 2 , and the combined filtrates were purified by flash chromatography (silica gel, 3-δ% MeOH/CH 2 Cl 2 ) to give the title compound (lδ.2g). Η NMR lδ (CDC1 3 ) δ 3.87 (2H, m), 4.19 (IH, m), δ.03 (IH, m), 6.84 (IH, br s), 7.29 (IH, d, J = 8.3Hz), 7.42 (IH, t of d, J = 7.6 and 0.8Hz), 7.60 (IH, t of d, J = 7.6 and 1.6Hz), 7.93 (IH, dd, J = 7.8 and 1.6Hz). MS (CI+, NH 3 ) m e 2δ9 [MH]-*-. 20 c) 1.2-Dihvdro-5-(4.4-dimethylpiperidin-l-ylV3-(Q- ethvlaminocarbonvDoximido-l-(2.2.2-trifluoroethvl)-3H-1.4- benzodiazepin-2-one Prepared by the procedure of Example 4, steps c)-e) from the product of part b) (18.0g) and 4,4-dimethylpiperidine (3.51g). 5 Η NMR (CDC1 3 ) δ 0.97 and 1.05 (6H, 2 x br s), 1.10 and 1.13 (3H, 2 x t, J = 7.3Hz), 1.16-1.26 (4H, m), 3.25 (2H, m), 3.39-4.11 (5H, m), δ.24-δ.42 (IH, m), 6.16 and 6.33 (IH, 2 x br t), 7.31-7.δ6 (4H, m). MS (CI+, NH 3 ) m/e 4δ4 [ME]*. d) N-r3(_R.SV2.3-Dihvdro-5-(4.4-dimethylpiperidin-l-yl)-2- 0 oxo-l-(2.2.2-trifluoroethyl -lH-1.4-benzodiazepin-3-yll N'-(3- methvlphenvl) urea Following the procedure of Example 4f), the product of part c) (4δ0mg) was hydrogenated to give 3-amino-l,2-dihydro-5-(4,4- dimethylpiperidin-l-yl)-l-(2,2,2-trifluoroethyl)-3H-l,4- benzodiazepin-2-one (313mg). This was dissolved in anhydrous tetrahydrofuran (6ml) under nitrogen and cooled with an ice/water bath before adding m-tolyl isocyanate (0.110ml) 5 dropwise. The mixture was stirred for 40 min before removing the cooling bath and stirring for a further hour. The solvent was removed in vacuo and the residue triturated with diethyl ether (10ml) to afford the title compound (347mg); mp 236-239°C. Η NMR (CDC1 3 ) δ 0.96 (6H, s), 1.30-1.50 (4H, m), 2.29 (3H, s), 3.30 10 (4H, m), 4.08 (IH, m), 5.23 (IH, m), δ.38 (IH, d, J = 8.2Hz), 6.46 (IH, br d, J = 7.9Hz), 6.84-6.88 (2H, m), 7.08-7.17 (2H, m), 7.21 (IH, s), 7.34-7.37 (2H, m), 7.δ3-7.δ8 (2H, m). MS (CI+, NH 3 ) m/e δ02 [MH]+. Anal. Found: C, 61.21; H, δ.88; N, 13.19% C 26 H 30 F 3 N 5 O 2 .0.6.H 2 O.0.1 C 4 H 8 0 requires: C, 61.03; H, 6.21; N, lδ 13.48%. EXAMPLE 28: Chiral separation of N-r3(2r!._Sf)-2.3-dihvdro-5- (4 -dimethyl i ridi f t- γl)-2-oyo-l-(2.g < 2 rifluo Q hyl)-lH- l 4- benzodiazepin-3-vll N'-rø-methvlphenvll urea 20 A solution of N-[3(i2,S)-2,3-dihydro-5-(4,4- dimethylpiperidin-l-yl)-2-oxo-l-(2,2,2-trifluoroethyl)-lH-l,4- bromodiazepin-3-yl] N'-[3-methylphenyl]urea (330mg) in 50% CHClg/EtOH (5ml) was injected in 0.5ml volumes onto a dinitrobenzoyl leucine column (250 x 20.4mm i.d., δμm), eluting 2δ with 50% ethanol hexane at 20ml/min. The fractions containing each enantiomer were separately evaporated in vacuo, the residues were redissolved in filtered dichloromethane (10ml) and ethereal hydrogen chloride (2ml) was added. The solvents were then removed in vacuo and the residues triturated with diethyl 0 ether (5ml) to give: Peak A. HCI salt (134mg); mp 153-158°C; Η NMR (d 6 - DMSO) at 353K: δ 0.98 (6H, s), 1.26-1.51 (4H, m), 2.23 (3H, s), 3.41-3.63 (4H, br m), 4.73 (IH, m), 5.15 (IH, m), 5.35 (IH, m), 6.75 (IH, d, J = 7.1Hz), 7.06-7.20 (4H, m), 7.59 (IH, m), 7.78-7.85 (3H, m), 9.16 (IH, br s). MS (CI + , NH 3 ) m/e 502 [MH] + . [αP D = -19δ.δ° (c=0.2, MeOH). Purity A:B = > 99.δ:0.δ. Anal. Found: C, δδ.83; H, 6.04; N, 11.93%. C 26 H 30 F 3 N 5 O 2 .HC1.1.42 H 2 0 0.06 δ C 4 H 10 O. requires C, δδ.48; H, 6.11; N, 12.33%. Peak B. HCI salt (128mg); mp 14δ-lδl°C; Η NMR (d 6 - DMSO) at 3δ3K same as for Peak A. MS (Cl-, NH 3 ) m/e δ02 [MH]-*-* [a]2° D = +204° (c=0.2, MeOH). ee = 99%. Anal. Found: C, δ6.67; H, δ.86; N, 12.29%. C 26 H 30 F 3 N 5 O 2 .HC1.0.8 H 2 0: requires 10 C, δ6.δ3; H, δ.9δ; N, 12.68%. EXAMPLE 29: N-r3( S)-2.3-Dihvdro-5-(4.4-dimethvlpiperidin- l-vl)-l-ethvl-2-oxo-lH-1.4-benzodiazepin-3-yll '-r3-ιpe hγl phepyll urea lδ a) 1.2-Dihvdro-5-(4.4-dimethylpiperidin-l-vlVl-ethvl-3-(0- ethvlaminocarbonvl)oximido-3H-1.4-benzodiazepin-2-one Prepared as described in Example 4, steps c) to e) from 1- ethyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,δ-dione ( 18g) and 4,4-dimethylpiperidine (lOg). -B NMR (360MHz, d 6 -DMSO) 20 δ 0.9-1.20 (16H, br m), 2.94-3.03 (2H, m), 3.1-3.96 (δH, br m), 4.26 (IH, m), 7.2-7.7 (δH, m). b) N-r3(i?.^)-2.3-Dihvdro-5-(4.4-dimethvlpiperidin-l-vD-l- ethvl-2-oxo-5-(4.4-dimethvlpiperidin-1-vD-lH-1.4-benzodiazepin- 3-vll N'-r3-methvl phenvll urea δ The amine was prepared as in Example 4f) from the product of part a) (δ.2g). The title compound was then prepared from the amine and m-tolyl isocyanate (1.6ml) as described in Example 16d) and recrystallised from petroleum ether. 0 EXAMPLE 30: Chiral separation of N-r3(K.SV2.3-dihvdro-5- (4.4-dimethylpiperidin-l-yl)-l-ethyl-2-oxo-lH-1.4-benzodiazepin- 3-γl] N'-r3- ethγlphenyll urea N-[3(_R,_S)-2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-l- ethyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea (2.4g) was dissolved in 9:1 chloroform:methanol (20ml). 1ml of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., 5pM) per run using 96:3:1 chlorobutane: methano acetic acid as the mobile phase. Using a flow rate of 20ml/min and u.v. detection at 330nm, the two enantiomers were efficiently separated. The fractions containing enantiomer A were combined and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (50ml) and potassium carbonate solution. The organic phases were separated, dried (MgS0 4 ), filtered and evaporated under reduced pressure to give a foam. Peak A was purified using the Gilson Prep HPLC using 3:2 acetonitrile/water (containing 0.1% TFA) as mobile phase. The solution containing the desired product was evaporated under reduced pressure to remove the acetonitrile. The aqueous solution was basified with sodium carbonate and extracted with ethyl acetate (3 x 100ml). The ethyl acetate extracts were combined, dried (MgS0 4 ), filtered and evaporated to give a foam (0.45g). The foam was recrystallised from diethyl ether (0.28g). mp 211-213°C. Found: C, 69.82; H, 7.24; N, 15.60. requires C, 69.77; H, 7.43; N, 15.65. Η NMR (360MHz, CDC1 3 ) δ 0.95 (6H, s), 1.09 (3H, t), 1.31 (2H, m), 1.47 (2H, m), 2.28 (3H, s), 3.2 (4H, br m), 3.68 (IH, m), 4.33 (IH, m), 5.30 (IH, d), 6.74 (IH, d), 6.80 (IH, d), 7.07-7.37 (6H, m), 7.52 (2H, m). EXAMPLE 31: N-r3(fl.SV5-(3-Azabicvclor3.2.21nonan-3-yl)- 2.3-dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-yll-N'- r3-methvlphenvl1 urea Method A a) 5-(3-Azahicvclor3.2.21nonan-3-yl)-1.3-dihvdro-2H- l-methyl-3-oximido-1.4-benzodiazepin-2-one Prepared analogously to Example 4, steps c) and d) from l-methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (lO.Og) and 3-azabicyclo[3.2.2]nonane (6.89g). mp 220-222°C. 1H NMR (360MHz, CDCy δ 1.30-2.30 (10H, m), 3.32-3.40 (IH, 5 m), 3.45 (3H, s), 3.47-3.54 (IH, m), 3.74-3.80 (IH, m), 4.66-4.73 (IH, m), 7.20-7.35 (3H, m), 7.49 (IH, ddd, J. « J ≥ = 7Hz, 3 = 1Hz). Found: C, 66.31; H, 6.93; N, 17.07. C^H^O,, requires C, 66.24; H, 6.79; N, 17.17%. b) 3(R.SVAmino-5-(3-azabicvclor3.2.21nonan-3-vl)- 10 1.3-dihvdro-l-methyl-2H-1.4-benzodiazepin-2-one The foregoing oxime (6.68g) was hydrogenated over 5% rhodium on carbon (6.7g) in methanol (670ml) at 40 psi and 60°C for 6.δ hours. The mixture was filtered then evaporated to give the crude amine which was used immediately in the next step. lδ c) N-r3(R.SV5-(3-Azabicvclor3.2.21nonan-3-vD-2.3- dihvdro-1-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N'-r3- methvlphenvll urea m-Tolyl isocyanate (3.17ml) was added to an ice cold solution of the foregoing amine (6.4g) in anhydrous 20 tetrahydrofuran (70ml) then left standing at 4°C for 16 hours. The solution was evaporated and the residue partitioned between potassium carbonate solution (100ml) and dichloromethane (200ml). The organic layer was separated and the aqueous re-extracted with dichloromethane (5 x 100ml). The δ combined organics were dried (sodium sulphate) then evaporated and the crude product crystallised from dichloromethane to afford the title compound (l.δδg). mp > 242°C (dec). 1 H NMR (360MHz, CDC1 3 ) δ 1.54-2.04 (10H, m), 2.29 (3H, s), 3.26-3.40 (2H, m), 3.42 (3H, s), 3.52-3.60 (2H, m), δ.28 (IH, d, J = 8Hz), 0 6.44 (IH, d, J = 8Hz), 6.80-6.84 (2H, m), 7.07-7.16 (2H, m), 7.22-7.33 (3H, m), 7.47-7.55 (2H, ). Found: C, 63.39; H, 6.65; N, 14.15. C 26 H 31 N 5 O 2. 2H 2 O.0.15CH 2 Cl 2 requires C, 63.δ4; H, 7.20; N, 14.17%. Method B a) 5-(3-Azabicvclor3.2.21nonan-3-yl)-1.3-dihvdro-2H- l-methvl-3-(0-(ethvlaminocarbonvl)oximido)-1.4-benzodiazepin- 2-ope 5 5-(3-Azabicyclo[3.2.2]nonan-3-yl)-l,3-dihydro-2H-l-methyl -3-oximi do- 1 ,4-benzodiazepin-2-one (δ.l7g) and ethylisocyanate (1.9ml) were heated at 60°C in anhydrous tetrahydrofuran (200ml) for 18 hours. The solvent was evaporated and the residue was purified by column chromatography on silica using 10 dichloromethane _ 1% methanol/dichloromethane to afford a cream foam (δ.δ3g, 90%, mixture of E/Z isomers). mp 168°C. ' B NMR (360MHz, CDCy δ 1.10 and 1.12 (3H, each t, J=7Hz), 1.24-1.96 (9H, m), 2.16-2.28 (IH, m), 3.12-3.36 (3H, m). 3.38-3.δ2 (IH, m) overlapped with 3.44 and 3.4δ (3H, each s), 3.δ8-3.70 lδ (IH, m), 4.δ6-4.78 (IH, m), 6.13-6.22 and 6.36-6.44 (IH, each m), 7.18-7.δ2 (4H, m). b) 3(i?.S)-Amino-5-(3-azabicvclor3.2.21nonan-3-yl - l,3-dihγdro-l-methγl-2*H- 4-beι ?Qdiazepin-2-ope δ-(3-Azabicyclo[3.2.2]nonan-3-yl)-l,3-dihydro-2H-l-methyl- 20 3-(0-(ethylaminocarbonyl)oximido)- 1 ,4-benzodiazepin-2-one (δ.4g) was hydrogenated at 40 psi in methanol (δOOml) over 10% palladium on carbon (1.8g) for 3 hours at room temperature. The mixture was filtered then evaporated to dryness to afford the title amine (4.4δg) δ c) N-r3(R. « ?)-5-(3-A7ahi vclor3.2.21nonan-3-vD-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3- methvlphenvll urea The foregoing amine (4.4δg) in anhydrous tetrahydrofuran (lδml) was treated with m-tolylisocyanate (1.9ml). After 0 standing for 10 minutes the precipitate was collected to afford the title compound free base (4.90g) which had the same chromatographic and spectroscopic characteristics as the product obtained using Method A. EXAMPLE 32: N-r3fR.SV2.3-Dihvdro-5-((lS.4S 5-methvl-2.5- diazabicvclor2.2.11heptan-2-vl)-2-oxo-l-propvl-lH-1.4- benzodiazepin-3-vll-N'-r3-methvlphenvn urea a) 1.3-Dihvdro-5-((lS.4SV5-methyl-2.5-diazabicvclo δ r2.2.11heptan-2-vl -2H-l-propvl-1.4-benzodiazepin-2-one Prepared analogously to Example 4c) from l-propyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,δ-dione (δ.Og) and (lS,4S)-2- methyl-2,δ-diazabicyclo[2.2.1]heptane dihydrobromide (17.3g), J. Org. Chem. 1990, ≤≤, 1684-1687). 0 b) 1.3-Dihvdro-5-((lS.4S)-5-methyl-2.δ-diazabicvclo r2.2.11heptan-2-vlV2H-3-oximido-l-propvl-1.4-benzodiazepin-2- one Potassium t-butoxide (3.6g) was added in portions to a stirred, cooled (-20°C) suspension of δ l,3-dihydro-δ-((lS,4S)-δ-methyl-2,δ-diazabicyclo[2.2.1]heptan-2- yl)-2H-l-propyl-l,4-benzodiazepin-2-one (2.0g) in anhydrous toluene (250ml) under a nitrogen atmosphere. After stirring at -20°C for 30 minutes isopentylnitrite (1.9ml) was added and the reaction mixture was stirred at -20°C for 1 hour then at room temperature for 3 days. The mixture was re-cooled to -20°C and further potassium t-butoxide (1.8g) and isopentylnitrite (1ml) were added. The mixture was stirred at -20°C for 1 hour then at room temperature for 1 day. The reaction mixture was treated with solid carbon dioxide then evaporated to dryness. The residue was purified by column chromatography on alumina using dichloromethane - 10% methanol/dichloromethane (containing 1% ammonia) to afford the oxime (0.60g). MS, m/z = 341 for M + . c) 3(fl.S)-Aιmno-1.3-dihvdro-5-((lS.4S)-5-methyl-2.5- diazabicvclor2.2.πheptan-2-vl)-2H-l-propvl-1.4-benzodiazepin-2- one Trifluoroacetic acid (1.36ml) and activated zinc powder (Fieser and Fieser, 1967, Volume 1, 1276, 1.14g) were added to a stirred solution of the foregoing oxime (0.6g) in glacial acetic acid (70ml) at 40°C then the mixture was stirred at this temperature for 6 hours. The reaction mixture was cooled, filtered then evaporated to dryness to give the crude amine trifluoroacetate. 5 d) N-r3(R ?V2.3-Dihvdro-5-r(lR.4SV5-methvl-2.5- diazabicvclor2.2.11heptan-2-vP-2-oxo-l-propvl-lH-l_4- benzodiazepin-3-vn-N'-r3-methvlphenvn urea Triethylamine (0.3ml) was added to a stirred suspension of the foregoing amine trifluoroacetate in anhydrous 10 tetrahydrofuran (30ml). The reaction mixture was then treated with m-tolylisocyanate (0.3ml) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness then the residue was partitioned between ethyl acetate (δOml) and IM citric acid (δOml). The lδ organic layer was extracted with a further portion of IM citric arid (50ml) and the combined aqueous was washed with ethyl acetate (3 x 50ml) then basified to pH > 9 with sodium bicarbonate and extracted with ethyl acetate (3 x δOml). The combined organics were dried (sodium sulphate) then evaporated 20 to dryness to give a solid which was purified by column chromatography on silica using dichloromethane _ 20% methanol/dichloromethane (containing 1% ammonia). The resulting solid was recrystallised from ethanol/water to afford the title compound (2δmg) as a 1:1 mixture of diastereomers. mp δ 126-128°C. MS, CF, m/z = 461 for (M+H) + . Found: C, 66.07; H, 7.08; N, 16.94. C 26 H 32 N 6 O 2. 1.2δH 9 0 requires C, 64.64; H, 7.20; N, 17.39%. EXAMPLE 33: (-VN-r5-(3-Azahi vclor3.2.21nonan-3-vD-2.3- 0 dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3-methv1 phenvll urea Hydrochloride The racemic compound (Example 31, 1.5g) was separated into its enantiomers using semi-preparative chiral HPLC on a Pirkle dinitrobenzoylleucine column (δμ) [(250 x 21.4)mm] eluting with 3% methanol in 1-chlorobutane (including 1% acetic acid). Flow rate 20ml/minute, U.V. detection at 290nm. Analysis was performed on an analytical Pirkle dinitrobenzoylleucine column (5μ) [(250 x 4.6)mm] eluting with 5% methanol in 1-chlorobutane (induding 1% acetic arid). Flow rate lml/minute, U.V. detection at 250nm. The free base was liberated and obtained as a colourless solid (680mg). The hydrochloride salt had mp 188-190°C (dec.) (ethyl acetate/acetone (10:1). Rf 0.55 in dichloromethane/ methanol (9:1) on silica plates. MS, CI + , m/z = 446 for (M+H) + . ia] 23rc D = -216° (c=0.2, methanol). Found: C, 63.75; H, 6.99; N, 13.98. C 26 H, 31 N 5 O 2 HC1.0.5H 2O requires C, 63.60; H, 6.77; N, 14.26%. HPLC: (Pirkle dinitrobenzoylleucine column, 5% methanol in 1-chlorobutane (including 1% acetic acid)): > 99% ee (R = 5.6 minutes). HPLC: (Spherisorb 5μm Phenyl column [(250 x 4.6)mm], 50% acetonitrile/50% of 0.2% triethylamine in water and δOmM potassium phosphate, pH = 3): > 99% chemically pure. EXAMPLE 34: (+ -N-r5-(3-Azabicvclor3.2.21nonan-3-vl)-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3-methvl phenvll urea Hydrochloride The title compound was obtained (660mg) using the procedure described in Example 33. The hydrochloride salt had mp 189-191°C (dec.) (ethyl acetate/acetone (10:1)). Rf 0.55 in dichloromethane/methanol (9:1) on silica plates. MS, CI + , m/z = 446 for (M+H) + . [α3 3°c D = +222° (c=0.2, methanol). Found: C, 63.59; H, 7.05; N, 13.86. 63.60; H, 6.77; N, 14.26%. HPLC: (Pirkle initro enzoy eucine column, 5% methanol in 1-chlorobutane (including 1% acetic acid)): 99% ee (R = 8.24 minutes). HPLC: (Spherisorb 5μm Phenyl column [(250 x 4.6)mm], 50% acetonitrile/50% of 0.2% triethylamine in water and 50mM potassium phosphate, pH = 3): > 99% chemically pure. EXAMPLE 35: N-r3(R.SV5-(3-Azabicvclor3.2.21nonan-3-vD-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-[3- fluorophenvn urea The title compound was obtained (450mg) from 3-fluorophenyl isocyanate and 3(R,S)-amino-5-(3-azabicyclo [3.2.2]nonan-3-yl)-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2- one as described in Example 31, Method A. mp 196-197°C (dichloromethane/diethyl ether). MS, CI + , m/z = 450 for (M+H) + . 1H NMR (360MHz, CDCy δ 1.54-1.90 (8H, m), 1.95-2.02 (2H, m), 3.26-3.40 (2H, m), 3.43 (3H, s), 3.52-3.62 (2H, m), 5.28 (IH, d, J=8Hz), 6.62-6.67 (2H, m), 6.98 (IH, dd, J^lHz, J 2 =8Hz), 7.10-7.55 (7H, m). Found: C, 67.23; H, 6.12; N, 15.46. C 25 H 28 FN 5 0 2 requires C, 66.80; H, 6.28; N, 15.58%. EXAMPT.E 36: f- N-r5-(3-Azabicvclor3.2.21nonan-3-vD-2.3- dihvdro-1 -methvl-2-oxo- -l .4-benzodiazepin-3-vn-N'-r3- fluorophenyl! urea Hydrochloride The racemic compound (Example 35, 320mg) was separated into its enantiomers using semi-preparative HPLC on a Pirkle dinitrobenzoylleucine column (5μ) [(250 x 21.4)mm] eluting with 5% methanol in 1-chlorobutane (including 1% acetic arid). The free base was liberated and obtained as a colourless solid (140mg). The hydrochloride salt had mp 208-210°C (acetone/ethyl acetate (1:1)). [α] 24°c D = -235° (c=0.2, methanol). 1 H NMR (360MHz, D ≥ 0) δ 1.24-1.98 (9H, m), 2.28-2.36 (IH, m), 3.50 (3H, s), 3.61 (IH, d, J=15Hz), 3.70 (IH, d, J=15Hz), 3.76-3.84 (IH, m), 3.96-4.04 (IH, m), 5.58 (IH, s), 6.88 (IH, ddd, 1 (IH, ddd, 7.58 (IH, dd, J 1= 2 =8Hz), 7.65 (IH, d, J=8Hz), 7.75 (IH, d, J=8Hz), 7.86 (IH, dd, J lβ J 2 s8Hz). Found: C, 60.84; H, 6.15; N, 13.32. C 25 H 28 FN 5 O 2.HC1.0.5H t. O.0.5CH 3 COCH 3, requires C, 60.74; H, 6.35; N, 13.36% EXAMPT.E 37: (-+ N-r5-(3-Azahicvc1or3.2.21nonan-3-vD-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N'-r3- fluorophenvll urea Hydrochloride The title compound was obtained (llδmg) using the procedure described in Example 36. The hydrochloride salt had mp 207-209°C (acetone/ethyl acetate (1:1)). [α] 24*c D ■= +240° (c=0.2, methanol). Found: C, 60.87; H, 6.23; N, 13.44. C C2 255 H H 2 288. F F N N55° O22-. H H C C1.0.5H 2 O.0.6CH 3 „COCH requires C, 60.74; H, 6.35; N, 13.36%. EXAMPLE 38: N-r3(R.S 5-(3-Azahi vc1or3.2.11octan-3-vD-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N 3-methvl phePYll wea a) 5-(3-Azabicvclor3.2.11octan-3-vn-1.3-dihvdro-2H-l- iPethγT-3-oπ ido- 4-beιιgodia?epiyι-g-oπe The tide compound was obtained from l-methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione and 3-azabicyclo[3.2.1]octane (J. Pharm. Sci. 1968, 51, 1785-1787) as described in Example 4, steps c) and d). mp 249-252°C (ethyl acetate/diethyl ether). MS, CI + , m/z = 313 for (M+H) + . Found: C, 62.28; H, 6.41; N, 16.54. C^H^N^.H,,© requires C, 61.80; H, 6.71; N, 16.95%. b) N-r3(fi.^-5-(3-Azabicvclor3.2.noctan-3-vD.2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N'-r3- methylphenyll urea The title compound was obtained (1.75g) from the foregoing oxime as described in Example 31, Method A. mp 237-239°C. MS, CI\ m/z = 432 for (M+H) + . 1H NMR (360MHz, CDCy δ 1.46-1.49 (6H, m), 1.90-2.24 (2H, m), 2.28 (3H, s), 2.74-2.82 (IH, m), 3.06-3.12 (IH, m), 3.40-3.50 (2H, m), 3.42 (3H, s), 5.35 (IH, d, J=8Hz), 6.66-6.78 (IH, m), 6.81 (IH, d, J=8Hz), 7.06-7.58 (8H, m). Found: C, 69.38; H, 6.79; N, 15.92. 5 C H N 0 requires C, 69.58; H, 6.77; N, 16.23%. EXAMPLE 39: (-VN.r5-(3-Azabicvclor3.2.11octøn-3-vlV2.3- dihvdro-1-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3-methvl phenvll urea Hydrochloride 0 The title compound free base was obtained (580mg) from the racemate (Example 38, 1.4g) using the procedure described in Example 36. The hydrochloride salt had mp 218-220°C (acetone/ethyl acetate (1:1)). [α] 23° ° D = -215.5° (c=0.2, methanol). MS, Cl * , m/z = 432 for (M+H) + . Found: C, 62.90; H, 6.46; N, 5 14.59. C 25 H 29 N 5 O 2 .HC1.0.5H 2 O requires C, 62.95; H, 6.5δ; N, 14.68%. EXAMPLE 40: (+VN-r5-(3-Azahicvclor3.2.11octan-3-vD-2.3- dihvdro-1-methvl-2-oxo-lH-1.4-benzodiazepin-3-vll-N'-r3-methvl 0 henyl! urea Hydrochloride The title compound free base was obtained (610mg) from the racemate (Example 38, 1.4g) using the procedure described in Example 36. The hydrochloride salt had mp 190°C (dec) MS, CF, m/z = 432 for (M+H) + . [α] 3° ° D = +182° (c=0.2, methanol). δ Found: C, 62.77; H, 6.66; N, 14.07. C^H^O,,. HC1.0.6H 2 O.0.1CH 3 CO 2 CH 2 CH 3 requires C, 62.δ6; H, 6.61; N, 14.36%. EXAMPLE 41: (-VN-r5-(3-Azahicyclor3.2.21nonan-3-vD-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-henzodiazepin-3-vll-N'-r5-indanvl 0 l urea a) α-amino-N-(5-(3-azabicv or3.2.21nonan-3-vlV2.3- dihvdro-l-methvl-2-oxo-1H-1.4-benzodiazepin-3-vl benzenepropanamide To a stirred solution of 3(i2,S)-amino-5-(3-azabicyclo [3.2.2]nonan-3-yl)-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2- one (2.22g) in anhydrous dimethylformamide (25ml) were added BOC-D-phenylalanine (2.07g), 1-hydroxybenzotriazole (1.02g), δ l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.49g) and triethylamine (δml). After stirring at room temperature for 30 mintues, the reaction mixtures was left standing at 4°C for 16 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and 10% 0 potassium carbonate solution. The organic layer was dried (sodium sulphate), evaporated to dryness, and the resulting oil purified by column chromatography on silica using dicMoromethane-methanol/dicMoromethane (1:99). The product obtained (2.7g) was treated at 4°C with ethyl acetate (lδml), 5 saturated with hydrogen chloride gas and stirred at room temperature for 40 minutes. The solution was cooled down to 4°C and basified with saturated potassium hydrogen carbonate solution, the organic layer was separated and the aqueous re-extracted with ethyl acetate (30ml). The combined organics were dried (sodium sulphate) and evaporated to dryness. The resulting oil was purified by column chromatography on silica using dichloromethane to ammonia/methanol/ dichloromethane (0.2: 2:98) (gradient elution) to afford diastereomer A (0.38g) HPLC (Spherisorb ODS2 column, 70% acetonitrile/30% of 0.2% triethylamine in water, pH to 3 with orthophosphoric arid): R, 6.8 minutes, and diastereomer B (O.δlg, 23%), Rf 0.37 in methanol/dichloromethane (1:9) on silica plates, HPLC (same conditions as in diastereomer A): R t 8.4 minutes. b) (-V3-Amino-5-(3-Azabicvclor3.2.21nonan-3-yl)-1.3- dihvdro-l-methyl-2H-benzodiazepin-2-one Trifluoroacetate Phenyl isothiocyanate (120μl) was added to a stirred soluction of the foregoing diastereomeric amide A (380mg) in anhydrous dichloromethane (10ml) then heated at 40°C (oil bath temperature) for 3 hours. The reaction mixture was evaporated and the residue purified by column chromatography on silica using dichloromethane _ methanol/dichloromethane (5:9δ), to afford the thiourea (440mg). Anhydrous trifluoroacetic arid 6 (16.8ml) was added to the solid thiourea (430mg) and the solution stirred at room temperature for δO minutes. The mixture was evaporated to dryness and the yellow oil azeotroped with toluene. The residue was partitioned between water and diethyl ether, then the aqueous was freeze dried and azeotroped 0 with toluene to afford the homochiral amine trifluoroacetate (218mg). Rf 0.30 in methanol/dichloromethane (1:9) on silica plates, [α] 23°c D = -20.δ° (c=0.2, methanol). c) (-VN-r5-(3-Azabicvclor3.2.21nonan-3-vD-2.3-dihvdro- l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N'-r5- indanvll urea 5 A stirred, cooled (0°C) solution of δ-aminoindan (81mg) in anhydrous tetrahydrofuran (15ml) was treated with triphosgene (60.4mg) and triethylamine (250μl). After stirring at 0°C for lδ minutes a solution of (-)-3-amino-δ-(3-azabicyclo[3.2.2] nonan-3-yl)-l,3-dihydro-l-methyl-2H-benzodiazepin-2-one 0 trifluoroacetate (218mg) in anhydrous tetrahydrofuran (lδml) was added. After stirring at 0°C for 10 minutes the reaction mixture was left standing at 4°C for 2 days. The reaction mixture was evaporated to dryness and the residue partitioned between saturated potassium carbonate solution and ethyl δ acetate. The organic layer was dried (sodium sulphate) then evaporated and the residue purified by column chromatography on silica using dichloromethane 2% methanol in dichloromethane (gradient elution). The title compound was obtained as a colourless solid (14δmg, 60%). mp 2δ6°C. [ f 2°c D = 0 -124° (c=0.1, methanol). 1H NMR (360MHz, DMSO-de) δ 1.5-1.66 (6H, m), 1.76-1.87 (2H, m), 1.9-2.04 (4H, m), 2.76 (4H, dd, J^^β.δHz), 3.23-3.36 (2H, m), 3.32 (3H, s), 3.6-3.7 (2H, m), 4.96 (IH, d, J=7Hz), 6.79 (IH, d, J=7Hz), 7.0-7.64 (7H, m), 8.78 (1H, s). Found: C, 71.69; H, 6.82; N, 14.73. C^H^N^ requires C, 71.31; H, 7.0δ; N, 14.86%. EXAMPLE 42: N-r3 .SV5-(3-Azabicvc1or3.2.21nonan-3-vD-2.3- δ dihvdro-l-methv1-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3- trifluoromethvl-phenvn urea The title compound was obtained (690mg) from 3(.R,S)-amino-δ-(3-azabicyclo[3.2.2]nonan-3-yl)-l,3-dihydro-l- methyl-2H-l,4-benzodiazepin-2-one and 3-trifluoromethylphenyl 0 isocyanate as described in Example 31, Method A. mp 152-154°C (dichloromethane/diethyl ether (2:1)). MS, CI + , m/z = δOO for (M+H) + . Found: C, 60.58; H, 5.96; N, 12.91. C 26 28 3, 5O 2,.H, 20 requires C, 60.34; H, 5.84; N, 13.50%. 5 EXAMPLE 43: N-r3(R.£ 2.3-Dihvdro-5-(8-methv1-3.8- diazabicvclor3.2.11octan-3-vlV2-oxo-l-propvl-lH-1.4- benzodiazepin-3-yl1-NV3-methylphenvI1 urea Prepared analogously to Example 32 from 1-propyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,δ-dione and 8-methyl- 0 3,8-diazabicyclo[3.2.1] octane (J. Med. Chem. 1974, H, 481-487). mp 247-250°C. MS, CI + , m/z = 474 (M+H) + . <H NMR (360MHz, DMSOde) δ 0.70 (3H, t, J = 7Hz), 1.24 (IH, m), 1.39 (IH, m), 1.67 (IH, ), 1.79 (IH, m), 1.92 (IH, m), 2.15 (3H, s), 2.21 (3H, s), 2.62 (IH, m), 3.0 (4H, m), 3.62 (IH, m), 4.42 (IH, m), 4.93 (IH, d, J = 8Hz), 6.71 (IH, d, J = 7Hz), 6.98 (IH, d, J = 8Hz), 7.06 (3H, m), 7.59 (4H, m), 9.80 (IH, s). Found: C, 67.99; H, 6.95; N, 17.54. C 27 H 34 N 6 0 2 requires C, 67.68; H, 7.26; N, 17.19%. EXAMPT.E 44: N-(3(R.SV5-(3-Azahicvclor3.2.21nonan-3-vD-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N'-r3-fluoro- 4-methvlphenvll urea Prepared as described in Example 31, Method B. mp 254- 255°C. Found: C, 65.87; H, 6.36; N, 14.54. CaβHaoFNgOg.O.δHgO requires C, 66.08; H, 6.61; N, 14.82%. EXAMPLE 45: (-VN-r5-(3-Azabicv lor3.2.21nonan-3-vl)-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-vll-N'-r3-fluoro- 4-methvlphenvn urea Hydrochloride The racemic compound (Example 44, l.δg) was separated into its enantiomers using semi-preparative HPLC on a Pirkle dinitrobenzoylleucine column (5μ) [(260 x 21.4)mm] eluting with 3% methanol in 1-chlorobutane (including 1% acetic arid). 20ml minute, λ = 305nm. The fractions from peak A were evaporated to dryness and the free base liberated and obtained as a colourless foam (660mg). The hydrochloride salt had mp 235-236°C (acetone/ethyl acetate). [α] a " c D = -242° (c=0.2, methanol). 1 H NMR (360MHz, DMSOds) δ 1.50-1.80 (10H, m), 2.12 (3H, d, J = 2Hz), 3.10-3.38 (IH, m), 3.41 (3H, s), 3.44-3.58 (2H, m), 3.70-4.00 (IH, m), 5.28-5.36 (IH, broad d), 6.90-7.86 (8H, m), 9.46 (IH, broad s). Found: C, 61.65; H, 6.20; N, 13.49. C 26 H 30 FN 5 O 2 .HC1.0.5H2O requires C, 61.35; H, 6.33; N, 13.75%. EXAMPLE 4β: (+)-N-r5-(3-Azahicvclor3.2.21nonan-3-yl)-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3-fluoro- 4-methvlphenvll urea Hydrochloride The title compound was obtained using the procedure described in Example 45. The fractions from peak B were evaporated to dryness and the free base liberated and obtained as a colourless foam (560mg). The hydrochloride salt had mp 232-234°C (acetone/ethyl acetate). [αP° c D = +275° (c=0.2, methanol). Found: C, 61.54; H, 6.30; N, 13.23. C 26 H 3O FN 5 O 2 .HC1.0.5H 2 O.0.1CH 3 CO 2 CH 2 CH 3 requires C, 61.23; H, 6.38; N, 15.52%. EXAMPLE 47- N-r3(R.SV5-(3-Azahicvclor3.2.21nonan-3-vP-2.3- dihvdro-1-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3- iodophenvll urea The title compound was obtained from 3(R,S)-amino-δ-(3- azabicyclo[3.2.2]nonan-3-yl)-l,3-dihydro-l-methyl-2H-l,4- benzodiazepin-2-one (Example 31, Method B) and m-iodoaniline as described in Example 41. mp > 176°C (chloroform). MS, CI + , m/z = 558 for (M+H) + . Found: C, 52.02; H, δ.00; N, 11.86. C 25 H 28 .lN 5 O 2 .H 2 O requires C, 52.18; H, 5.2δ; N, 12.17%. EXAMPLE 48: (-VN.r5-(3-Azahicv lor3.2.21nonan-3-vD-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vll-N'-r3- iedpphenyll ur a The racemic compound was separated into its enantiomers using semi-preparative HPLC on a Pirkle dinitrobenzoylleucine column (5μ) [(2δ0 x 21.4)mm] eluting with 4% methanol in 1- chlorobutane (including 1% acetic arid). 20ml/minute, λ = 305nm. The free base was liberated then recrystallised from ethyl acetate to afford a colourless solid (600mg). mp 219-221°C. [α] 23 ° C D = -132° (c=0.2, methanol). Found: C, 64.23; H, 5.03; N, 12.54. C 25 H 28 IN 5 0 2 requires C, 63.87; H, 5.06; N, 12.56%. EXAMPLE 49: (+VN-r5-(3-Azabicvclor3.2.21nonan-3-vD-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N'-r3- iodophenvll urea The title compound was obtained using the procedure described in Example 48. mp 220-222°C. [ c D = +132° (c=0.2, methanol). Found: C, 54.31; H, 4.99; N, 12.28. 0 25 ^-^ 5 0., requires C, 53.87; H, 5.06; N, 12.56%. EXAMPLE 50: N-r3fR.RV5-(3-Azabicvclor3.2.21nonan-3-vl)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-henzodiazepin-3-vll-N'-rphenvn urea The title compound was prepared using the procedure described in Example 31 but replacing m-tolylisocyanate with phenyl isocyanate. mp 214-215°C (tetrahydrofuran). MS, CI + , m/z = 432 for (M+H) + . Found: C, 69.78; H, 7.29; N, 14.62. 0^^ 5 0 3 .0.5 C 4 H 8 0 requires C, 69.35; H, 7.11; N, 14.98%. EXAMPLE 51 : N.r3(R.S -5-f2-Azahicvclor2.2.21octan-2-vD-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-henzodiazepin-3-vll-N , -r3- methvlphenvH urea a) 2-Azabicvclor2.2.21octane Anhydrous diethyl ether (150ml) was added to a stirred solution of IM lithium aluminium hydride in diethyl ether (57ml). Powdered 3-isoquinuclidinone (9g, Organic Synthesis. Coll. Vol. V, 670) was added in portions over 15 minutes then the reaction mixture was heated at reflux for 5 hours. The mixture was cooled, quenched with saturated sodium chloride solution (5ml) then stirred for 30 minutes. Diethyl ether (150ml) was added then the reaction mixture was filtered, dried (potassium carbonate), evaporated to approximately 10ml volume then treated with n-hexane (20ml) and aged at -20°C for 1 hour. 2- Azabicyclo[2.2.2]octane was isolated (4.80g) as a colourless solid, mp 175-180°C. 1 H NMR (360MHz, CDC1 3 ) δ 1.50-1.95 (9H, m), 2.84 (IH, s), 3.00 (2H, s), 3.38 (IH, broad s). b) 5-(2-Azabi vc1or2.2.21octan-2-vl)-1.3-dihvdro-2H-l- methyl-1.4-benzodiazepin-2-one The title compound was prepared from 1-methyl- 1,2,3,4- tetrahydro-3H-l,4-benzodiazepin-2,5-dione and 2-azabicyclo [2.2.2]octane as described in Example 31. mp 140-142°C (diethyl ether/n-hexane). MS, CI + , m/z = 284 for (M+H) + . Found: C, 70.62; H, 7.27; N, 14.41. C 17 H 21 N 3 O.0.25H 2 O requires C, 70.93; H, 7.53; N, 14.60%. c) 5-(2-Azabicvclor2.2.21octan-2-yl)-1.3-dihvdro-2H-l- methvl-3-oximido-1.4-benzodiazepin-2-one 5 The title compound was obtained from the foregoing benzodiazepine as described in Example 31. mp 264-266°C. MS, Cl-, m/z = 313 for (M+H Found: C, 63.68; H, 6.44; N, 17.01. 0^ 2 ^ 4 0 2 .0.5^0 requires C, 63.53; H, 6.59; N, 17.43%. d) N-r3(R.SV5-(2-Azabicvclor2.2.21octan-2-yl)-2.3-dihvdro- 10 l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3-methvlphenvll urea The title compound was prepared from the foregoing oxime as described in Example 31, Method B. mp 242-243°C (dec) (ethyl acetate). MS, CI + , m/z = 432 for (M+H Found: C, lδ 69.9δ; H, 6.77; N, 16.25. 0^ 2 ^0 2 requires C, 69.58; H, 6.77; N, 16.23%. EXAMPLE 52: N-r3(R.SV5-(3-Azahicvclor3.2.21nonan-3-vD-2.3- dihydre-l-πιethyl-2-ς>yo-ιS[-ι,4-benzodiagepip-3-yD-N'-f4-flμς>ro- 20 3-methvlphenvll urea A stirred, cooled (4°C) solution of 3(R,S)-amino-5-(3- azabicyclo[3.2.2]nonan-3-yl)-l,3-dihydro-l-methyl-2H-l,4- benzodiazepin-2-one (1.20g) in anhydrous tetrahydrofuran (15ml) was treated with triphosgene (388mg) and triethylamine 25 (1.6ml). After 10 minutes 4-fluoro-3-methylaniline (576mg) was added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 4 hours then evaporated to dryness. The residue was partitioned between chloroform (50ml) and water (50ml). The organic layer was separated, washed 0 with water (30ml), dried (potassium carbonate) then evaporated to dryness. The solid obtained was recrystallised from hot ethyl acetate to afford the title compound (1.10g, 63%). mp 160-162°C. 1 H NMR (360MHz, CDC1 3 ) δ 1.56-1.90 (8H, m), 1.94-2.02 (2H, m), 2.19 (3H, d, J = 2Hz), 3.24-3.40 (2H, m), 3.41 (3H, s), 3.50- 3.60 (2H, m), 5.28 (IH, d, J = 8Hz), 6.57 (IH, d, J = 8Hz), 6.85 (IH, dd, J, = J 2 = 9Hz), 7.00-7.05 (IH, m), 7.17 (IH, s), 7.21-7.32 (3H, m), 7.47-7.54 (2H, m). Found: C, 65.27; H, 6.58; N, 14.45. C 26 H 3O FN 5 O 2 .0.75H2O requires C, 65.46; H, 6.66; N, 14.68%. EXAMPLE 53: (- -N-r5-(3-Azabicvdor3.2.21nonan-3-vD-2.3- dihvdro-1-methvl-2-oxo-lH-1.4-benzodiazepin-3-vll-N'-r4-fluoro- 3-methvlphenvll urea Hydrochloride The racemic compound (Example 52, 620mg) was separated into its enantiomers using semi-preparative HPLC on a Pirkle dinitrobenzoylleucine column (5μ) [(250 x 21.4)mm] eluting with 5% methanol in 1-chlorobutane (induding 1% acetic arid). 20ml minute, λ = 305nm. The fractions from peak A were evaporated to dryness and the free base Hberated (255mg). The hydrochloride salt had mp 221-223°C (acetonitrile/ethyl acetate). [αP° c D = -248° (c=0.2, methanol). MS, CI + , m/z = 464 for (M+H) + of free base. Found: C, 61.41; H, 6.22; N, 13.46. CaeHaoFNgOg.HCl.O.δHgO requires C, 61.36; H, 6.34; N, 13.76%. EXAMPLE 54: (+VN-r5-(3-Azabicvclor3.2.21nonan-3-yl)-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-yl " l-N'-r4-fluoro- 3-methvlphenvll urea Hydrochloride Obtained using the procedure described in Example 53. mp 221-223°C (acetonitrile/ethyl acetate). [αP° c D = +240° (c=0.2, methanol). Found: C, 61.73; H, 6.20; N, 13.60. 0^^^0 2 ^01.0.5^0 requires C, 61.35; H, 6.34; N, 13.76%. EXAMPLE 55: (-)-N-r5-(3-Azahicvclor3.2.21nonan-3-yl -2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-yl " l-N'-r3- trifluoromethylphenvn ureε( Hydrochloride The racemic compound (Example 42, 400mg) was separated into its enantiomers as described in Example 53. mp 215-217°C (acetonitrile/ethyl acetate). [αP° c D = -216° (c=0.2, methanol). MS, CI + , m/z = 500 for (M+H) + of free base. Found: C, 57.76; H, 5.18; N, 12.79. requires C, 57.78; H, 5.50; N, 12.96%. EXAMPLE 56: (+ -N-r5-(3-Azahicvclor3.2.21nonan-3-vD-2.3- dihvdro-1 -methvl-2-oxo-lH-l .4-henzodiazepin-3-vn-N'-r3- trifluoromethvlphenvn urea Hydrochloride Obtained using the procedure described in Example 53. mp 209-212°C (acetonitrile/ethyl acetate). [αP° c D = +212° (c=0.2, methanol). Found: C, 53.25; H, 5.32; N, 11.86. C 2 eH 28 F 3 N 5 O 2 .HCl.3H 2 O requires C, 52.93; H, 5.88; N, 11.87%. EXAMPLE j7 ~ N-r3(RSV2.3-Dihvdro-l-methyl-5-( - octahvdroisoindol-2-vl)-2-oxo-lH-1.4-benzodiazepin-3-vll-N'-r3- methvlphenvll urea a) Cts-Octahvdroisoindole Cis-4-cyclohexene-l,2-dicarboximide (10.9g) was hydrogenated over 10% palladium on carbon (lg) in absolute ethanol (420ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cydohexane-1,2- dicarboximide (10.6g). To anhydrous diethyl ether (200ml) was cannulated under nitrogen a IM diethyl ether solution (200ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cydohexane-l,2-dicarboximide (10.6g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0°C, water (7ml) was added followed by 4N sodium hydroxide (7.6ml) and water (23ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil. b) 1.3-Dihvdro-l-methvl-5-(cts-octahvdroisoindol-2-vl)-2H- l ,4-pen?Qdiazepin-2-pne A solution of phosphorus pentachloride (6.15g) in dichloromethane (250ml) was added dropwise over 30 minutes to a stirred solution of l-methyl-l,2,3,4-tetrahydro-3H-l,4- benzodiazepin-2,5-dione (4.56g) in dichloromethane (150ml). The solution was stirred at room temperature for 2 hours, the solvent evaporated in vacuo and the residue azeotroped with toluene. The dark solid was re-dissolved in dichloromethane (200ml), cooled to 4°C and a solution of crude cis- octahydroisoindole (3g) and triethylamine (6.6ml) in dichloromethane (100ml) was added over 30 minutes. The cooling bath was removed and the reaction mixture was stirred for 2 hours, then washed sequentially with 10% potassium carbonate and brine (twice). The organic layer was separated, treated with potassium carbonate, silica (Kieselgel) and decolourizing charcoal. The mixture was filtered then evaporated to dryness and purified by column chromatography on silica using dichloromethane → 10% methanol/dichloromethane (containing 1% ammonia) to afford the title compound (3.3g). mp > 128°C ( dec). Η NMR (360MHz, CDC1 3 ) δ 1.16-1.72 (8H, m), 2.04-2.18 (IH, m), 2.3-2.43 (IH, m), 2.9-3.2 (2H, m), 3.36 (3H, s), 3.54 (IH, d, J = 12Hz), 3.5-3.76 (2H, m), 4.23 (IH, d, J = 12Hz), 7.19-7.32 (2H, m), 7.44-7.52 (2H, m). c) 1.3-Dihvdro-l-methvl-5-( ts-octahvdroisoindol-2-vD-2H- 3-oximido-1.4-benzodiazepin-2-one Potassium t-butoxide (2.94g) was added in portions to a stirred, cooled (-25°C) solution of l,3-dihydro-l-methyl-5-(cis- octahydroisoindol-2-yl)-2H-l,4-benzodiazepin-2-one (3.2g) in anhydrous toluene (110ml) under a nitrogen atmosphere. After stirring at -25°C for 50 minutes isopentylnitrite (1.6ml) was added. The reaction mixture was stirred at -25°C for 6 hours, then isopentylnitrite (0.8ml) was added followed sequentially by potassium t-butoxide (300mg) after 18 hours, isopentylnitrite (0.4ml) after a further 30 minutes and finally isopentylnitrite (1.6ml) after a further 5 hours. The mixture was then stirred at -25°C overnight. Whilst warming to room temperature the reaction mixture was treated with water (30ml) containing citric arid (2.3g) and diethyl ether (40ml) then stirred for 1 hour. The precipitate was collected to afford the oxime (2.3g). mp 236- 238°C. -B NMR (360MHz, CDC1 3 ) δ 1.08-1.84 (8H, m), 2.12-2.56 (2H, m), 3.0-4.0 (4H, m), 3.41 and 3.45 (3H, each s), 7.18-7.64 (4H, m). d) 1.3-Dihvdro-l-methvl-5-( -octahvdroisoindol-2-vIV2H- 3-(Q-(ethvlaminocarbonvDoximido)-1.4-benzodiazepin-2-one The foregoing oxime (2.3g), ethylisocyanate (2.8ml) and triethylamine (1ml) were heated at 65°C in anhydrous tetrahydrofuran (150ml) for 18 hours. The solvent was evaporated and the residue was purified by column chromatography on silica using dichloromethane — 3% methanol/dichloromethane to afford a white foam (2.8g, mixture of E/Z isomers). mp 175-180°C. VS. NMR (360MHz, CDC1 3 ) δ 1.08-1.78 (8H, m), 1.13 (3H, t, J = 7Hz), 2.06-2.37 (2H, m), 2.90- 3.12 (IH, m), 3.25 (2H, q, J = 7Hz), 3.44 and 3.45 (3H, each s), 3.53-3.80 (3H, m), 6.20-6.30 and 6.36-6.46 (IH, each m), 7.20- 7.55 (4H, m). e) 3(fi._g)-Amino-1.3-dihvdro-l-methvl-5-(cts-octahvdro is9i^ o^ -yl)-2lf-^4-b hzodia?epih-2-ρp The product of part a) (2.4g) was hydrogenated at 45 psi in methanol (160ml) over 10% palladium on carbon (lg) for 3 hours at room temperature. The mixture was filtered then evaporated to dryness to afford the title amine (2g). D N-r3ffl. ?)-2.3-Dihvdro-l-methvl-5-(cts-octahvdro isoindol-2-vlV2-oxo-lH-1.4-benzodiazepin-3-vll-N , -r3- methvlphenvll urea The foregoing amine (2g) in anhydrous tetrahydrofuran 5 (5ml) was treated with m-tolylisocyanate (0.72ml). After standing for 5 minutes 1 drop of dichloromethane was added. After ageing at 4°C for 18 hours the precipitate was collected to afford the title compound as a free base (2.2g). mp > lδ6°C (dec). Η NMR (360MHz, DMSO) δ 1.12-1.64 (8H, m), 1.96-2.09 0 (IH, m), 2.21 (3H, s), 2.30-2.36 (IH, m), 2.74-3.1 (IH, m), 3.27- 3.37 (IH, m), 3.31 (3H, s), 3.4δ-3.62 (2H, m), 4.94 (IH, d, J = 8Hz), 6.68-7.67 (8H, m), 6.91 (IH, d, J = 8Hz), 8.79 (IH, s). Found: C, 65.40; H, 6.70; N, 14.83. C 26 H 31 N 5 0 2 .1.7H 2 0 requires C, 65.57; H, 7.28; N, 14.70%. 5 EXAMPLE 58: (- N-r2.3-Dihvdro-l-methyl-5-(cts- octahvdroisoindol-2-vl)-2-oxo-lH-1.4-benzodiazepin-3-vll-N'-r3- methvlphenvllurea hydrochloride The racemic compound (Example δ7, lg) was separated 0 into its enantiomers using semi-preparative chiral HPLC on a Pirkle dinitrobenzoylleucine column (δμ) [(2δ0 x 21.4)mm] eluting with ethanol/hexane (1:1), flow rate 20ml/minute, U.V. detection at 310nm. The hydrochloride salt (3δ0mg) had mp > 190°C (dec). δ MS, CI+, m/z = 446 for (M+HK [αP° c D = -107.5° (c=0.2, methanol). Found: C, 61.65; H, 6.96; N, 13.33. C 26 H 31 N 5 O 2 .HCl.l.δH 2 O.0.1 C 4 H 8 0 requires C, 61.42; H, 6.99; N, 13.δ7%. HPLC (spherisorb ODS2, 70% acetonitrile/30% of 0.2% triethylamine in water and orthophosphoric acid to pH = 3): 0 98. δ% chemically pure. EXAMPLE 59: (+VN-r2.3-Dihvdro-1 -methvl-5-tos- octahvdroisoindol-2-vl)-2-oxo-1H-1.4-benzodiazepin-3-vn-N , -r3- methvlphenvnurea hydrochloride The title compound was obtained (360mg) using the δ procedure described in Example 58. The hydrochloride salt had mp > 190°C (dec). MS, CI+, m/z = 446 for (M+H [ά\∞' = +109° (c=0.2, methanol). Found: C, 62.10; H, 7.02; N, 13.50. C 26 H 31 N 5 0 2 .HC1.1.2H 2 θ requires C, 62.00; H, 6.88; N, 13.90%. HPLC (spherisorb ODS2, 70% acetonitrile/30% of 0.2% 0 triethylamine in water and orthophosphoric arid to pH = 3): > 99% chemically pure. EXAMPLE flO- N-r3(R.SV5-(N-Cvdohexyl-N-methylaminoV 2.3-dihvdro-2-oxo-l-propvl-lH-1.4-benzodiazepin-3-vn-N'-r3- 5 methvlphenvll urea a) 5-(N-Cvclohexvl-N-methvlaminoV2-oxo-l-propvl-1.4- benzodiazepine Prepared analogously to Example la) from l-propyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (lO.Og) and N-methylcydohexylamine (lδ.6g) and purified by flash diromatography, eluted with 2% methanol/0.δ% 0.88 ammonia solution/dichloromethane then δ% methanol/0.5% 0.88 ammonia solution/dichloromethane. l B NMR (DMSO) δ 0.68 (3H, t, sl = 7.3Hz), 1.84-2.04 (3H, m), 2.72 (3H, s), 3.40 (IH, d, i = 12.2Hz), 3.δ4 (IH, m), 3.88 (IH, d, i = 12.2Hz), 4.22 (IH, m), 7.34 (IH, m), 7.δ0 (IH, d, si = 7.43Hz), 7.60 (2H, m). b) δ-(N-Cvclohexyl-N-methylamino)-3-oximino-2-oxo-l- propvl-1.4-benzodiazepine Prepared analogously to Example lb) from product from step (a) (5g). The product was purified using flash silica chromatography, eluting with 0.δ%. 0.88 ammonium solution/2% methanol/dichloromethane followed by chromatography on an alumina column, eluting with 2% methanol/dichloromethane followed by δ% methanol/dichloromethane. l B NMR (DMSO) δ 0.52-2.06 (16H, m), 2.60-2.92 (3H, m), 3.60 (IH, m), 4.26 (IH, m), 7.22-7.66 (14H, m), 9.84 and 10.02 (IH, 2 x s). c) N-r3fR.SV5-(N-Cvclohexyl-N-methylamino)-2.3-dihvdro- 5 2-oxo- l-propvl-lH-1.4-benzodiazepin-3-vl1-N^-r3-methvlphenvll urea The product from step b) (2.31g) was dissolved in acetic arid (40ml), with activated zinc (8.83g) and trifluoroacetic acid (δ.21ml). The reaction was heated at 40°C for 8h with vigorous 10 stirring, then cooled to room temperature, filtered through hiflo, and washed through with acetic acid (2 x 20ml). The solvent was removed in vacuo, the resulting oil was azeotroped with toluene and dried under high vacuum for 30 min to give a yellow foam. The foam was redissolved in tetrahydrofuran (δOml), and lδ triethylamine (1.0ml) was added followed by m-tolylisocyanate (0.87ml). The reaction was stirred at room temperature for 2h then concentrated under vacuum. The residue was redissolved in dichloromethane (100ml), washed with saturated sodium hydrogen carbonate solution (100ml), separated and the aqueous 0 phase was reextracted with dichloromethane (2 x 2δml). The combined organic layers were washed with brine (δOml), dried (sodium sulphate) and the solvent was removed in vacuo to give a solid which was purified by flash column chromatography with 0.δ% 0.88 ammonia solution/dichloromethane as the eluant on a δ Lobar column. Mp = 118°C (uncorr); X B NMR (DMSO) δ 0.70 (3H, t, sl = 7.4Hz), 0.90-1.90 (13H, m), 2.23 (3H, s), 2.68 (3H, s), 3.64 (IH, m), 4.26 (IH, m), 4.90 (IH, d, sl = 8.4Hz), 6.71 (IH, d, = 8.0Hz), 6.92 (IH, d, sl = 8.6Hz), 7.12 (2H, m), 7.16 (IH, s), 7.38 (IH, m), 7.51 (IH, d, s i = 7.5Hz), 7.64 (2H, m); MS (CD m/e 462 0 [MH] + . Anal. Found C, 66.38; H, 7.72; N, 14.07. C 27-H 3,5 N 502.1.δH 9 ___ 0, requires C, 66.37; H, 7.84; N, 14.33%. EXAMPLE 61 : (- 5-(N-Cv ohe*vl-N-methvlamino)-2.3- dihvdro-2-oxo-l-propvI-lH-1.4-benzodiazepin-3-vl-N , -r3- methvlphenvll urea The racemate (430mg) of Example 60 was separated using δ preparative chiral HPLC with a dinitrobenzoyl leucine column (250 x 20 mm i.d. δμm) using 94:5:1 l-chlorobutane:methanol:acetic arid as the mobile phase (with a flow rate of 20ml/min and UV detection at 330nM). The two enantiomers were efficiently separated into Peak A (eluted first) 10 and peak B (eluted second). Peak A was evaporated in vacuo, and was partitioned between dichloromethane and sodium carbonate solution. The organic phases were dried (MgSO ), evaporated in vacuo and the residue obtained was triturated with diethyl ether and the lδ resulting solid was collected by filtration to give: Peak A (127mg). Mp = 121-123°C; ~ B NMR (360MHz, D 6 -DMSO) δ 0.69 (3H, t, s = 7.4Hz), 0.9-1.90 (13H, m), 2.21 (3H, s), 2.66 (3H, s), 3.64 (IH, m), 4.2δ (IH, m), 4.89 (IH, d, si = 8.4Hz), 6.70 (IH, d, s∑ = 8.0Hz), 6.94 (IH, d, i = 7.5Hz), 7.10 (2H, m), 7.16 (IH, s), 7.37 0 (IH, m), 7.50 (IH, d, si = 7.5Hz), 7.65 (2H, m), 8.80 (IH, s); MS (CD m/e 462 [MH] + . Anal. Found. C, 68.38; H, 7.74; N, 14.29. C 27 H 35 N 5 O 2 .0.85 H 2 0 requires C, 68.00; H, 7.76; N, 14.69. [α] 22 D -114° (C=0.1, MeOH). Purity A:B = > 99%. 5 EXAMPLE 62: (+) 5-(N-Cvclohexvl-N-methvlamino)-2.3- dihvdro-2-oxo-l-propvl-lH-1.4-benzodiazepin-3-vl-N'-r3- methvlphenvll urea Peak B from Example 61 was treated in the same way as Peak A Example 61. Mp = 126-127°C; ' B NMR (360MHz, 0 D 6 -DMSO) δ 0.69 (3H, t, si = 7.4Hz), 0.9-1.90 (13H, m), 2.21 (3H, s), 2.66 (3H, s), 3.62 (IH, m), 4.25 (IH, m), 4.89 (IH, d, si = 8,4Hz), 6.70 (IH, d, si = 8.0Hz), 6.94 (IH, d, si = 7.5Hz), 7.00 (2H, m), 7.17 (IH, s), 7.38 (IH, m), 7.50 (IH, d, si = 7.5Hz), 7.6δ (2H, m), 8.80 (IH, s); MS (CD m/e 462 [MH] + . Anal. Found. C, 69.93; H, 7.δ4; N, 14.62. CZ7 35N 6O 2.0.2 H IO requires C, 69.71; H, 7.67; N, lδ.05%. [αr D +108 o (C=0.1, MeOH). Purity B:A = > 96:4. δ EXAMPLE 63: N-r3(RS 5-(N-Cvdohexyl-N-methylamino)-2.3- dihvdro-l-methvl-2-oxo-1H-1.4-benzodiazepin-3-vn-N'- r3-methylphenyll urea Prepared as for Example 60 parts a, b, and c, from 1- 10 methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione and recrystallised from methanol, water. Mp 14δ-147°C. ' B NMR (360MHz, D 6 -DMSO) δ 0.99 (10H, m), 2.21 (3H, s), 2.6δ (3H, s), 3.31 (4H, m), 4.92 (IH, d, si = 8.4Hz), 6.70 (IH, d, s∑ = 8.0Hz), 6.93 (IH, d, si = 7.δHz), 7.09 (2H, m), 7.17 (IH, s), 7.36 (IH, m), lδ 7.49-7.69 (3H, m), 8.80 (IH, s); MS (CD m/e 434 [MH] + . Anal. Found. C, 67.22; H, 7.23; N, lδ.29. requires C, 67.17; H, 7.33; N, lδ.67%. EXAMPLE 64: (-) 5-(N-Cvdohexvl-N-methvlamino)-2.3- 0 dihvdro-2-oxo-l-methvl-lH-1.4-benzodiazepin-3-vl-N'- r3-methvlphenvll urea. Hydrochloride Separated from the racemate of Example 63 by chiral HPLC as for Example 61. Peak A free base was dissolved in dichloromethane. Ethereal hydrogen chloride was added and 2δ after δ minutes the solvent was removed in vacuo. The resulting oil was crystallised from dichloromethane/ether. Mp 193-19δ°C. -B (360MHz, D 6 -DMSO, trifluoroacetic arid) δ 0.9δ-1.9δ (10H, m), 2.23 (3H, s), 3.12 (3H, s), 3.43 (4H, m), δ.39 (IH, m), 6.76 (IH, d, si = 7.2Hz), 7.11-7.90 (7H, m). MS (Cl) m/e 434 [MH] + . 0 Anal. Found. C, 60.4δ; H, 7.02; N, 14.06. C^H N 0 2 .HC1. l.δH 2 0 requires C, 60.41; H, 7.02; N, 14.35%. [α] 2 ^-195° (c = 0.1, MeOH). Purity A:B = >99%. EXAMPLE 65: f+)5.t\τ-πv nheτv1-N-methvlamino)-2.3- dihvdro-2-oxo-i-methvl • „ 1 ,4-benzodiazepiτ>-3-yl-N'- r3-methvlphenvl1 urea. I - QCfrloή Separated from the racemate of Example 63 by chiral 5 HPLC as for Example 61. Peak B (eluted second) was treated as in Example 64 to yield the desired hydrochloride (90mg). Mp 194-196°C. X H NMR (360MHz, D 6 -DMSO + trifluoroacetic arid) δ 0.95-1.95 (10H, m), 2.24 (3H, s), 3.12 (3H, s), 3.43 (4H, m), 5.39 (IH, m), 6.76 (IH, d, si = 7.5Hz), 7.06-7.86 (7H, m), 9.20 (IH, s); 0 MS (CD m/e 434 [MH] + . Anal. Found. C, 58.28; H, 6.82; N, 13.47. C 25 H 31 N 5 O 2.HC1.2.35H 2 O requires C, 58.61; H, 7.22; N, 13.67%. [c r D +154 0 (C=0.1, MeOH). Purity B:A = > 9δ%. EXAMPLE 66: N-r3(R.S)-5-(N-Cvdoheptyl-N-methylamino)-2.3- 5 dihvdro- l-methyl-2-oxo- IH- 1.4-benzodiazepin-3-yl1-N'- r3-methylphenyll urea Prepared analogously to Example 60 from N- methylcycloheptylamine. Mp = 135°C (uncorr); 1H NMR (DMSO) δ 1.10 (IH, m), 1.20-1.50 (7H, m), 1.50-1.84 (4H, m), 0 1.91 (IH, m), 2.22 (3H, s), 2.63 (3H, s), 3.31 (3H, s), 4.94 (IH, d, si = 8.0Hz), 6.70 (IH, d, si = 6.9Hz), 6.94 (IH, d, J = 8.4Hz), 7.09 (2H, m), 7.17 (IH, s), 7.37 (IH, t, si = 6.9Hz), 7.51 (IH, dd, = 7.8 and 1.3Hz), 7.62 (2H, m), 8.82 (IH, s); MS (CD m/e 448 [MHf. Anal. Found. C, 70.02; H, 7.41; N, lδ.60. C 26 H 33 N 5 O 2 requires C, δ 69.77; H, 7.43; N, lδ.6δ%. EXAMPLE 67: (-)-5-(N-Cvcloheptyl-N-methylamino)-2.3-dihvdro l-methyl-2-oxo-lH-1.4-benzodiazepin-3-vl-N'-r3-methvlphenvn vxea, Bydrochlpride 0 a) The racemate (700mg) of Example 66 was separated using preparative chiral HPLC with a dinitrobenzoylleurine column (250 x 20mm i.d, 5 μM) using 89:10:1 l-chlorobutane:methanol:acetic acid as the mobile phase, with a flow rate of 20ml/minute and u.v. detection of 330nM. Peak A was evaporated in vacuo and redissolved in the τmn * iττι * nττι of dichloromethane. The hydrochloride salt has formed by adding a saturated solution of hydrogen chloride in ether (5ml). The resulting solution was triturated with ether, filtered and dried under high vacuum. Mp. 172=174°C; ~ B NMR (360MHz, D 6 -DMSO, V.T. α 353K) δ 1.04-2.12 (13H, m), 2.24 (3H, s), 3.04 (3H, s), 3.38 (3H, s), δ.32 (IH, d, si = 7.6Hz), 6.72 (IH, d, si = 7.6Hz), 7.04-7.26 (4H, m) 7.δ2 (IH, t, si = 7.6Hz), 7.70 (2H, m), 7.82 (IH, t, si = 7.3Hz), 9.24 (IH, s(b)); MS (CD m/e 448 [MH] + . Anal. Found. C, 62.44; H, 7.29; N, 13.71. es C, 62.20; H, 7.23; N, 13.95. MeOH). Purity A:B > 99%. EXAMPLE 68: (+)-5-(N-Cvcloheptyl-N-methylamino)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl-N'- r3-p_ietfrylphenyl1 urea, Pydrochloride Peak B from Example 67 was treated in the same way as peak A to give the required product. Mp 173-175°C; 1H NMR (360MHz, D 6 -DMSO, V.T. α 3δ3K) δ 1.06-2.14 (13H, m), 2.24 (3H, s), 3.0δ (3H, s), 3.38 (3H, s), δ.33 (2H, d, si = 7.6Hz), 6.74 (IH, d, si = 7.2Hz) 7.04-7.26 (4H, m), 7.54 (IH, t, si = 7.5Hz), 7.63-7.74 (2H, m), 7.82 (IH, t, si = 7.δHz), 9.2δ (IH, s(b)); MS (CD m/e 448 [MH] + . Anal. Found. C, 62.36; H, 7.26; N, 13.53. C 26 H 33 N 5 0 2 .HC1 requires C, 62.20; H, 7.23; N, 13.95. [α] 22 D =+172° (c = lmgm MeOH). Purity B:A = 96.2% EXAMPLE 69: N-r3(R.S)-5-(N-Cvdoheptyl-N-methylamino)-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'- rδ-indanvH urea a) (±)-N-r3-amino-5-(N-cvcloheptyl-N-methylamino-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepine. (TFA salt) To a solution of 5-(N-cydoheptyl-N-methylamino)- l-methyl-3-oximino-2-oxo-l,4-benzodiazepine (l.OOg,) in acetic arid (40ml) was added activated zinc (3.99g) and trifluoroacetic arid (3.48g). The reaction was stirred at 40°C for 30 minutes, δ cooled to room temperature, filtered through hiflo, and washed with acetic arid (2 x 20ml). The solvent was removed in vacuo, and the resulting oil was azeotroped with toluene and dried under high vacuum. b) N-r3(R.S)-5-(N-Cvdoheptvl-N-methvlamino)-2.3- 10 dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r5- indanvll urea 5-aminoindane (0,41g) was dissolved in tetrahydrofuran (δOml) and cooled (0°C) under nitrogen. Triphosgene (0.31g) was added and the reaction stirred vigorously (2 minutes). lδ Triethylamine (0.92g) was added and the reaction stirred for a further 30 minutes. A solution of the product from part a) and triethylamine (sufficient to take solution to pH9) in tetrahydrofuran (2δml) was added dropwise and the reaction allowed to stir overnight. 0 The solvent was removed in vacuo, and the reaction mixture redissolved in dichloromethane (100ml). This solution was washed with saturated sodium bicarbonate solution (50ml), reextracted with dichloromethane (3 x 25ml) and the combined organics washed with brine (50ml). The solution was dried over 5 sodium sulphate and the solvent removed in vacuo to give an oil that was purified by column chromatography with 0.2% 0.88 ammonia solution/dichloromethane then by 0.2% 0.88 ammonia solution/2% methanol/dichloromethane as the eluent. The product was recrystallised from ethyl acetate/60-80 petrol. Mp 0 183-185°C. l B NMR (360MHz, D 6 -DMSO, V.T. α 3δ3K) δ 0.80-1.80 (11H, m), 1.86-2.04 (3H, m), 2.6δ (3H, s), 2.74 (4H, q, si = 7.0Hz), 3.30 (3H, s), 3.59 (IH, m), 4.94 (IH, d, si = 7.1Hz), 6.74 (IH, d, si = 8.4Hz), 7.02 (2H, m), 7.22 (IH, s), 7.34 (IH, t, s∑ = 8.4Hz), 7.48 (IH, m), 7.52 (IH, m), 7.60 (IH, m), 8.60 (IH, s). MS (CD m/e 474 [MH] + . Anal. Found. C, 71.69; H, 7.86; N, 14.14. C 28 H 35 N 502.0.3C 6 H 4 requires C, 71.66; N, 7.91; N, 14.02% 5 EXAMPT.E 70: (- 5-(N-Cvcloheptvl-N-methvlamino)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl-N'-rδ-indanvll yrea, HydrogWoride a) The racemate of Example 69 (600mg) was separated using preparative chiral HPLC with a dinitrobenzoylleucine 10 column (2δ0 x 20mm i.d, δμm) using 70% ethanol in hexane as eluent at a flow rate of 20ml min and u.v. detection at 330nM. Peak A was concentrated in vacuo and redissolved in dichloromethane (~2ml). A saturated solution of hydrogen chloride in dry diethyl ether (δml) was added and the resulting lδ suspension was triturated with more diethyl ether (20ml). The product was collected by filtration. Mp 181-187°C dec; 1H NMR (360MHz, DMSO) δ 1.20-2.12 (14H, m), 2.76 (4H, q, si = 7.0Hz), 2.93-3.12 (3H, 2s, CH 3 restricted rotation), 3.42 (3H, s), 3.62 and 4.18 (IH, 2m), δ.36 (IH, m), 7.0δ-7.90 (8H, m), 9.48-9.63 (IH, 20 2s). 10.17 and 10.32 (IH, 2br s); MS (CD m/e 474 [MH] + . Anal. Found C, ' 62.83; ' H,' 7.19; ' N,' 13.07. C 28 H 35 N 5 O 2.HCl.l.δH 20 requires C, 62.61; H, 7.32; N, 13.04%. [α] 2 D -175° (c = 0.1, MeOH). Purity A:B > 99%. δ EXAMPLE 71 : (+ 5-(N-Ovdoheptyl-N-methylamino)-2.3- dihvdro-l-ethvl-2-oxo-lH-1.4-benzodiazepin-3-vll-N'-r5-indanvll urea Hydrochloride Prepared analogously to Example 70. m.p. 181-187°C dec; ~ B NMR (360MHz, DMSO) δ 1.20-2.19 (14H, m), 2.76 (4H, q, si = 0 7.0Hz), 2.93 and 3.12 (3H, 2s, CHg restricted rotation), 3.42 (3H, s), 3.62 and 4.18 (IH, 2m), 5.36 (IH, m). 7.05-7.90 (8H, m), 9.40 and 9.42 (IH, 2s), 10.10 and 10.26 (IH, 2br s); MS (CD m/e 474 [MHT. Anal. Found C, 62.83; H, 7.20; N, 13.06. C H 35 N 5 0 2 .HC1.1.5H 2 0 requires C, 62.61; H, 7.32; N, 13.04%. [ccr 2 D +197° (c=0.1, MeOH). Purity B:A > 99%. EXAMPLE 72: N-r3(R.S)-5-fN-Benzvl-N-methvlamino)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vll-N'- [3-methvlphenvl1 urea To a solution of 5-(N-benzyl-N-methylamino)-3- oximino-2-oxo-l-methyl-l,4-benzodiazepine (prepared as for Example 1 parts a and b, from l-methyl-l,2,3,4-tetrahydro-3H- l,4-benzodiazepin-2,5-dione and N-methylbenzylamine) in methanol was added rhodium on carbon (600mg) and the resultant mixture was hydrogenated at 50psi at 60°C for δh. The reaction mixture was allowed to cool, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, cooled to 0°C and m-tolylisocyanate added. This mixture was stirred at room temperature for 12 hours, solvent removed in vacuo and the residue purified by flash column chromatography with 0.5% 0.88 ammonia solution, methanol and dichloromethane as the eluent, to yield the product which was recrystallised from dichloromethane, ethyl acetate (1:1). Mp 172-174°C. l B NMR (360MHz, D 6 -DMSO) δ 2.21 (3H, s), 2.74 (3H, s), 4.26 and 4.5δ (2H, dd, si = 15.8Hz), δ.OO (IH, d, si = 8.4Hz), 6.70 (IH, d, si = 8.0Hz), 6.96-7.76 (12H, m), 8.81 (IH, s); MS (CD m/e 442 (MH) + . Anal. Found C, 70.86; H, 6.39; N, 15.8δ% CJ 26327N 5O 2 requires C, 70.73; H, 6.16; N, 15.86%. EXAMPLE 73: N-r3(R.S)-5-(N-(4-N-Methylpiperidinyl)-N- methvlamino)-2.3-dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin- 3-yll-N'-r3- methylphenyllurea Prepared analogously to Example 60 from 1-methyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione and N- methyl-(4-methylamino)piperidine. Mp = 146°C (uncorr); 1H NMR (DMSO) δ 1.24 (IH, m), 1.60-1.90 (6H, m), 2.12 (3H, s) 2.21 (3H, s), 2.65 (3H, s), 2.75 (IH, m), 2.82 (IH, m), 3.32 (3H, s), 4.92 (IH, d, si = 8.4Hz), 6.70 (IH, d, s = 7.1Hz), 6.95 (IH, d, si = 8.4Hz), 7.09 (2H, m), 7.17 (IH, s), 7.38 (IH, m), 7.51 (IH, dd, si = 1.4 + 7.8Hz), 7.62 (2H, m), 8.82 (IH, s); MS (CD m/e 449 [MH] + . Anal. Found: C, 63.37; H, 7.04; N, 17.46. C^H^O,,. 1.3H 2 0 requires C, 63.62; H, 7.39; N, 17.81%. EXAMPT_E 74- N-r3(R.S)-5-(N-Cvdohe vlmethvl-N- methvlamino)-2.3-dihvdro-2-oxo-l-propvl-lH.1.4-benzodiazepin- 3-γll-N'-f3- ethylphenyllnrea Prepared as described in Example 60 from N- methylcyclohexylamine and l-methyl-l,2,3,4-tetrahydro-3H-l,4- benzodiazepin-2,5-dione; mp 218-225°C. 1H NMR (DMSO) δ 0.31 (IH, m), 0.66 (IH, m), 0.96-1.54 (9H, m), 2.21 (3H, s), 2.81 (3H, s), 2.92 (IH, m), 3.16 (IH, m), 3.30 (3H, s), 4.94 (IH, d, si = 8.4Hz), 6.70 (IH, d, si = 7.0Hz), 6.91 (IH, d, si = 8.4Hz), 7.05-7.65 (7H, m), 8.81 (IH, s); MS (CD m/e 448 [MH] + . Anal. Found C, 65.59; H, 7.44; N, 15.46. C 26H 33N 502 o requires C, 69.77; H, 7.47; N, 15.65%. EXAMPLE 75; N-r3(R.S -5-(N.N-Di- a propylamino)-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-yll-N'--r3-methyl phenyllwrea Prepared as for Example 60, using di-n-propylamine in place of N-methylcyclohexylamine and recrystalHzed from ethyl acetate and hexane. Mp 164-166°C. 1H NMR (360MHz, D 6 -DMSO-TFA) δ 0.60 (3H, t, si = 7.3Hz), 0.99 (3H, t, si *= 7.4Hz), 1.57 (2H, m), 1.73 (2H, m), 2.25 (3H, s), 3.43 (5H, m), 3.88 (2H, m), 5.40 (IH, d, si = 6.3Hz), 6.78 (IH, d, si = 7.1Hz), 7.35-7.70 (8H, m), 9.30 (IH, s) MS (CD m/e 422 [MH] + . Anal. Found: C, 68.33; H, 7.44; N, 16.27%. C H N O requires C, 68.38; H, 7.41; N, 16.61%. EXAMPLE 76; N-r3(R,S)-5-(N-Ov Qpentyl-N-ethyiamino)- 2.3-dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'- [3-τnethylphenyll urea Prepared as for Example 72, but using N-ethylcydopentylamine in place of N-methylbenzylamine and recrystallized from ethyl acetate hexane. Mp = 252-255°C, l B NMR (360MHz, D 6 -DMSO) δ 0.70-1.60 (11H, m), 2.21 (3H, s), 2.91-3.90 (6H, m), 5.37 (IH, d, si = 8.4Hz), 6.72 (IH, d, si = 8.0Hz), 6.92 (IH, d, si = 7.5Hz, 7.10 (2H, m), 7.29-7.63 (5H, m), 10.24 (IH, s). Anal. Found: C, 69.70; H, 7.21; N, 15.41%. C 25H 31N 5O, 2 O.lδC 6 H 14 requires C, 69.68; H, 7.47; N, 15.69%. EXAMPLE 77: N-[3(R,S)-6-(N-(4,4-Di ethγlcγclohe??γlVN- methyla ino)-2.3-dihydro-l-methγl-2-pχe-lH-l,4-benzodiazepin vl-3-vl1-N'-r3- methylphePYll rea a ) N-Methγl-4,4-dimethγlgγglohe? y-lamine To a solution of 4,4-dimethylcyclohexanone (25.2g) in dry methanol under an atmosphere of nitrogen was added methylamine hydrochloride (13.2g) and 3A mol sieves (lg). The reaction mixture was stirred for lhr then sodium cyanoborohydride (12.7g) added portionwise. The mixture was stirred for 17hrs. A saturated solution of hydrogen chloride in methanol (200ml) was added and the reaction mixture stirred for lhr the filtered through hyflo and concentrated in vacuo. The residue was partitioned between IN sodium hydroxide (300ml) and dichloromethane (200ml). The layers were separated and the aqueous re-extracted with dichloromethane (2 x 200ml). The combined organics were washed with saturated sodium hydrogen carbonate (300ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was distilled under reduced pressure. Bpt 40-45°C at O.lmmHg. l B NMR (CDC1 ύ ) δ 0.92 (6H, s), 1.10-1.30 (5H, m), 1.30-1.50 (2H, m), 1.66-1.72 (2H, m), 2.26 (IH, m), 2.42 (3H, s). b) 5-(N-(4.4-Dimethvlcvriohexvl)-N-methvlaminoV3- oximino-l-methvl-2-oxo-1.4-benzodiazepine Prepared as described in Example 1, steps a) and b) from l-methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione and N- methyl-4,4-dimethylcydohexylamine. c) N-r3(R.RV5-(N-(4.4-Dimethvl vclohexvD-N- methvlamino)-2.3-dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin- 3-γll-N'-r3-τpf hγlphenγllurea The product from step b) (800mg) was dissolved in dry tetrahydrofuran under an atmosphere of nitrogen and ethyl isocyanate (0.37ml) added. The reaction mixture was heated at 60°C for 12h with stirring, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica elution with l-→3% methanol/0.5% 0.88 ammonia solution in dichloromethane. The product was dissolved in methanol (20ml) and palladium on activated charcoal (400mg) was added. The reaction was hydrogenated at 40psi for 2hrs then filtered through a glass fibre filter and concentrated in vacuo without heating. The product was dissolved in dry tetrahydrofuran (2ml) and m-tolylisocyanate (212μl) added. After 20mins diethyl ether (10ml) was added and the product collected by filtration and recrystallised from ethyl acetate, mp = 172°C (uncorr). ~ B NMR (DMSO) δ 0.82 (3H, s), 0.88 (3H, s), 0.90-1.20 (3H, m), 1.20-1.42 (2H, m), 1.56-2.84 (3H, m), 2.21 (3H, s), 2.69 (3H, s), 3.31 (3H, s), 4.92 (IH, d, si = 8.4Hz), 6.70 (IH, d, si = 8.8Hz), 6.94 (IH, d, si = 8.4Hz), 7.10 (2H, m), 7.17 (IH, s), 7.36 (IH, m), 7.50 (IH, dd, si = 1.3 & 7.7Hz), 7.60 (2H, m), 8.80 (IH, s); MS (Cl) m/e 462 [MH] + . Anal. Found: C, 69.48; H, 7.69; N, 15.18. C H N O, 0.2H O requires C, 69.71; H, 7.67; N, 15.05%. EXAMPLE 78- N-r3rR.R 5-(N-Cvclohexv1-N-ethvlamino)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn-N , -[3- ethYlphenyll urea Prepared as for Example 60 using N-ethylcydohexylamine in place of N-methylcyclohexylamine and recrystallized from ethyl acetate. Mp = 206-207°C. l B NMR (360MHz, D g -DMSO) δ 0.83 (3H, m), 0.83-1.9 (10H, m), 2.2 (3H, s), 3.0 (IH, m), 3.3 (4H, m), 4.9 (IH, d, j∑ = 8.9Hz), 6.7 (IH, d, si = 6.5Hz), 6.9-7.6 (8H, Aromatics), 8.8 (IH, s). MS (Cl) m/e 448 (MH) + . Anal. Found: C, 69.79; H, 7.6; N, 14.82%. C 26H 33N 5O, 2 requires C, 70.04; H, 7.49; N, 15.18%. EXAMPLE 79: N-r3(R.S 5-(N-Cvclohexyl-N-propylamino)-2.3- dihvdro-1-methvl-2-oxo-lH-benzodiazepin-3-vll-N'-[3- methvlphenvnurea Prepared as described in Example 60 from 1-methyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-l,5-dione and N- propyl(yclohexylamine. Mp = 146°C (uncorr); 1H NMR (360MHz, DMSO) δ 0.77 (3H, s), 0.86-1.18 (3H, m), 1.20-1.56 (6H, m), 1.56-1.80 (2H, m), 1.88 (IH, m), 2.12 (3H, s), 2.82 (IH, m), 3.31 (3H, s), 3.43 (IH, m), 4.93 (IH, d, s∑ = 8.3Hz), 6.70 (IH, d, s∑ = 6.9Hz), 6.89 (IH, d, s∑ = 8.3Hz), 7.10 (2H, m), 7.18 (IH, s), 7.38 (IH, m), 7.48 (IH, dd, s∑ = 1.3 & 7.9Hz), 7.61 (2H, m), 8.12 (IH, s); MS (CD me 462 [MH] + . EXAMPLE 80: N-r3(R.S)-5-(N-Benzyl-N-cvclohexylamino)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N'- r3-methvlphenvll urea a: N-Benzvlcvclohexvlamine To a stirred solution of cyclohexylamine (9.34g) in methanol (300ml) was added benzaldehyde (lO.Og) followed by activated 3A molecular sieves. After lh, sodium cyanoborohydride (7.13g) was added followed by the dropwise addition of acetic acid (9.2ml), and the reaction was stirred overnight. The reaction mixture was filtered through hiflo, the solvent removed in vacuo and the resulting white solid was heated raider reflux in 5M potassium hydroxide solution for 30 mins. The product was extracted into dichloromethane (3 x 100ml) and the combined organic layers were washed with brine (100ml), dried over sodium sulphate and the solvent was removed in vacuo to give a dear oil. The product was purified by column chromatography (eluting with ethyl acetate) then distillation; bpt = 137°C at l.Ombarr. 1H NMR (360MHz, D 6 -DMSO) δ 0.94-1.24 (δH, m), 1.48-1.88 (δH, m), 2.32 (IH, m), 2.32 (IH, m), 3.10 (2H, s(b)), 3.72 (2H, s), 7.14-7.40 (δH, m). b) N-r3(R.S)-5-N-Benzyl-N-cvclohexylamino)-2.3- dihγdrQ-l-methyl-2-oxo-lH-l,4-bengodiazepin-3-γn-N'-r-3- methvlphenvllurea Prepared as for Example 60 from l-methyl-1,2,3,4- tetrahydro-3H-l,4-benzodiazepin-2,5-dione and N- benzylcydohexylamine and recrystallised from ethyl acetate/60-80 petrol, mp = 178-179°C, 'B NMR (360MHz, D 6 -DMSO, VT α 353K) δ 0.92-1.94 (10H, m), 2.21 (3H, s), 3.16 (3H, s), 3.66 (IH, m), 4.22 (IH, d, s∑ = 16Hz), 4.70 (IH, d, s∑ = 16Hz), 4.92 (IH, d, s ∑ = 8.3Hz), 6.72 (2H, m), 7.02-7.24 (8H, m), 7.32 (IH, m), 7.44 (IH, m), 7.56 (2H, m), 8.62 (IH, s); MS (CD m/e = 510 [MH] + ; Anal. Found: C, 73.08; H, 6.85; N, 13.74. C lH OON OO J,t requires C, 73.06; H, 6.92; N, 13.74%. EXAMPLE 81: N-r3fR_S 5-(N-Cvclohexvlamino)-2.3-dihvdro-1- methyl-2-oxo-lH-1.4-benzodiazepin-3-yl1-N'-[3- methYlphenyllwea To a stirred solution of the product of Example 80 (0.50g) in methanol (40ml) under nitrogen was added ammonium formate (0.31g) followed by 10% palladium on carbon (O.δOg). The reaction mixture was heated under reflux for 2h then cooled to room temperature, filtered, washed with methanol (3 x 20ml) and the solvent removed in vacuo. The product was redissolved in dichloromethane (200ml), washed with brine (100ml), dried over sodium sulphate and the solvent removed in vacuo to give a white solid. Recrystallised from ethyl acetate 60-80 petrol, mp = 153-lδ5°C; ~ B NMR (360MHz, D 6 -DMSO) δ 0.88 (IH, m), 1.06-1.34 (4H, m), 1.88-2.00 (δH, m), 2.22 (3H, s), 3.28 (3H, s), 3.68 (IH, m), 4.88 (IH, d, j∑ = 8.6Hz), 6.54 (IH, d, s∑ = 7.7Hz), 6.68 (IH, d, ,∑ = 6.9Hz), 6.86 (IH, d, s∑ = 8.6Hz), 7.08 (2H, m), 7.14 (IH, s), 7.34 (IH, t, s∑ = 7.8Hz), 7.60 (2H, m), 8.77 (IH, s); MS (CD; m/e = 420 [MH] + . Anal. Found: C, 65.77; H, 6.97; N, 15.98. C 24 H 29 H δ O 2.H 2 O req ~~uires C, 65.77; H, 7.14; N, 16.01%. EXAMPLE 82: N-r3(R.SV5-(N-Cvdnhexvl-N-methvlamino)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl1-N'- [5-indanvllurea Prepared as for Example 77c) and Example 69b) using 5-aminoindane. Mp = 232-234°C. 1H NMR (360MHz, D g -DMSO) δ 1.01-1.98 (16H, m), 2.65 (3H, s), 2.76 (H, m), 4.92 (H, d, s∑ = 8.46Hz), 6.88 (H, d, s∑ = 8.46Hz), 7.23-7.65 (7H, m), 8.65 (H, s). MS (CD m/3 461 [MH * ]. Anal Found: C, 68.78; H, 7.34; N, 13.26%. C 27H 33N δO, 2 0.7EtOAc 0.7H Λ) requires C, 68.48; H, 7.71; N, 13.39%. EXAMPLE 83: N-r3(R.S)-5-(N-Cvdooctvl-N-methvlamino)- 2.3-dihv ro- -methvl-2-oxo-lH-l■4-benz diazepin-3-vn-N , - [3-methvlphenvll urea Prepared as for Example 77 using N-methyl cyclooctylamine in place of N-methyl-4,4- dimethylcyclohexylamine. mp = 221-222°C. 1H NMR (360MHz, D g -DMSO) δ 1.1-1.6 (14H, m), 2.2 (3H, s), 2.66 (3H, s), 3.3 (3H, s), 4.96 (IH, d, s∑ = 1.18Hz), 6.7 (IH, d, s∑ = 6.6Hz), 6.9-7.6 (8H, m), 8.8 (IH, s). EXAMPT,E 84- N-r3(R.SV2.3-Dihvdro-5-(2-(N.N- dimethv1aminn)ethvlamino)-l-methvl-2-oxo-lH-1.4- benzodiazepin-3-vn-N , -r3- methvlphenvllurea dihvdrochloride a) 1 -2-Dihvdro-5-f2-(N.N-dimet,hvlπmino)ethv1aminoV1- methvl-3H-1 -4-benzodiazepin-2-one A solution of phosphorous pentachloride (8.10g) in anhydrous dichloromethane (350ml) was added dropwise to a stirred suspension of l-methyl-l,2,3,4-tetrahydro-3H-l,4- benzodiazepin-2,5-dione (6.0g) in anhydrous dichloromethane (150ml). After stirring for 3h the solvent was evaporated, the residue re-dissolved in dichloromethane (200ml), cooled to 4°C and treated dropwise with a solution of N,N-dimethylaminoethylamine (8.81g) in anhydrous dichloromethane (100ml). The cooling bath was removed and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was evaporated to dryness and the residue purified by column chromatography on neutral alumina (Grade 3) using dichloromethane/methanol (30:1) to (20:1) (gradient elution). MS, Cl*, m/z = 262 for (M+H) * . ' B NMR (CDCy δ 2.24 (6H, s), 2.46-2.60 (2H, m), 3.36 (s) and 3.32-3.47 (total 5H, m), 3.61 (IH, d, s∑ = 12Hz), 4.20 (IH, d, s∑ = 12Hz), 5.20 (IH, broad res.), 7.20-7.32 (2H, m), 7.46-7.59 (2H, m). b) 1.2-Dihvdro-5-(2-(N.N-dimethylamino)ethyl-(t- btttYlo^carb9 yl)aimnp)-l-iT ethyl-3H-l,4-ben?odiagepin-2-9Pe Di-5-butyldicarbonate (4.33g) was added in portions to a stirred, cooled (4°C) solution of the foregoing benzodiazepine (4.70g) in dichloromethane (40ml). After addition the cooling bath was removed and the reaction mixture stirred at room temperature for 16h. The reaction mixture was evaporated to dryness and the residue purified by column chromatography on neutral alumina (Grade 3) using dichloromethane/methanol (50:1). Mp < 35°C. MS, Cl*, m/z = 361 for (M+H) * . ~ B NMR (CDC1 3 ) δ 1.22 (9H, s). 2.45 (6H, s), 2.68-2.76 (IH, m), 2.79-2.87 (IH, m), 3.53 (3H, s), 3.72 (IH, d, s∑ •= 11Hz), 4.02-4.09 (IH, m), 4.24-4.32 (IH, m), 4.65 (IH, d, s∑ •= 11Hz), 7.35 (IH, dd, χ = ^ = 8Hz), 7.41 (IH, d, s∑ = 8Hz), 7.65 (IH, ddd, s∑ χ = 2Hz, ^ = .1, = 8Hz), 7.79 (IH, dd, s∑ χ = 2Hz, ^ = 8Hz). c) 1 -2-Dihvdro-5-(2-(N.N-dimethvlamino)ethvl-(t- butvloxvcarbonvl)amino)-l-methvl-3-oximido-3H-1.4- benzodiazenin-2-one Potassium t-butoxide (3.18g) was added in portions to a stirred, cooled (-20°C) solution of the foregoing benzodiazepine (3.75g) in anhydrous toluene (75ml) under a nitrogen atmosphere. After 15 minutes isopentylnitrite (1.53ml) was added and the reaction mixture was stirred at -20°C for 1.5h. Powdered carbon dioxide (1.6g) was added in portions and the mixture was stirred for 10 minutes then evaporated to dryness. The residue was purified by column chromatography on neutral alumina (grade 3) using dichloromethane/methanol (30:1) to (10:1) (gradient elution) to afford the oxime (2.50g). mp 105-109°C. -B NMR (360MHz, DMSO-d 6 ) δ 1.02 (9H, s), 2.18 and 2.20 (6H, each s), 2.41-2.51 (IH, m), 2.82-2.88 (IH, m), 3.29 and 3.32 (3H, each s), 3.93-3.97 (2H, m), 7.29-7.65 (4H, m), 10.10 and 10.97 (IH, each broad s). d) 3(R.S)-Amino-1.2-dihvdro-5-(2-(N.N-dimethvlamino) ethyl-(t-butyloxycarbonyl)amino)-l-methyl-3H-1.4- benzodiazepin-2-one The foregoing oxime (0.50g) was hydrogenated over 5% rhodium on carbon (0.40g) in ethanol (50ml) at 40psi and 60°C for 4h. The reaction mixture was filtered then evaporated to dryness to give the amine (0.462g). Rr- 0.18 in dichloromethane/methanol (5:1) on silica plates. ' B NMR (CDC1 3 ) δ 1.07 (9H, s), 1.90-2.30 (2H, broad resonance), 2.29 (6H, s), 2.55-2.70 (2H, m), 3.43 (3H, s), 3.87-3.94 (IH, m), 4.10-4.18 (IH, m), 4.29 (IH, s), 7.19-7.29 (2H, m), 7.48-7.66 (2H, m). e) N-r3(R-SV2.3-Dihvdro-5-(2-(N.N-dimethvlamino)ethvl- (t-butvloxvcarhnnvDamino)-l-methvl-2-oxo-lH-1.4- benzodiazepin-S-vn-N'-rS-methvlphenvllurea A stirred, cooled (4°C) suspension of the foregoing amine (0.45g) in anhydrous tetrahydrofuran (10ml) was treated with m-tolylisocyanate (0.145ml). The cooling bath was removed and the solution was stirred at room temperature for 30 minutes. The reaction mixture was evaporated to dryness and the residue purified by column chromatography on neutral alumina (grade 3) using dichloromethane/methanol (30:1) to afford the title compound which was recrystallised from ethyl acetate n-hexane (1:5) (0.48g). mp = 112-115°C. MS, Cl*, m/z » 509 for (M+H) * . Anal. Found: C, ' 63.82; ' H, 7.07; ' N,' 15.80. C 27 H 36 N 6 O 4. 0.1C 6 H 14 requires C, 64.09; H, 7.28; N, 16.24%. f) N-r3(R.SV2.3-Dihvdro-5-(2-(N.N-dimethvlamino) ethγlaιmno)-l- ethYΪ-?-o^Q-lH- 4-be*Ωzediagepin-3-γll-N'-r3- methγlphenyl1uτea dihydroghloride A stirred, cooled (4°C) solution of the foregoing benzodiazepine (O.lδg) in ethyl acetate (5ml) was treated with ethyl acetate (20ml), pre-saturated with hydrogen chloride gas. The solution was stirred at 4°C for lh followed by lh at room temperature, then evaporated to dryness. The product was recrystallised from propan-2-ol diethyl ether (0.10g). mp 189-192°C. MS, Cl * , m/z = 409 for (M+H)*. 1H NMR (D 2 0) δ 2.30 (3H, s), 2.98 (6H, s), 3.48 (3H, s), 3.53-3.57 (2H, m), 3.79-3.97 (2H, m), 5.56 (IH, s), 7.02 (IH, d, s∑ = 7.5Hz), 7.14-7.16 (2H, m), 7.27 (IH, dd, s∑ χ = £, = 7.5Hz), 7.δ5 (IH, dd, j∑. = ^ = 8Hz), 7.62 (IH, d, s∑ = 7.δHz), 7.86-7.91 (2H, m). Anal. Found: C, 63.89; H, 6.38; N, 16.89. C 22 H 28N 6 O 2. 2HC1. 0.6H 2 O requires C, 63.68; H, 6.39; N, 17.07%. EXAMPLE 85: N.r3(R.R)-2.3-Dihvdro-5-(N-(2-N- morpholinoet.hvn-N-methvlamino)-l-methvl-2-oxo-lH-1.4- benzodiazepin-3-vll-N , -r3-methvlphenvllurea Prepared in the same way as Example 77 except using N-methyl-(2-aminoethyl)morpholine. Mp = 174°C (uncorr); ~ B NMR (DMSO) δ 2.10-2.38 (9H, m), 2.43 (IH, m), 2.82 (3H, s), 3.12 (IH, m), 3.32 (3H, s), 3.48 (4H, m), 4.92 (IH, d, j∑ = 8.4Hz), 6.70 (IH, d, s∑ = 7.1Hz), 6.96 (IH, d, s∑ = 8.4Hz), 7.08 (2H, m), 7.17 (IH, s), 7.37 (IH, m), 7.57 (2H, m), 7.63 (IH, m), 8.81 (IH, s); MS (CD m/e 465 [MHf. Anal. Found: C, 64.54; H, 6.66; N, 18.04. C 25 H 32 N 603, requires. C, 64.64; H, 6.94; N, 18.09%. EXAMPLE 86: N-r3(R.S)-5-(N-Cvcloheptyl)-N-methylamino)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vn-N'-r3-(5- methvlpvridinefl urea a) 5-(N-Cvdoheptvl-N-methvlamino)-l-methvl-2-oxo- 1.4- benzodiazepine Prepared analogously to Example la) from 1-methyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione and N-methyl cydoheptylamine. l B NMR (250MHz, CDCy δ 1.0-1.90 (12H, m), 1.96 (IH, m), 2.78 (3H, s), 3.36 (3H, s), 3.48 (IH, d, s∑=12.2Hz), 4.23 (IH, d, sΣ=12.2Hz), 7.24 (2H, m), 7.48 (2H, m). b) 5-(N-cvcloheptyl-N-methylamino)-l-methyl-3-oximino- 2-oxo-1.4-henzodiazepine Prepared analogously to Example lb). c) N-r3(R.S)-5-(N-Cvcloheptyl -N-methylamino)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vll-N'-r3-(5- methylpyridine)! urea To the product of part b) (1.9g) in acetic acid (50ml) was added trifluoroacetic acid (4.5ml) and zinc (3.8g) and the reaction mixture was heated to 40°C with rapid stirring for 2hrs. The reaction mixture was cooled to room temperature, filtered through hyflo, evaporated and azeotroped with toluene. The residue was dissolved in dry tetrahydrofuran (10ml) and added to a solution of 3-amino-5-methyl pyridine (0.63g), triphosgene (0.57g) and triethylamine (2.2ml) in dry tetrahydrofuran (30ml) and the reaction was allowed to stir at room temperature for 17hrs. The reaction mixture was concentrated in vacuo and the residue purified by flash column chromatography elution with 0— 5% MeOH/0.5% 0.88 ammonia solution/dichloromethane followed by purification on HPLC elution with 0—>5% MeOH/0.5% 0.88 ammonia solution/dichloromethane. Product recrystallised from ethyl acetate, mpt = 235°C (uncorr). H NMR DMSO δ 1.18 (IH, m), 1.40 (6H, m), 1.90 (IH, m), 2.21 (3H, s), 2.63 (3H, s), 3.32 (3H, s), 4.93 (IH, d, 7.07 (IH, d, sI=8.3Hz), 7.37 (IH, m), 7.50 (IH, dd, s∑=1.4 and 7.8Hz), 7.61 (3H, m), 7.96 (IH, s), 8.29 (IH, d, sΣ=2.2Hz), 9.02 (IH, s). MS (CD m/e 449 [MH] * . Anal. Found C, 66.67; H, 7.19; N, 18.63. C 25H 32N 6O, 2 requires C, 66.94; H, 7.19; N, 18.74%. EXAMPLE 87: 3(R.S)-N-(5-(3-Azabi vclor3.2.21nonan-3-yl)-2.3- dihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-yl)-lH-indole-2- carboxamide a) 5-(3-Azabicvclor3.2.21nonan-3-yl)-1.2-dihvdro-3H- l-methvl-3-(0-(ethvlaminocarbonvl)oximido)-1.4-benzodiazepin- 2-on? The product of Example 31a) (17.5g), ethyl isocyanate (7.3ml) and triethylamine (4.6ml) were heated at 65°C, with stirring, in anhydrous tetrahydrofuran (900ml) for 4 hours. The solvent was evaporated and the residue was purified by column chromatography on silica using dichloromethane —> 2% methanol/dichloromethane (gradient). (20.8g). mp 168°C. b) 3(R,S)-Amin9-5-(3-a?abigγglof3,2,2ln9nan-3-γl)-J*,2- dihvdro-3H-l-methyl-1.4-benzodiazepin-2-one The foregoing oxime derivative (ll.Og) was hydrogenated in methanol (IL) over 10% palladium on carbon (4.5g) at 45 psi and ambient temperature for 3 hours. The mixture was filtered and the solvent was evaporated to give the amine as a foam (8.0g). mp 160-163°C (ethyl acetate). Found: C, 68.82; H, 7.67; N, 17.69. C 18 H 24 N 4 0 requires C, 69.20; H, 7.74; N, 17.93%. c) 3(R.SVN-(5-(3-Azabicvclor3.2.2]nonan-3-yl)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl)-lH-indole-2- carboxamide A solution of the foregoing amine (1.50g) in dimethylformamide (10ml) was treated with indole-2-carboxylic acid (8δ2mg), 1-hydroxybenzotriazole (714mg), l-(3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride (l.Olg) and triethylamine (1.4ml). After stirring for 18 hours at room temperature the solid obtained was collected then triturated with methanol to afford the title compound (1.60g). mp 210-214°C (chloroform/diethyl ether). MS, Cl * , m/z = 456 for (M+H)*. l B NMR (360MHz, CDCy δ 1.44-1.95 f8H, m), 1.95-2.08 (2H, m), 3.26-3.42 (2H, m), 3.44 (3H, s), 3.66-3.70 (2H, m), 5.46 (IH, d, J = 8Hz), 7.06-7.74 (10H, m), 9.22 (IH, broad resonance). Found: C, 69.11; H, 6.34; N, 14.74. C n 27 H £o Q ΌN 5 O 2.0.66H 2 O requires C, 69.36; H, 6.54; N, 14.98%. EXAMPLE 88: (-)-N-(5-(3-Azahicvclor3.2.21nonan-3-yl)-2.3- dihvdro-l-methvl-2-oxo-lH-1.4-benzodiazepin-3-vl)-lH-indole-2- carboxamide hydrochloride The racemic compound (Example 87, 1.60g) was separated into its enantiomers using preparative chiral HPLC on a Pirkle dinitrobenzoyleurine column (5μ) [(260 x 21.4)mm] eluting with 2% methanol in 1-chlorobutane (including 1% acetic acid). Flow rate 20ml minute, U.V. detection at 305nm. Analysis was performed on an analytical Pirkle dinitrobenzoylleurine column (5μ) [(260 x 4.6)mm] eluting with 5% methanol in 1-chlorobutane (induding 1% acetic arid). Flow rate 1.5π /minute, U.V. detection at 250nm. The free base was liberated and obtained as a colourless δ solid (780mg). The hydrochloride salt had mp 280-282°C (chloroform). MS, CI + , m/z = 466 for (M+H)*. [ f 3° ° O = -253° (c=0.2, methanol). HPLC: > 99% ee. Found: C, 65.86; H, 6.15; N, 1 144..4444;; CCll,, 66..8877.. C 27 H 29 N 502.HC1 requires C, 66.91; H, 6.14; N, 14.23; Cl, 7.20%. 0 EXAMPLE 89: (+ N-(5-(3-A Z ahicvdor3.2.21nonan-3-vl).2.3- ihvdro-l-methyl-2-oxo-lH-1.4-benzodiazepin-3-yl)-lH-indole-2- carboxamide dihydrochloride The title compound was obtained (800mg) using the 5 procedure described in Example 88. The dihydrochloride salt had mp 279-280°C (chloroform). MS, Cl * , m/z = 456 for (M+H) * . [α] 23°c D = +222° (c=0.2, methanol). HPLC: 93% ee. Found: C, 59.73; H, 6.60; N, 12.56; Cl, 15.34. C 27 H 29 N 502.2.4HC1 requires C, 59.72; H, 5.83; N, 12.90; Cl, 15.67%. 0 EXAMPLE 90: 3(R.SVN-(2.3-Dihvdro-5-(homopiperidin-l-vl)-1- (2-methvlpropvl)-2-oxo-lH-1.4-benzodiazepin-3-vl)-lH-indole-2- carboxamide a ) ι,2-DihydrQ-3H-5-(he ppiperidiiϊ-l-γl)- -(2-methyl 5 propyl)-1.4-benzodiazepin-2-one The title compound was prepared from l-(2-methylpropyl)- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione, phosphorus pentachloride and homopiperidine. mp > 210°C (dec). Found: C, 71.88; H, 8.70; N, 12.95. C 19 H 27 N 3 O.0.25H 2 O requires C, 0 71.78; H, 8.72; N, 13.22%. b) 1.2-Dihvdro-3H-5-(homopiperidin-l-ylVl-(2- methylpropyl)-3-oximido-1.4-benzodiazepin-2-one The title compound was prepared from the foregoing benzodiazepine, potassium t-butoxide and isopentylnitrite in toluene. c) 3(fl., < ?VAmino-1.2-dihvdro-3H-5-(homopiperidin-l-vl)-l- (2-methvlpropvl)-1.4-benzodiazepin-2-one The title compound was prepared from the foregoing oxime using previously described procedures. d) 3(Jg.g)-N-(2.3-Dihvdro-5-(homopiperidin-l-yl)-l-(2- methvlpropvD-2-oxo-lH-1.4-benzodiazepin-3-vl)-lH-indole-2- carboxamide The title compound was obtained from the foregoing amine, indole-2-carboxylic acid, 1-hydroxybenzotriazole, l-(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and triethylamine in dimethylformamide. mp > 264°C. Found: C, 71.47; H, 7.02; N, 15.14. C^H^N requires C, 71.31; H, 7.05; N, 14.85%. EXAMPLE 91 : (-VN-(2.3-Dihvdro-5-(homopiperidin-l-vl)-l-(2- methvlpropvD-2-oxo-lH-1.4-benzodiazepin-3-vl)-lH-indole-2- carboxamide The racemate of Example 90 was separated into its enantiomers using a semi-preparative dinitrobenzoylleurine Pirkle column (5μ) [(250 x 20)mm] eluting with 3% methanol in 1-chlorobutane (induding 1% acetic acid). The free base was Hberated and obtained as a colourless solid, mp 243-246°C. [αP° c D = -17° (c=0.2, methanol). Found: C, 71.56; H, 6.97; N, 14.80. CagHggNgOa requires C, 71.31; H, 7.05; N, 14.85%. EXAMPLE 92: (+VN-(2.3-Dihvdro-5-(homopiperidin-l-yl)-l-(2- methylpropyl)-2-oxo-lH-1.4-benzodiazepin-3-yl)-lH-indole-2- carboxamide Obtained as for Example 91. mp 240-241°C. [ά]∞° c O = +15° (c=0.2, methanol). Found: C, 65.91; H, 6.77; N, 13.36. C 28 H 33 N ε 0 2 .2H 2 0 requires C, 66.25; H, 7.35; N, 13.80%. EXAMPT.E 93: 3(^. ?VN-(2.3-Dihvdro-5-(homopiperidin-l-vl)-l- (2-methvlpropvl)-2-oxo-lH-1.4-henzodiazepm-3-vl)-(2S)-indoline- 2-carboxamide Prepared analogously to Example 87 from 3(i2,S)-amino- l,2-dihydro-3H-5-(homopiperidin-l-yl)-l-(2-methylpropyl)-l,4- benzodiazepin-2-one and (ιS)-(-)-indoline-2-carboxylic arid, mp 105-106°C. Found: C, 70.26; H, 7.24; N, 14.14. C 28 H 35 N 5 O 2 .0.4H 2 O requires C, 69.94; H, 7.51; N, 14.57%. EXAMPLE 94: 3( .SVN-(2.3-Dihvdro-5-(homopiperidin-l-yl)-l- (2-methylpropyl)-2-oxo-lH-1.4-benzodiazepin-3-yl)-lH-indole-3- acetamide Prepared analogously to Example 87 from 3(_R,S)-amino- l,2-dihydro-3H-5-(homopiperidin-l-yl)-l-(2-methylpropyl)-l,4- benzodiazepin-2-one and indole-3-acetic arid, mp 178-180°C. Found: C, 72.11; H, 7.10; N, 14.45. requires C, 71.72; H, 7.26; N, 14.42%. EXAMPLE 95: 3(i?._ < ?)-N-(2.3-Dihvdro-5-(4-methylpiperidin-l-yl)- l-(2-methylpropyl)-2-oxo-lH-1.4-benzodiazepin-3-yl)-lH-indole- 2-carboxamide a) 1.2-Dihvdro-3H-5-(4-methylpiperidin-l-yl)-l-(2- methvlpropvl)-1.4-benzodiazepin-2-one Prepared from l-(2-methylpropyl)-l,2,3,4-tetrahydro-3H- l,4-benzodiazepin-2,5-dione, phosphorus pentachloride and 4- methylpiperidine. Rf 0.76 in dichloromethane/methanol (9:1) on silica plates. MS, CI + , m/z = 314 [M+H] + . b) 1.2-Dihvdro-3H-5-(4-methylpiperidin-l-yl)-3-oximido-1.4- benzodiazepin-2-one Prepared from the foregoing benzodiazepine, potassium t- butoxide and isopentylnitrite in toluene, mp 188-191°C (ethyl acetate n-hexane). MS, CI+, m/z = 343 [M+H] + . -B NMR (360MHz, CDC1 3 ) δ 0.81-1.10 and 1.20-2.00 (14H, each m), 2.80- 3.00 (IH, m), 3.10-3.35 (IH, m), 3.34 (IH, dd, J x = 6Hz, J 2 = 14Hz), 3.60-3.90 (2H, m), 4.34 (IH, dd, J x = 9Hz, J 2 = 14Hz), 4.44-5.00 (IH, m), 7.12-7.48 (4H, m). c) 1.2-Dihvdro-3-(0-(ethvlaminocarbonvl)-oximidoV3H-5-(4- methvlpiperidin-l-vl)-l-(2-methvlpropyl)-1.4-benzodiazepin-2- one The foregoing oxime (800mg) was treated with triethylamine (0.2ml) and ethyl isocyanate (0.37ml) in anhydrous tetrahydrofuran (80ml) then heated at reflux for 4 hours. The reaction mixture was cooled, evaporated to dryness to give a cream foam (960mg). mp 75-79°C. MS, CI + , m/z 414 for [M+H]*. d) 3(Jϋ.,g)-Amino-1.2-dihvdro-3H-5-(4-methylpiperidin-l-yl)- l-(2-methvlpropvD-1.4-benzodiazepin-2-one The foregoing carbamate-oxime (960mg) was hydrogenated at 45 psi over 10% palladium on charcoal (960mg) in ethyl acetate (120ml) for 5 hours. The reaction mixture was filtered, then evaporated to dryness to give the amine (725mg). Rf 0.28 in dichloromethane/methanol (9:1) on silica plates. e) 3(Jϋ.S)-N-(2.3-Dihvdro-5-(4-methvlpiperidin-l-vlVl-(2- methylpropylV2-oxo-lH-1.4-benzodiazepin-3-yl)-lH-indole-2- carboxamide A stirred solution of the foregoing amine (725mg) in dimethylformamide (10ml) was treated with l-(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (497mg), 1-hydroxybenzotriazole (35mg), indole-2-carboxylic acid (419mg) then finally triethylamine (0.72ml). The reaction mixture was stirred at ambient temperature for 18 hours, treated with water (30ml), and the resulting solid collected by filtration. The solid was purified through a short silica column using dichloromethane/methanol (20:1) then recrystallised from ethyl acetate/n-hexane (455mg). mp 248-249°C. MS, CI + , m/z = 472 [M+H]*. Found: C, 71.79; H, 7.01; N, 14.58. requires C, 71.31; H, 7.05; N, 14.85%. EXAMPLE 96: N-r3(R.S)-2.3-Dihvdro-l-methyl-5-(4- methylpiperidin-l-vI)-2-oxo-lH-1.4-benzodiazepin-3-yll N'-r3-(N-methvl-N'-piperazinvl)phenvl1urea a) 1.2-Dihvdro-l-methyl-5-(4-methylpiperidin-l-yl)-3-Q- ethvlaminocarbonvl)oximido-3H-1.4-benzodiazepin-2-one Prepared analogously to Example 17e from 1,2-dihydro-l- methyl-5-(4-methylpiperidin-l-yl)-3-oximido-3H-l,4- benzodiazepin-2-one (Example 7b, 0.5g). ~ B NMR (360MHz, CDC1 3 ) δ 1.00 (3H, brs), 1.13 (3H, t, J = 7.2Hz), 1.22-1.42 (2H, m), 1.54-1.90(3H, m), 2.78-3.30 (4H, m), 3.44 (3H, s), 3.56-3.78 (IH, m), 4.54-4.86 (IH, m), 6.37-6.45 (IH, m), 7.21-7.38 (3H, m), 7.46-7.54 (IH, m). b) 3-(N-Methyl-N'-piperazinyl)-l-nitrobenzene A mixture of N-methylbis (2-chloroethyl)arnine hydrochloride (9.8g) and 3-nitroaniline (7.0g) in 1-butanol (100ml) was heated at reflux for 60h then cooled to room temperature. Sodium carbonate (2.8g) was then added and the mixture heated at reflux for a further 18h, then cooled to 0°C and filtered. The solid was collected, washed with anhydrous ether then partitioned between dichloromethane (200ml) and sodium hydroxide solution (IM, 150ml). The organic layer was separated and the aqueous phase washed once more with dichloromethane (200ml). The combined organic layers were dried (KgCOg) and evaporated in vacuo. The resultant residue was chromatographed on silica gel, using dichloromethane:methanol (96:4) as the eluant, to afford an orange oil. The oil crystallised on standing and the resultant solid was triturated with petrol (60/80) to give the desired piperazine (5.64g). -B NMR (360MHz, CDC1 3 ) δ 2.37 (3H, s), 2.58 (4H, t, J = 5Hz), 3.30 (4H, t, J = 5Hz), 7.18 (IH, dd, J = 9 and 3Hz), 7.35 (IH, t, J = 8Hz), 7.64 (IH, dd, J = 9 and 2Hz), 7.71 (IH, d, J = 2Hz). MS (Cl, NH 3 ) 222 (M+l). c) l-Amipo-3-fN-methvl-N'-piperazinvl ' )benzene A solution of 3-(N-methyl-N-piperazinyl)-l-nitrobenzene (1.17g) in ethanol (40ml) was hydrogenated at 25 psi for 20 min in the presence of a palladium on carbon catalyst (200mg, 17% (w/w)). The catalyst was filtered off and the solvent evaporated in vacuo. The residue was chromatographed on silica gel, using a gradient elution of petro ether (1:1) followed by dicbloromethane:methanol (95:5) to give a colourless oil, which was azeotroped with toluene (20ml) then left at 0°C overnight. After this time the oil had crystalHzed, and after trituration with petrol (60/80) the desired aniline (0.86g) was isolated as a white soHd. i H NMR (360MHz, CDC1 3 ) δ 2.34 (3H, s), 2.55 (4H, t, J = 5Hz), 3.18 (4H, t, J = 5Hz), 3.60 (2H, brs), 6.20 (IH, dd, J = 8 and 2Hz), 6.25 (IH, t, J = 2Hz), 6.36 (IH, dd, J = 8 and 2Hz), 7.04 (IH, t, J = 8Hz). MS (Cl, NH 3 ) 192 (M+l). d) N-r3(fi.g)-2.3-Dihvdro-l-methyl-5-(4-methylpiperidin-l- yl)-2-oxo-lH-1.4-benzodiazepin-3-yl1 N'-r3-(N-methvl-N'- piperazinyl)phenyl1 urea To a solution of the product of part a) (0.62g) in methanol (30ml) was added 10% paUadium on carbon (0.2g, 32% (w/w)). The mixture was hydrogenated at 40 psi for 2h. Further 10% palladium on carbon (O.lg, 16% (w/w)) was added and the mixture hydrogenated at 40 psi for another lh. The catalyst was then filtered off and washed with methanol. The solvent was evaporated in vacuo to give the amine (0.48g). To a solution of l-amino-3-(N-methyl-N'-piperazinyl) benzene (0.48g) in anhydrous tetrahydrofuran (30ml) cooled to 0°C under an atmosphere of nitrogen was added triphosgene (0.25g). Triethylamine (1.0ml) was added dropwise. After stirring at 0°C for 30 min a solution of the amine (0.48g) in anhydrous tetrahydrofuran (10ml) was added dropwise. The mixture was stirred at 0°C for 5 min and then allowed to warm to ambient temperature and stirred for 10 min. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (50ml) and water (50ml). The undissolved soHd was collected by filtration and purified by chromatography on silica gel using 95:5:1, dichloromethane:methanol:aqueous ammonia solution increasing the ratio to 90:10:1, to give the title compound (0.55g). Mp 160°C (dec). Η NMR (360MHz, CDC1 3 ) δ 0.95 (3H, d, J = 6.2Hz), 1.05-1.21 (IH, m), 1.28-1.37 (IH, m), 1.46-1.62 (2H, m), 1.64-1.74 (IH, m), 2.45 (3H, s), 2.57-2.80 (6H, m), 3.25-3.35 (4H, m), 3.41 (3H, s), 3.47-3.60 (IH, m), 3.86-3.96 (IH, m), 5.26 (IH, d, J = 7.8Hz), 6.52-6.58 (2H, m), 6.65 (IH, d, J = 7.9Hz), 6.98 (IH, brs), 7.11 (IH, t, J = 8.1Hz), 7.16-7.20 (IH, m), 7.21-7.33 (2H, m), 7.47-7.55 (2H, m). EXAMPLE 97A Tablets containing 1-25mσ of compound Amount m Compound of formula (I) Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate EXAMPLE 97B Tablets containing 26-100mq of compound Amount m Compound of formula (I) Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate The compound of formula (I) , cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing l.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet. EXAMPLE 98 Parenteral injection Amount g Compound of formula (I) 1 to 100 Citric Acid Monohydrate 0.75 Sodium Phosphate 4.5 Sodium Chloride 9 Water for Injections to 1ml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The compound of formula (I) is dissolved or suspended in the solution and made up to volume. EXAMPLE 99 Topical formulation Amount mg Compound of formula (I) 1-10 Emulsifying Wax 30 Liquid paraffin 20 White Soft Paraffin to 100 The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The compound of formula (I) is added and stirring continued until dispersed. The mixture is then cooled until solid. BIOLOGICAL ACTIVITY The CCK-A and CCK-B antagonising activity of the compounds described herein was evaluated using the assays described in published European patent application no. 0514133. The method essentially involves determining the concentration of the test compound required to displace 50% of the specific 125 I-CCK from rat pancreas (CCK-A) or guinea pig brain (CCK-B) . The data in Table 1 were obtained for compounds of the Examples. TABLE I CCK RECEPTOR BINDING RESULTS IC 50 (nM) 0 1 2 3 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 93 94 95 96 94.1 148

Claims: CLAIMS : 1. A compound of formula (I) , or a salt or prodrug thereof: (I) wherein: R 1 represents H, Cx-βal yl optionally substituted by one or more halo, C 3 _7cycloalkyl, cyclopropylmethyl, (CH2) r im i dazol Y 1 ' (CH2) r tria2ol yl, (CH ) r tetrazolyl (where r is 1 , 2 or 3), CH2CO2 11 (where R 11 is C 1 _ 4 alkyl) or CH 2 C0NR 6 R 7 (where R 6 and R 7 each independently represents H or Cι-4alkyl, or R 6 and R 7 together form a chain (CH2)p where p is 4 or 5) ; R 2 represents NHR 12 or (CH 2 ) S R13 where s is 0, 1 or 2; R 3 represents Ci-βal yl, halo or NR 6 R , where R 6 and R 7 are as previously defined; R 4 and R 5 each independently represents H, c l -12 alk y 1 optionally substituted by NR 9 R 9 (where R 9 and R 9 are as previously defined) or an azacyclic or azabicyclic group, C4_ 9 cycloalkyl optionally substituted by one or more Cι_ 4 alkyl groups, C4_9cycloalkylC 1 _ alkyl optionally substituted in the cycloalkyl ring by one or more groups, optionally substituted aryl, optionally substituted arylCi-galkyl or azacyclic or azabicyclic groups, or R 4 and R 5 together form the residue of an optionally substituted azacyclic or azabicyclic ring system; x is 0 , 1, 2 or 3; R 12 represents a phenyl or pyridyl group optionally substituted by one or more substituents selected from Cx-gal yl, halo, hydroxy, C 1 _ alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by C 1 _ alkyl, (CH2)q-imidazolyl, (CH 2 )q-triazolyl (where q is 0, 1, 2 or 3) , 5-hydroxy-4-pyrone, NR 6 R 7 , NR 9 C0R 1:L , NR 9 CONR 9, R ι:L (where R 9 and R 9 ' are each independently H or C1-.4alkyl and R 11 is as previously defined) , CONR 6 R 7 (where R 6 and R 7 are as previously defined), SOfCi-galkyl) , SO2(Ci-galkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHCOR 8 (where R 8 is Ci-galkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl) , SO2NHR 10 (where R 10 is a nitrogen containing heterocycle), B(OH)2, (CH2)qCθ2H, where q is as previously defined; or R 12 represents a group where X 1 represents CH or N; W represents CH 2 or NR 9 , where R 9 is as previously defined, and W 1 represents CH 2 , or W and W 1 each represent 0; or R 12 represents phenyl substituted by a group wherein X 2 is 0, S or NR 9 , where R 9 is as previously defined; Z is a bond, 0 or S; m is 1, 2 or 3; n is 1, 2 or 3; and y is 0, 1, 2 or 3; R 13 represents a group wherein R 14 represents H or Ci-galkyl; R 15 represents H, halo or NR 6 R 7 , where R 6 and R 7 are a previously defined; and the dotted line represents an optional covalent bond; with the proviso that, when NR 4 R 5 represents an unsubstituted azacyclic ring system, R 2 does not represent NHR 12 where R 12 is optionally substituted phenyl or 2. A compound as claimed in claim 1 wherein R 1 represents Ci-βalkyl, C 3 -.ηcycloalkyl, cyclopropylmethyl, CH 2 C0 2 R 1:L or CH CONR 6 R 7 ; R 2 represents NHR 12 where R 12 represents a phenyl group optionally substituted by one or more substituents selected from C-ji_ 6 alkyl, halo, hydroxy, C 1 _ 4 alkoxy, (CH 2 )q-tetrazolyl optionally substituted in the tetrazole ring by Cι_ 4alkyl, (CH 2 )q-imidazolyl, (CH 2 ) q -triazolyl, 5-hydroxy-4- pyrone, NR 6 R 7 , NR 9 C0R 1:L , NR 9 C0NR 9 'R 1:L , C0NR 6 R 7 , S0(C 1 -_. 6 alkyl) , S0 2 (Cx-galkyl) , trifluoromethyl, C0NHSO 2 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(0H) 2 and (CH 2 )tC0 2 H, where t is zero, 1 or 2; or R 12 represents a group and NR 4 R 5 represents a group wherein each R 1 independently represents C^-galkyl, Cx-βalkoxy, hydroxy, oxo, SR 11 , NR 6 R 7 , NR 9 C 1 _ 4 alkylR 17 ( =NOR 9 or / ( C H 2, ) I d where R 11 , R 6 , R 7 and R 9 are as previously defined, R 17 is halo or trifluoromethyl, and d is 2 or 3; v is 1, 2, 3, 4, 5, 6, 7 or 8; and w is 4, 5, 6, 7, 8, 9, 10 or 11. 3. A compound as claimed in claim 2 wherein R 12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-gal yl, halo, hydroxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Cι_ 4 al yl, (CH 2 )q-imidazolyl, (CH2)qtriazolyl, 5-hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR 1:L , NR 9 COR 9 'R 11 , CONR 6 R 7 , SO(C ! » 6 alkyl) , S0 2 (C 1 _ 6 alkyl) , trifluoromethyl, C0NHSO 2 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(OH) 2 and (CH 2 )tC0 2 H; or R 12 represents a group where W represents CH2 or NR 9. R 16 represents Ci-ealkyl, Ci-galko , hydroxy, oxo, SR 11 , NR 6 R 7 , NR 9 C 1 _ 4 alkylR 17 , =NOR 9 or OR 18 where R 18 and R 19 each independently represent C 1 _ alkyl or R 18 and R 19 together form a chain CH 2 CH 2 or CH 2 CH 2 CH 2 ; and v is 1. 4. A compound as claimed in claim 1 wherein R 1 represents H, Cι_galkyl, C3_7cycloalkyl, cyclopropylmethyl, (CH2)r* im i d zol y 1 (CH2)r tr i zolyl, (CH 2 ) r tetrazolyl, CH2CO2 11 or CH 2 CONR 6 R 7 ; R 2 is NHR 12 where R 12 represents a phenyl group optionally substituted by one or more substituents selected from Cx-βalkyl, halo, hydroxy, Cι_ alkoxy, (CH 2 )q-tetrazolyl optionally substituted in the tetrazole ring by C ! _ 4 al yl, (CH 2 )q-imidazolyl, (CH2)q-triazolyl, 5- hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR ι:L , NR 9 CONR 9 'R 11 , CONR 6 R 7 , SO(C__ 6 alkyl) , SO2(Ci-β lk l) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHCOR 8 , S0 2 NRR 10 , B(OH) 2 and (CH 2 ) q C0 2 H; or R 12 represents a group and R 4 and R 5 together form the residue of a bridged azabicyclic ring system. 5. A compound as claimed in claim 4 wherein R 1 represents Ci-galkyl, C 3 _7cycloalkyl, cyclopropylmethyl, CH2CO2R 11 or CH 2 CONR 6 R 7 ; and R 12 represents a phenyl group optionally substituted by one or more substituents selected from Cι_galkyl, halo, hydroxy, Cι_ 4 alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by (CH2)q-imidazolyl, (CH2)qtriazolyl, 5-hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR i:L , NR 9 COR 9 'R 1:L , CONR 6 R 7 , SO(C ! _ 6 alkyl) , S0 2 (C 1 _ 6 alkyl) , trifluoromethyl, C0NHS0 2 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(OH) 2 and (CH 2 )t c0 2 H , where t is zero, l or 2; or R 12 represents a group where W represents CH2 or NR' 6. A compound as claimed in claim 1 wherein R 1 represents H, Ci-galkyl, C 3 _ 7 cycloal yl, cyclopropylmethyl, CH2CO2R 11 or CH 2 C0NR 6 R 7 ; R 12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-g l yl, halo, hydroxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Cι-_4alkyl, (CH2)q-imidazolyl, (CH2)q-triazolyl, 5-hydroxy-4-pyrone, NR 6 R 7 NR 9 COR 11 , NR 9 CONR 9 'R 1:L , CONR 6 R 7 , SO(C 1 _ 6 alkyl) S0 2 (C 1 _ 6 alkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHCOR 8 , S02NHR > 1- 1 -0", B(OH) 2 and (CH 2 ) q C0 2 H; or R 12 represents a group and R 4 and R 5 are independently selected from H, C__ 12alkyl, C 4 _ 9 cycloalkyl(CH2)k optionally substituted by one or more Cι_4alkyl groups, bridged Cg-iobicycloalkyl, (CH2)iςR 0 (where R 20 is NR 6 R 7 as previously defined, or an azacyclic or azabicyclic group and k is 0, l, 2, 3 or 4), optionally substituted aryl, and optionally substituted arylCi-galkyl. 7. A compound as claimed in claim 6 wherein R 1 represents C ] 6 alkyl, C 3 -.7cycloalkyl, cyclopropylmethyl, CH2 O2 11 or CH 2 C0NR 6 R 7 ; and R 12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-galkyl, halo, hydroxy, C 1 _ 4 alkoxy, (CH 2 )q-tetrazolyl optionally substituted in the tetrazole ring by Cι_ alkyl, (CH 2 )q-imidazolyl, (CH 2 ) q triazolyl, 5-hydroxy-4-pyrone, NR 6 R 7 , NR 9 COR i:L , NR 9 COR 9 'R 1:L , CONR 6 R 7 , SO(C ! _ 6 alkyl) , S0 2 (C 1 _ 6 alkyl) , trifluoromethyl, C0NHSO 2 R 8 , S0 2 NHC0R 8 , S0 2 NHR 10 , B(OH) 2 and (CH 2 )tC0 2 H, where t is zero, 1 or 2; or R 12 represents a group where W represents CH2 or NR 9 ; and R 4 and R 5 are independently selected from H, Cι_ 2alkyl, c 4- 9 θycloalkyl, optionally substituted aryl, optionally substituted arylCx-galkyl, and azacyclic and azabicyclic groups. 8. A compound as claimed in claim 1 wherein R 1 represents Cι_6 alkvl > C 3 _7cycloalkyl, cyclopropylmethyl, CH2CO2R 11 or CH2C0NR 6 R 7 ; R 2 represents NHR 12 where R 12 represents phenyl substituted by a group Z-(CH 2 ) and R 4 and R 5 each independently represents H, C 1 _ 12 alkyl, C ..9cycloalkyl, optionally substituted aryl, optionally substituted o an azacyclic or azabicyclic group, or R 4 and R 5 together form the residue of an azacyclic or a bridged azabicyclic ring system. 9. A compound as claimed in claim 1 wherein R 1 represents H, Cx-ealkyl, C3-7cycloalkyl, cyclopropylmethyl, (CH 2 ) r imidazolyl, (CH 2 ) triazolyl, (CH 2 ) r tetrazolyl, CH2CO2R 11 or CH 2 C0NR 6 R 7 ; R 2 represents NHR 12 where R 12 represents a pyridyl group optionally substituted by one or more substituents selected from Ci-βal yl, halo, hydroxy, Cι_4alko y, (CH 2 )q-tetrazolyl optionally substituted in the tetrazole ring by C 1 __ alkyl, (CH 2 )q-imidazolyl, (CH 2 )q-triazolyl, 5- hydroxy-4-pyrone, NR 6 R 7 , NR 9 C0R ι:L , NR 9 CONR 9 'R 11 , C0NR 6 R 7 , S0(Cχ_6alkyl) , S02(Cι_ 6 alkyl) , trifluoromethyl, CONHS0 2 R 8 , S0 2 NHC0R 8 , S0 2 NHR 10 , B(0H) 2 and (CH 2 ) q C0 2 H; or R 12 represents a group and R 4 and R 5 each independently represents H, C 1 _ 12 alkyl, C4_9cycloalkyl optionally substituted by one or more Cι_ 4 alkyl groups, C4_ 9 cycloalkylCι_4alkyl, optionally substituted aryl, optionally substituted arylCi-galkyl or an azacyclic or azabicyclic group, or R 4 and R 5 together form the residue of an optionally substituted azacyclic or a bridged azabicyclic ring system. 10. A compound as claimed in claim 1 wherein R 1 represents H, Cx-g lkyl, C3-.7cycloalkyl, cyclopropylmethyl , (CH 2 ) r imidazolyl , (CH2) r triazolyl , (CH 2 )r t etrazolyl, CH2CO2R 11 or CH 2 CONR 6 R 7 ; R 2 represents (CH2) S R 13 '* and R 4 and R 5 together form the residue of an azacyclic or azabicyclic ring system. 11. A compound as claimed in claim 1 wherein R 1 represents H, Ci- alkyl, C 3 _7cycloalkyl, cyclopropylmethyl, (C^Jr-^idazolyl, (CH2) r tr i azol y 1 , (CH 2 ) r tetrazolyl, CH2CO2R 11 or CH 2 CONR 6 R 7 ; R 2 is NHR 12 where R 12 represents a phenyl group optionally substituted by one or more substituents selected from Cι_ 6 alkyl, halo, hydroxy, Cι_ 4 al o y, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Cι_4alkyl, (CH2)q-imidazolyl, (CH2)q-triazolyl, 5- hydroxy-4-pyrone, NR 6 R 7 , NR 9 C0R 1:L , NR 9 CONR 9 'R 11 , C0NR 6 R 7 , SO(C]__ 6 alkyl) , S0 2 (C -galkyl) , trifluoromethyl, C0NHS0 2 R 8 , S0 2 NHCOR 8 , S0 2 NHR 10 , B(OH) 2 and (CH 2 )qC0 2 H; or R 12 represents a group and R 4 and R 5 together form the residue of a fused or spiro azabicycic ring system. 12. A compound as claimed in any preceeding claim wherein R 1 is Cι_galkyl. 13. A compound as claimed in claim 1 wherein R is Cι_s lkyl substituted by one or more halo. 14. A compound as claimed in claim 1, claim 12 or claim 13 wherein R 2 represents NHR 12 and R 12 represents phenyl substituted by one or two substituents selected from Cx-ealkyl, halo and trifloromethyl; or R 12 represents 15. A compound as claimed in claim 1, claim 12, claim 13 or claim 14 wherein R 4 and R 5 together form the residue of an azacyclic ring system substituted by one or more methyl groups, or R 4 and R 5 together form the residue of a bridged azabicyclic ring system. 16. A compound as claimed in claim 1 selected from: N-[3(R,S)-2,3-dihydro-5-(1,4-dioxa-8-azaspiro[4.5]decan- 8-yl)-2-oxo-l-propyl-lH-l,4-benzodiazepin-3-yl]-N•-[3- methylphenyl]urea; N-[3(R,S)-2,3-dihydro-2-oxo-5-(4-oxopiperidin-l-yl)-2- oxo-l-propyl-lH-l,4-benzodiazepin-3-yl] N'-[3- methylpheny 1 ] urea ; N- [ 3 (R, S ) -2 , 3-dihydro-2-oxo-l-propyl-5- ( 4- [ 1 , 1 , 1- trifluoroethylamine]piperidin-l-yl) -1H-1 , 4-benzodiazepin- 3-yl ] N ' - [ 3-methylphenyl]urea ; N- [ 3 (R, S) -2 , 3-dihydro-5- (4 , 4-dimethylpiperidin-l-yl) -l- methyl-2-oxo-lH-l , 4-benzodiazepin-3-yl ] N • - [ indan-5- yl]urea ; (-)-N-[2,3-dihydro-5-( ,4-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[indan-5- yl]urea; (+)-N-[2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[indan-5- yl]urea; N-[3(R,s)-2,3-dihydro-5-(cis-2,6-dimethylpiperidin-l-yl) ■ l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylpheny1]urea; N-[3(R,S)-2,3-dihydro-l-methyl-5-(4-methylpiperidin-l- yl)-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3-methyl phenyl]urea; (+)-N-[2,3-dihydro-l-methyl-5-(4-methylpiperidin-l-yl)-2- oxo-lH-1,4-benzodiazepin-3-yl] N » -[3-methylpheny1]urea; (-)-N-[2,3-dihydro-l-methyl-5-(4-methylpiperidin-l-yl)-2- oxo-lH-1,4-benzodiazepin-3-yl] N » -[3-methylpheny1]urea; N-[3(R,S)-2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methyl phenyl]urea; (+)-N-[2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methyl phenyl]urea; (-)-N-[2 ,3-dihydro-5-(4 ,4-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l ,4-benzodiazepin-3-yl] N ■ -[3-methyl phenyl]urea; N-[3(R,S)-2,3-dihydro-5-(4-methoxypiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N » -[3-methyl phenyl]urea; (-)-N-[2,3-dihydro-l-methyl-5-(4-methylpiperidin-l-yl)-2- oxo-lH-l,4-benzodiazepin-3-yl] N'-[indan-5-yl]urea; N-[3(R,S)-2,3-dihydro-5-(cis-2,6-dimethylpiperidin-l-yl) ■ l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N*-[indan-5- yl]urea; (+) -N- [ 2 , 3-dihydro-5- (4-methoxypiperidin-l-yl ) -1-methyl- 2-oxo-lH-l , 4-benzodiazepin-3-yl ] N « - [ 3 -methy lpheny 1 ] urea ; (-) -N- [ 2 , 3-dihydro-5- (4-methoxypiperidin-l-yl) -1-methyl- 2-oxo-lH-l ,4-benzodiazepin-3-yl] N « -[3-methylpheny1]urea; (+)-N-[2 ,3-dihydro-5-(cis-2 ,6-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[indan-5- yl]urea; (-)-N-[2,3-dihydro-5-(cis-2,6-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[indan-5- yl]urea; N-[3(R,S)-2,3-dihydro-5-(cis-2,6-dimethylmorpholin-4-yl)- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methyl phenyl]urea; N-[3(R,S)-2,3-dihydro-5-(4-methylpiperidin-l-yl)-2-oxo-l- propyl-lH-l,4-benzodiazepin-3-yl] N'-[3-methyl phenyl]urea; (+)-N-[2,3-dihydro-5-(4-methylpiperidin-l-yl)-2-oxo-l- propyl-lH-1,4-benzodiazepin-3-yl] N'-[3-methyl phenyl]urea; (-)-N-[2,3-dihydro-5-(4-methylpiperidin-l-yl)-2-oxo-l- propyl-lH-1,4-benzodiazepin-3-yl] N•-[3-methyl phenyl]urea; N-[3(R,S)-2,3-dihydro-l-methyl-2-oxo-5-(4- trifluoromethylpiperidin-1-yl)-IH-l,4-benzodiazepin-3-yl] N 1 -[3-methylpheny1]urea; (+)-N-[2,3-dihydro-l-methyl-2-oxo-5-(4- trifluoromethylpiperidin-l-yl)-IH-l,4-benzodiazepin-3-yl] N•-[3-methylpheny1]urea; (-)-N-[2,3-dihydro-l-methyl-2-oxo-5-(4- trifluoromethylpiperidin-l-yl)-IH-l,4-benzodiazepin-3-yl] N • -[3-methylpheny1]urea; N-[3(R,S)-2,3-dihydro-5-(2,2-dimethylpiperidin-l-yl)-l- methyl-2-oxo-lH-l ,4-benzodiazepin-3-yl] N'-[3- methylpheny1]urea; (+)-N-[2,3-dihydro-5-(2,2-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylphenyl]urea; (-)-N-[2,3-dihydro-5-(2 ,2-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylphenyl]urea; N-[3(R,S)-2,3-dihydro-l-methyl-2-oxo-5-(cis-2,4,6- trimethylpiperidin-1-yl)-IH-l,4-benzodiazepin-3-yl] N • - [3-methylpheny1]urea; (+)-N-[2,3-dihydro-l-methyl-2-oxo-5-(cis-2,4,6- trimethylpiperidin-l-yl)-lH-l,4-benzodiazepin-3-yl] N'- [3-methylpheny1]urea; (-)-N-[2 ,3-dihydro-l-methyl-2-oxo-5-(cis-2,4,6- trimethylpiperidin-l-yl)-lH-l,4-benzodiazepin-3-yl] N 1 - [3-methylpheny1]urea; N-[3(R,S)-2,3-dihydro-5-(3 ,3-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l ,4-benzodiazepin-3-yl] N'-[3- methylphenyl]urea; (+)-N-[2,3-dihydro-5-(3 ,3-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylpheny1]urea; (-)-N-[2,3-dihydro-5-(3,3-dimethylpiperidin-l-yl)-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylpheny1]urea; N-[3(R,S)-2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-2- oxo-l-(2,2,2-trifluoroethyl)-IH-l,4-benzodiazepin-3-yl] N'-[3-methylpheny1]urea; (+)-N-[2 ,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-2-oxo- 1-(2,2,2-trifluoroethyl)-IH-l,4-benzodiazepin-3-yl] N'- [3-methylpheny1]urea; (-)-N-[2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-2-oxo- 1-(2,2,2-trifluoroethyl)-IH-l,4-benzodiazepin-3-yl] N'- [3-methylpheny1]urea; N-[3(R,S)-2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-1- ethyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylpheny1]urea; (-)-N-[2,3-dihydro-5-(4,4-dimethylpiperidin-l-yl)-1- ethyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylphenyl]urea; N-[3(R,S)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylpheny1]ure ; N-[3(R,S)-2,3-dihydro-5-((IS,4S)-5-methyl-2,5- diazabicyclo[2.2.l]heptan-2-yl]-2-oxo-l-propyl-lH-l,4- benzodiazepin-3-yl] N'-[3-methylpheny1]urea; (-)-N-[5-(3-azabiσyclo[3.2.2]nonan-3-yl)-2,3-dihydro-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N -[3- methylphenyl]urea; (+)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N -[3- methylphenyl]urea; N-[3(R,S)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- fluorophenyl]urea; (-)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- fluorophenyl]urea; (+)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- fluorophenyl]urea; N-[3(R,S)-5-(3-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N • -[3- methylphenyl]urea; (-)-N-[5-(3-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylphenyl]urea; (+)-N-[5-(3-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- methylphenyl]urea; (-)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methγl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[5- indanyl]urea; N-[3(R,S)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N » [3- trifluoromethylpheny1]urea; N-[3(R,S)-2,3-dihydro-5-(8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-2-oxo-l-propyl-lH-l,4- benzodiazepin-3-yl] N•-[3-methylphenyl]urea; N-[3(R,S)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3-fluoro-4- methylphenyl]urea; (-)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-fluoro-4- methylpheny1]urea; (+)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2 ,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-fluoro-4- methylphenyl]urea; N-[3(R,S)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- iodophenyl]urea; (-)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- iodophenyl]urea; (+)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- iodopheny1]urea; N-[3(R,S)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•- [phenyl]urea; N-[3(R,S)-5- ( 2-azabicyclo [ 2.2.2]octan-2-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N » -[3- methylphenyl]urea; N-[3(R,S)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N"-[4-fluoro-3- methylphenyl]urea; (-)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N « -[4-fluoro-3- methylphenyl]urea; (+)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N*-[4-fluoro-3- methylphenyl]urea; (-)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- trifluoromethylphenyl]urea; (+)-N-[5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l ,4-benzodiazepin-3-yl] N•-[3- trifluoromethylpheny1]urea; N-[3(R,S)-2,3-dihydro-l-methyl-5-(cis-octahydroisoindol- 2-yl)-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylpheny1]urea; (-)-N-[2,3-dihydro-l-methyl-5-(cis-octahydroisoindol-2- yl)-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylpheny1]urea; (+)-N-[2,3-dihydro-l-methyl-5-(cis-octahydroisoindol-2- yl)-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylphenyl]ure ; N-[3(R,S)-5-(N-cyclohexyl-N-methylamino)-2,3-dihydro-2- oxo-l-propyl-lH-l,4-benzodiazepin-3-yl] N•-[3- methylphenyl]urea; (-)-5-(N-cyclohexyl-N-methylamino)-2,3-dihydro-2-oxo-l- propyl-lH-1,4-benzodiazepin-3-yl N'-[3-methylpheny1]urea; (+)-5-(N-cyclohexyl-N-methylamino)-2,3-dihydro-2-oxo-l- propyl-lH-1,4-benzodiazepin-3-yl '-[3-methylphenyl]urea; N-[3(R,S)-5-(N-cyclohexyl-N-methylamino)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- methylpheny1]urea; (-)-5-(N-cyclohexyl-N-methylamino)-2,3-dihydro-2-oxo-l- methyl-lH-l,4-benzodiazepin-3-yl N•-[3-methylphenyl]urea; (+)-5-(N-cyclohexyl-N-methylamino)-2 ,3-dihydro-2-oxo-l- methyl-lH-l,4-benzodiazepin-3-yl N'-[3-methylphenyl]urea; N-[3(R,S)-5-(N-cycloheptyl-N-methylamino)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N*-[3- methylphenyl]urea; (-)-5-(N-cycloheptyl-N-methylamino)-2,3-dihydro-1-methyl- 2-oxo-lH-l ,4-benzodiazepin-3-yl N•-[3-methylphenyl]urea; (+)-5-(N-cycloheptyl-N-methylamino)-2 ,3-dihydro-l-methyl- 2-oxo-lH-l ,4-benzodiazepin-3-yl N'-[3-methylphenyl]urea; N-[3(R,S)-5-(N-cycloheptyl-N-methylamino)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[5- indanyl]urea; (-)-5-(N-cycloheptyl-N-methylamino)-2,3-dihydro-1-methyl- 2-oxo-lH-l ,4-benzodiazepin-3-yl N'-[5-indanyl]urea; (+)-5-(N-cycloheptyl-N-methylamino)-2,3-dihydro-l-methyl- 2-oxo-lH-l,4-benzodiazepin-3-yl N•-[5-indanyl]urea; N-[3(R,S)-5-(N-benzyl-N-methylamino)-2,3-dihydro-1- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- methylphenyl]urea; N-[3(R,S)-5-(N-(4-N-methylpiperidinyl)-N-methylamino)- 2,3-dihydro-l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'- [3-methylphenyl]urea; N-[3(R,S)-5-(N-cyclohexylmethyl-N-methylamino)-2,3- dihydro-2-oxo-l-propyl-lH-l,4-benzodiazepin-3-yl] N•-[3- methylphenyl]urea; N[3(R,S)-5-(N,N-di-n-propylamino)-2,3-dihydro-l-methyl-2- oxo-lH-1,4-benzodiazepin-3-yl] N'-[3-methylphenyl]ure ; N-[3(R r S)-5-(N-(N-cyclopentyl-N-ethylamino)-2,3-dihydro- l-methyl-2-oxo-lH-l, -benzodiazepin-3-yl] N•-[3- ethylphenyl]urea; N-[3(R,S)-5-(N-(4,4-dimethylcyclohexyl)-N-methylamino)- 2,3-dihydro- l -methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'- [3-methylphenyl]urea; N-[3(R,s)-5-(N-cyclohexyl-N-ethylamino)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylphenyl]urea; N-[3(R,S)-5-(N-cyclohexyl-N-propylamino)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3- methylphenyl]urea; N-[3(R,S)-5-(N-benzyl-N-cyclohexylamino)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N•-[3- methylphenyl]urea; N-[3(R,S)-5-(N-cyclohexylamino)-2,3-dihydro-l-methyl-2- oxo-lH-l,4-benzodiazepin-3-yl] N•-[3-methylphenyl]urea; N-[3(R,S)-5-(N-cyclohexyl-N-methylamino)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[5- indany1]urea; N-[3(R,S)-5-(N-cyclooctyl-N-methylamino)-2,3-dihydro-l- methy1-2-oxo-lH-l ,4-benzodiazepin-3-y1] N'-[3- methylphenyl]urea; N-[3(R,S)-2,3-dihydro-5-(2-(N,N- dimethylamino)ethyla ino)-l-methyl-2-oxo-lH-l,4- benzodiazepin-3-yl] '-[3-methylphenyl]urea; N-[3(R,S)-2,3-dihydro-5-(N-(2-N-morpholinoethyl)-N- methylamino)-l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N • -[3-methylphenyl]urea; N-[3(R,S)-5-( (N-cycloheptyl)-N-methylamino)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-(5- methylpyridine) ]urea; 3(R,S)-N-(5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro- l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl)-lH-indole-2- carboxamide; (-)-N-(5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl)-lH-indole-2- carboxamide; (+)-N-(5-( 3 -azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl)-lH-indole-2- carboxamid ; 3(R,S)-N-(2,3-dihydro-5-(homopiperidin-1-yl)-1-(2- methyIpropyl)-2-oxo-lH-l,4-benzodiazepin-3-yl)-lH-indole- 2-carboxamide; (-)-N-(2,3-dihydro-5-(homopiperidin-1-yl)-1-(2- ethyIpropyl)-2-oxo-lH-l,4-benzodiazepin-3-yl)-lH-indole- 2-carboxamide; (+)-N-(2 ,3-dihydro-5-(homopiperidin-1-yl)-1-(2- ethyIpropyl)-2-oxo-lH-l f 4-benzodiazepin-3-yl)-lH-indole- 2-carboxamide; 3(R,S)-N-(2,3-dihydro-5-(homopiperidin-1-yl)-1-(2- methyIpropyl)-2-oxo-lH-l,4-benzodiazepin-3-yl)-(2S)- indoline-2-carboxamide; 3(R,S)-N-(2 ,3-dihydro-5-(homopiperidin-1-yl)-1-(2- ethyIpropyl)-2-oxo-lH-l,4-benzodiazepin-3-yl)-lH-indole- 3-acetamide; 3(R,S)-N-(2,3-dihydro-5-(4-methylpiperidin-l-yl)-l-(2- methyIpropyl)-2-oxo-lH-l,4-benzodiazepin-3-yl)-lH-indole- 2-carboxamide; N-[3(R,S)-2,3-dihydro-l-methyl-5-(4-methylpiperidin-l- yl)-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-(N-methyl-N'- piperazinyl) henyl]urea; and salts and prodrugs thereof. 17. A compound as claimed in any preceding claim for use in therapy. 18. A process for the preparation of a compound as claimed in claim 1, which process comprises; (A) reacting an intermediate of formula (II) with a compound of formula (III) (II) (Ml) wherein R 1 , R 3 , R 4 , R 5 , R 12 and x are as defined for formula (I) , one of R 30 and R 31 represents NH 2 and the other of R 30 and R 31 represents -N=C=0; or (B) reacting an intermediate of formula (II) wherein R 30 is NH with a compound of formula H0C(=0) (CH2) S R13 , wherein R 13 and s are as defined for formula (I) , in the presence of a base and a coupling reagent; and optionally converting the compound of formula (I) obtained to a salt or prodrug thereof. 19. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 16 in association with a pharmaceutically acceptable carrier. 20. The use of a compound as claimed in any one of claims 1 to 16 for the manufacture of a medicament for the treatment of a physiological disorder involving CCK and/or gastrin. 21. The use of a compound as claimed in any one of claims 1 to 16 for the manufacture of a medicament for the treatment of panic, anxiety or pain. 22. A process for preparing a composition as claimed in claim 19 which process comprises bringing a compound as claimed in any of claims 1 to 16 into association with a pharmaceutically acceptable carrier or excipient. 23. A method for the treatment or prevention of a physiological disorder involving CCK and/or gastrin, which method comprises administration to a patient in need thereof of a CCK and/or gastrin reducing amount of a compound according to claim 1. 24. A method as claimed in claim 23 for the treatment or prevention of anxiety. 25. A method as claimed in claim 23 for the treatment or prevention of panic. 26. A method as claimed in claim 23 for the treatment or prevention of pain.

Inventors: CARLING WILLIAM ROBERT, CASTRO PINEIRO JOSE LUIS, CHAMBERS MARK STUART, FLETCHER STEPHEN ROBERT, HOBBS SARAH CHRISTINE, MATASSA VICTOR GIULIO, MOORE KEVIN WILLIAM, RUSSEL MICHAEL GEOFFREY NEIL, SHOWELL GRAHAM ANDREW, CARLING, WILLIAM, ROBERT, CASTRO PINEIRO, JOSE, LUIS, CHAMBERS, MARK, STUART, FLETCHER, STEPHEN, ROBERT, HOBBS, SARAH, CHRISTINE, MATASSA, VICTOR, GIULIO, MOORE, KEVIN, WILLIAM, RUSSEL, MICHAEL, GEOFFREY, NEIL, SHOWELL, GRAHAM, ANDREW
Applicants: CARLING WILLIAM ROBERT, CASTRO PINEIRO JOSE LUIS, CHAMBERS MARK STUART, FLETCHER STEPHEN ROBERT, HOBBS SARAH CHRISTINE, MATASSA VICTOR GIULIO, MERCK SHARP & DOHME, MOORE KEVIN WILLIAM, RUSSEL MICHAEL GEOFFREY NEIL, SHOWELL GRAHAM ANDREW, MERCK SHARP & DOHME LIMITED
Application year: 1993
Main classification: C07D243
IPC codes: A61K31, A61P1, A61P25, A61P27, A61P35, A61P39, A61P43, C07D221, C07D243, C07D401, C07D403, C07D413, C07D453, C07D471, C07D487, C07D491