Benzodiazepine derivatives

BENZODIAZEPINE 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, f;aRtroint«>«i-in?n Hormones, G.B.J. Green, Ed., Raven Press, N.Y., p.169 and G. Nission, ibic p.127).

Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form (see. Mutt and Jorpes, piochero. J. ,1,25, 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 2 0 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, Patinq gnIts 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. Pranae et al.. "Peptides in the Central Nervous WO 94/0343? |»CT/t;B93/01599 System", Ann. Repts MpH. Chem 17, 31, 33 and references cited therein; J. A. Williams, Firmed Res. 3 107; and J.E. Morley, Life Scj.. 30, 479).

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 ai-, "Two brain cholecystokinin receptors:

implications for behavioural actions". Brain fies., 362, 175-79). 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 22j6, 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.

WO 94/03437 ITT/GBW/OISW O'Neill et ai., wr-ain 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, *"*•- -T Pharmacol., 209, 135-138; Woodruff et. al., 1991, MAiirooeptides, 19, 45-46; Cervo et. al. , 1988, pt- .t. 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, 0- 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, ttv- -t. Pharmacol., 105, 8-10) and neuroadaptive processes.

Since CCK and gastrin also have trophic effects on certain tumours [K. Okyama, Hokkaido J,. Wed. Scj., 206-216 (1985)], antagonists of CCK and gastrin are useful in treating these tumours [see, R.D. Beauchamp et al., Ann. Surg., 202, 203 (1985)].

WO 94/03437 I'CT/CB'B/OISW 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., 211(2), 183-187; A. Bill et al, Acta Physiol. Scand., 138, 479-485), 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 e£ al-, J- Med Chem., 32, 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 Calkyl or phenyl and substituted at the 5-position by an amino, alkylamino or dialkylamino group or a 3 to S-membered azacycle, bound through nitrogen, which azacycle may optionally contain a further 0, 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):

WO 94/03437 PCT/GB93/01599 _ 5 - (I) wherein:

R1 represents Hr Ci-ealkyl optionally substituted by one or more halo, C3_7cycloalkyl, cyclopropymethyl, (CH2) riiaida2olylf (CH2) rtriazolyl, (CH2)rtetra2olyl (where r is 1, 2 or 3), CHCR11 (where R11 is C1_4alkyl) or CH2C0NR6R7 (where R6 and R each independently represents H or C1_4allcyl» or R and R together form a chain (CH2)P where p is 4 or 5); r2 represents NHR12 or (CH2)SR13 where s is 0, 2 0 1 or 2 ; R3 represents Cealkyl, halo or NR6R', where R6 and R7 are as previously defined; R4 and R5 each independently represents H, Cl_12alkyl optionally substituted by NR9R9' (where R9 and R9' are as previously defined) or an azacyclic or azabicyclic group, Cgcydoalkyl optionally substituted by one or more Calkyl groups, cgcycloalkylCalkyl optionally s ostituted in the cycloalkyl ring by one or more Calkyl groups, optionally substituted aryl, optionally substituted arylCi-ealkyl or azacyclic or azabicyclic groups, or R4 and R5 together form the residue of an optionally substituted azacyclic or azabicyclic ring system; x is 0, 1, 2 or 3; WO 94/03437 PCr/GB93/01599 R12 represents a phenyl or pyridyl group optionally substituted by one or more substituents selected from Ci-galkyl, halo, hydroxy, Cjalkoxy, (CH2)q-tetra2olyl optionally substituted in the tetrazole ring by C1_4alkyl, (CHaJq-imidazolyl, (CH2)q-triazolyl (where q is 0, 1, 2 or 3), 5-hydroxy-4-pyrone, NR R , NR9COR:L1, NR9CONR9,Ri:L (where R9 and R9' are each independently H or C1_4alkyl and R1X is as previously defined), CONR6R7 (where R6 and R7 are as previously defined), SO(C1-6alkyl), S02(Cx-galkyl), trifluoromethyl, coNHS02R8, SO2NHCOR8 (where R8 is d-ealkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl), SO2NHR10 (where R10 is a nitrogen containing heterocycle), B(0H)2r (CH2)qC02H, where q is as previously defined; or R12 represents a group where X1 represents CH or N; w represents CH2 or NR , where R9 is as previously defined, and W1 represents CH2, or W and W1 each represent 0; or R 12 represents phenyl substituted by a group Z-(CH2) WO 94/03437 PCT/GB93/01599 wherein X2 is o, S or NR9, where R9 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; r13 represents a group wherein R14 represents H or d-ealkyl; R15 represents H, Ci-ealkyl, halo or NR6R7, where R6 and R7 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 NR4R5 represents an unsubstituted azacyclic ring system, R2 does not represent NHR12 where R12 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 racemates.

As used herein, the definition of each expression, when it occurs more than once in any WO 94/03437 1>CI7GB93/01S99 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 0, 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 R1 represents Cx-ealkyl, c3-7cycloalkyl, cyclopropylmethyl, CH2CO2R or CH2CONR6R7; R2 represents NHR12 where R12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-galkyl, halo, hydroxy, C1_4alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Calkyl, (CH2) q-imidazolyl, WO 94/03437 |»CT/(;B93/0159«> (CH2)q-triazolyl, 5-hydroxy-4-pyrone, NR6R7, NR9C0R , nr9conr9,R11, C0NR6R7, sofCx-ealkyl), so2(Ci-ealkyl), trifluoromethyl, C0NHS02R8, S02NHCOR8, S02NHR] and (CH2)tC02H, where t is zero, 1 or 2; or R12 represents a group >10 B(0H)2 and NR4R5 represents a group (CH2)W wherein each R16 independently represents Ci-ealkyl, Ci-ealkoxy, hydroxy, oxo, SR NR6R7, NR9C1_4alkylR =NORy or 0 o (CH?) d where R11, R6, R7 and R9 are as previously defined, R is haxo 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 R12 represents a phenyl group WO 94/03437 KT/CBW/OISW optionally substituted"by one or more substituents selected from Ci-ealkyl, halo, hydroxy, Ci-lkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Cxallcyl, (CH2)q-imidazolyl, (CH2) qtriaZolyl, 5- hydroxy-4-Pyrone, NH6R7, NHOR11, KR9COR9 R11, CONR6R , SOfCi-ealkyl), SOzCCi-galkyl), trifluoromethyl, CONHS02R8, S02NHCOR8, S02NHR10, B(OH)2 and (CH2)tC02H; or R12 represents a group where W represents CH2 or NR r16 represents Ci-ealkyl, Cx-ealkoxy, hydroxy, oxo, SR11, NR6R7, NR9C1.4alkylR17, -NOR9 or OR18 OR19 where R18 and R19 each independently represent Calkyl or R18 and R19 together form a chain CH2CH2 or CH2CH2CH2; 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 R1 represents H, Ci-galkyl, C3-7cycloalkyl/ cyclopropylmethyl, (CH2)rimidazolyl, (CH2)rtria2olyl, (CH2)rtetrazolyl, CH2CO2R11 or CH2CONR6R7; R2 is NHR12 where R12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-ealkyl, halo, hydroxy, C1„4alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Calkyl, (CH2) q-imidazolyl, (CH2)q-triazolyl, 5-hydroxy-4-pyrone, NR6R , NR COR , NR9GONR9'R11, CONR6R7, SOtCx-ealkyl), S02(Ci-6alkyl), trifluoromethyl, CONHSO2R8, SO2NHCOR8, S02NHR10, B(OH)2 and (CH2>qC02H; or WO 94/03437 |»CT/C;B93/01599 R12 represents a group ,11 and R4 and R5 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 R1 represents d-ealkyl, C3_7cycloalkyl, cyclopropylmethyl, CCOsR or CH2CONR6R7; and R12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-ealkyl, halo, hydroxy, Calkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Calkyl, (CHzJq-imidazolyl, (CH2) qtriazolyl, 5- hydroxy-4-pyrone, NR6R7, NR9CORi:L, NROR911, CONR6*7, SOCCealkyl), S02(C1-6alkyl), trifluoromethyl, CONHS02R8, S02NHC0R8, SO2NHR10, B(OH)2 and (CHsKH, where t is zero, 1 or 2; or R12 represents a group where W represents CH2 or NR .

3 0 A third subgroup of compounds according to the invention is represented by compounds of formula (I), and salts and prodrugs thereof, wherein R1 represents H, Ci-ealkyl, C3_7cycloalkyl, cyclopropylmethyl, CH2CO2R or CH?CONR6R7; R12 represents a phenyl group optionally WOW/03437 P(T/CB93/«IS99 substituted by one or more substituents selected from Cgalkyl, halo, hydroxy, calkoxy, (CH2) q-tetrazolyl optionally substituted in the tetrazole ring by C1-4alkyl, (CH2)q-iTnidaZolyl, (CH2) q-triaZolyl, 5- hydroxy-4-pyrone, NRR7, NROR11, NR9CONR9 R11, CONR6R7, S0(C1_6allcyl), S02(C1_6alkyl), trifluoromethyl, C0NHSO2R8, SO2NHC0R8, S02NHR10, B(OH)2 and (CH2)qC02H; or R12 represents a group and R4 and R5 are independently selected from H, C i2alkyl, C4-9cycloalkyl(CH2)k optionally substituted by one or more Calkyl groups, bridged C6_iobicycloalkyl, (CH2)kR20 (where R20 is NR6R7 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 thfere may be identified a subclass of compounds of formula (I), and salts and prodrugs thereof, wherein R1 represents Cx-ealkyl, C3-7cycloalkyl, cyclopropylmethyl, CH2C02R or CH2CONR6R7; and R12 represents a phenyl group optionally substituted by one or more substituents selected from Cx-galkyl, halo, hydroxy, Calkoxy, (CH2) q-tetrazolyl optionally substituted in the tetrazole ring by Cialkyl, (CH2)q-imidazolyl, (CH2) qtriazolyl, _5-hydroxy- 4-pyrone, NR6R7 , NROR11, NRCORR11, CONR6R, SOfGi-ealkyl), S02(C1_6alkyl), trifluoromethyl, CONHS02R8, S02NHC0R8, SO2NHR10, B(0H)2 and (CH2)tC02H, where t is zero, 1 or 2; or WO 94/0343" I»CT/(;BV3/OI59y R12 represents a group where W represents CH2 or NR9; and R4 and R are independently selected from H, C1-i2alkyl, C4-9cycloalkyl, optionally substituted aryl, optionally substituted arylCi-ealkyl, 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, wherein R1 represents R Cj-ealkyl, c3_7cycloalkyl, cyclopropylmethyi, CH2CO2 or CH2CONR6R7; R2 represents NHR12 where R12 represents phenyl substituted by a group Z-(CH2) (CH2)m X2 -(CH2)B and R4 and R5 each independently represents H, C1.12alkyl, C4-9cycloalkyl, optionally substituted aryl, optionally substituted arylCx-ealkyl or an azacyclic or azabicyclic group, or R4 and R5 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 R1 represents H, Ci-galkyl, C3-7cycloalkyl, cyclopropylmethyi.

WO 94/03437 I>(T/G 1193/01599 (Clrimidazolyl, (CH2) rtriazolyl, (CH2) rtetrazolyl, CH2CO2R11 or CH2CONR6R7; R2 represents NHR12 where R represents a pyridyl group optionally substituted by one or more substituents selected from Ci-ealJcyl, halo, hydroxy, C1_4alkoxy, (CH2)q-tetrazolyl optionally substituted in the tetrazole ring by Ci_4alkyl, (CH2)q-imidazolyl, (CH2)q-triazolyl, 5-hydroxy-4-pyrone, NR6R7, NR9COR11, NR9CONR9'R11, CONR6R7, SO(Ci-ealkyl), SCCi-galkyl) , trifluoromethyl, CONHSO2R8 , SO2NHCOR8 , SO2NHR10, B(OH)2 and (CH2)qC02H; or R12 represents a group and R4 and R5 each independently represents H, C1_12alkyl, C4_9cycloalkyl optionally substituted by one or more C1_4alkyl groups, C4_9cycloalkylC1_4alkyl, optionally substituted aryl, optionally substituted arylCi-ealkyl or an azacyclic or azabicyclic group, or R and R5 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 R1 represents H, Ci-galkyl, C3_7cycloalkyl, cyclopropylmethyl, (CH2)riinidazoly1' (CH2)r"triazoly1' (CH2) rtetrazoly1' CH2CO2R11 or CH2CONR6R7; R2 represents (CH2)sK13'" and R4 and R5 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), WO 04/03437 l»CT/C;B93/015W and salts and prodrugs thereof, wherein R1 represents H, Cx-ealkyl, C3-7cycloalkyl, cyclopropylmethyl, (CH2)riinidazolyl, (CHa) rtriazolyl, (CH2)rtetra2olyl, CH2C02R11 or CH2CONR6R7; R2 is NHR12 where R12 represents a phenyl group optionally substituted by one or more substituents selected from Ci-ealkyl, halo, hydroxy, C1_4alkoxy, <CH2>q-tetraZolyl optionally substituted in the tetrazole ring by Calkyl, (CH2) q-inidazolylf (CH2)q-tria2olYl, 5-hydroxy-4-pyrone, NR6R7, NR COR , NRONRR11, CONR6R7, SO (Cx-ealkyl) , S02 (Ci-galkyl) , trifluoromethyl, C0NHS02R8, S02NHC0R8, S02NHR10, B(OH)2 and (CH2)qC02H; or R12 represents a group and R4 and R5 together form the residue of a fused or spiro azabicycic ring system.

When R1 is C3_7cycloalkyl, suitable cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl groups, preferably cyclopropyl.

Preferably R1 represents Ci-ealkyl optionally substituted by one or more halo, such as Cx-alkyl optionally substituted by one, two or three fluoro.

Preferred values for R1 include methyl, ethyl, n-propyl, i-butyl and 2,2,2-trifluroethyl.

When R2 represents NHR12 and R12 represents phenyl or pyridyl substituted by C0NHSO2R8 or SO2NHCOR8, suitable values for R8 include Cialkyl, optionally substituted aryl and trifluoromethyl.

When R8 is optionally substituted aryl, this will preferably be optionally substituted phenyl.

WO 94/03437 PCT/<;B93/0I599 Suitable substituents include Calkyl, c1_4alkoxy, halo and trifluoromethyl. Preferred is unsubstituted phenyl or phenyl substituted by Ci-ealkyl, such as methyl, for example, phenyl substituted by Ci-ealkyl in the ortho position.

When R8 is Cx-eaUcyl, it will preferably represent C1_4alkyl. Particularly preferred are methyl and iso-propyl, especially iso-propyl.

When R12 is phenyl or pyridyl substituted by SO2NHR10, suitable values of R10 include, for example, thiazole, thiadiazole and pyrazine.

Preferably q is zero.

When R2 represents NHR12, and R12 represents optionally substituted phenyl or pyridyl, the substituents will preferably be selected from Cx-ealkyl, such as methyl and ethyl, halo, such as chloro, bromo, fluoro and iodo, and trifluoromethyl.

When R12 represents monosubstituted phenyl, the substituent will preferably be located at the 3- or 4- position of the phenyl ring, more preferably at the 3- position. When R12 represents disubstituted phenyl the substituents will preferably be located at the 3- and 4- positions of the phenyl ring.

When R12 represents optionally substituted pyridyl it will preferably represent optionally substituted 3-pyridyl. When R12 represents monosubstituted- 3-pyridyl, the substituent will preferably be located at the 5-position of the pyridyl ring.

When R12 represents a group WO 94/03437 PCT/GB93/0I599 where X1 is CH the fused 5-meinbered ring will preferably be fused across the 3- and 4-positions of the phenyl ring and where X1 is N the 5-membered ring will preferably be fused across the 4- and 5-positions of the phenyl ring.

group Preferably W and W1 are CH2.

When R12 represents phenyl substituted by a Z-(CH2) the substituent will preferably be located at the 3- or 4- position of the phenyl ring, more preferably at the 3- position.

Preferably m is 1 or 2, more preferably 1.

Preferably n is 1 or 2, more preferably 1.

preferably y is 0 or 1, more preferably 0.

Suitable values for X2 include 0, S, NH and NCH3.

Preferably Z represents a bond.

When R2 represents (CH2)ER13, s is preferably 0 or 1, more preferably 0, P14 is preferably H and R15 is preferably H. The optional covalent bond may suitably be either present or absent, preferably present.

WO 94/03437 l»nVGB93/01599 - 18 Particularly preferred are compounds of formula (I) wherein R2 represents NHR12 and R12 represents phenyl substituted by one or two substituents selected from Ci-ealkyl, halo and trifloromethyl; or R1 represents Suitable values for R3 include methyl and dimethy1amino.

Preferably x is 0 or 1, more preferably 0.

When R4 or R5 represents optionally substituted aryl or optionally substituted arylCi-ealkyl, suitable aryl groups include phenyl, thienyl, furyl, pyrrolyl and pyridyl, preferably phenyl. Suitable aryl substituents include, for example, Cjalkyl, Calkoxy, halo and trifluoromethyl.

When R4 or R5 represents an azacyclic or azabicyclic group, or Ci-galkyl 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 NR21, where ft21 is H or C1-4alkyl.

When R4 or R5 represents an azacyclic group or Csalkyl substituted by an azacyclic group, the azacyclic group will suitably contain from 5 to 10 ring atoms.

When R4 oi R5 represents an azabicyclic group or Ci-ealkyl substituted by an azabicyclic group, the azabicyclic group will suitably contain from 7 to 10 ring atoms.

WO 94/03437 PCT/G1193/01599 When R4 or R5 represents C4_9cycloalkyl substituted by one or more calkyl groups or C4_9cycloalkylC1_4alkyl substituted in the cycloalkyl ring by one or more Calkyl groups, the Calkyl groups may be located on any available ring carbon atom.

In particular, geminal disubstitutidn is provied for.

The C1-4alkyl groups will preferably be methyl groups.

Suitably R4 and R5 are selected from H, Ci_6alkyl, such as methyl, ethyl and n-propyl, C4_9cycloalkyl, such as cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, optionally substituted by one or more methyl groups, C4_9cycloalkylC1_4al)cyl, such as cyclohexyimethyl, arylCx-galkyl, such as benzyl, Ci-alkyl substituted by NR9R9', such as CH2CH2N(CH3)2, Ci-ealkyl substituted by an azacyclic group, such as C1_4alkyl substituted by morpholinyl, and azacyclic groups, such as N-methylpiperidine.

When R4 and R5 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 R4 and R5 are attached, a second heteroatom selected from 0, S or a group NR22, where R22 is H, C1_4alkyl, C02Ra, CORa or S02Ra where Ra is C!- 6alkyl, optionally substituted phenyl or benzyl optionally substituted in the phenyl ring by one or more substituents, where the phenyl substituents are selected from dalkyl, C1_4alkoxy, halo and trifluoromethyl.

When R4 and R5 together form the residue of an .

azacyclic ring system, the ring system may be substituted by one or more groups selected from Cx-ealkyl, Cx-galkoxy, hydroxy, halo, trifluoromethyl, oxo, SR1 , NR6R7, NR9C1.4alkylR23, =N0R9 or WO 94703437 1'C'I /(JB9.V01599 where R6, R7, R9 and R11 are as previously defined, R23 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, Cx-ealkyl, Ci-galkoxy, trifluoromethyl and NHC1-4alkylCF3 groups. Preferred are Cx-ealkyl groups, especially methyl.

When R4 and R5 form the residue of an azacyclic ring system, the ring system suitably contains from 5 to ring atoms, preferably 6, 7 or 8 ring atoms, more preferably 7 ring atoms.

When R4 and R5 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 Calkyl, 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 R4 and R5 together form the residue of an WO 94/03437 PCT/GB93/01599 - 21 azacyclic ring system sxibstituted by one or more methyl groups, or R4 and R5 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- pharmaceutically 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, roethanesulphonic, 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 WO 94/03437 l>CI/(;iW3/01599 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 compostion, 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.

WO 94/03437 PCT/GB93/01599 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, 5,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious 2 0 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, WO 94/03437 VCT/V. 1193/01599 gastrocsophagenal 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.

WO 94/03437 PCI7GB93/01599 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 adenocarcinomas 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, Huntington's chorea, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Olivo-ponto-cerebellar atrophy, anoxia such as from 2 0 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 (1) for use in therapy.

WO 94/03437 PCT/GB93/015W 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 SOmg/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 2 0 limits. For example, animal experiments have indicated that doses as low as Ing 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.)r 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 img/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 WO 94/03437 PCI 7GB93/01599 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 2 0mg/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 is NHR12 may be prepared by reaction of intermediates of formula (II) with compounds of formula (III) (ID 3 1.

(III) wherein R B3, R4, R5, R 12 and x are as defined for formula (I) above, one of R30 and R31 represents NH2 and the other of R30 and R31 represents -N=C=0.

WO 94/03437 l»CI7GB<»3/01599 The reaction is conveniently effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran.

The compounds of formula (I) wherein R is (CH2)sK:L3 may be prepared by reaction of intermediates of formula (II) wherein R30 is NH2 (hereinafter intermediates (IIA)) with compounds of formula HOC(=0)(CH2)sR13' wherein s and R13 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 i-(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) :

()x—\ NR4R5 NOH ( IV) wherein R1, R2, R3, R4- R5 and x are as defined for formula (I) above, by reduction, for example, by WO 94/03437 PCT/GB93/01599 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) (R5)r-i (v) wherein R1, R2, R3, R4, R5 and x are as defined for formula (I) and R50 represents Calkyl, 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.

WO 94/03437 PCT/GB93/01599 -so¬ lo Intermediates of formula (II) wherein R 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 0*C.

Intermediates of formula (V) may be prepared from intermediates of formula (IV) by reaction with a ,50 compound of formula R50N=C=o, wherein R 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 60'C.

Intermediates of formula (IV) may be prepared from compounds of formula (VI) N R 4 R (VI) wherein R1, R2, R3, R4, R5 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.

WO 94/03437 PCT/G 893/01599 Compounds of formula (VI) may be prepared from compounds of formula (VII) Ha I (VII) • wherein R1, R3 and x are as defined for formula (I) and Hal represents halo, such as chloro, by reaction with an amine of formula HNR4R5.

3.5 Compounds of formula (VII) may be prepared as described in Dinted Kingdom Patent Specification no.

1,145,471.

Compounds of formula (III) wherein R3 is _N=c=0 (IIIB) may be prepared from the corresponding compounds of formula (III) wherein R31 is NH2 (IHA) analogously to the preparation of compounds of formula (IIB) from compounds of formula (IIA).

Compounds of formula (IIIA) and HOC(=0)(CH2)sR13 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 WO 94/03437 PCT/GB93/01599 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, 197 3; 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.

WO 94/03437 PCI7GB93/01599 M0.nT).ft.vn-9,-nyo-i-rr1-1H-1-4-hPn7n(iiin-3'Yl1 Nr3--mRt.hvlphpnY1"t nrea a) fi.fi A.ninTa-8-n7P''Fr4-spffT1-R-v11-g'Qn'1'17r0PYT' i-frPTnrfinsemne To a solution of l.Propyl-l,2,3f4-tetohydro-3H- 1 4-benzodiazepin.2f5-dione (13.5g) (prepared in the same way as described in Example 4a and b except using N-propylanthranilic add methyl ester as starting material) in dichloromethane (250ml) was added phosphorus pentachloride (15.9g) in dichloromethane UOOml) 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 M-dioxa-S-azaspiro.Sldecane (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 (MgS04), 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 2-) mp 1420C. 'H NMR (360MHz, D6-DMSO) 8 0.68 (3H, t, J=7 4Hz), 1.24 (1H, m), 1-38 (1H, m), 1.51 (2H, m), 1-72 (2H, m), 3 25 (4H, m), 3.35 (1H, d, J«11.4Ha), 3.55 (1H, m), 3.88 (4H, s), 3.94 (1H, d, J=11.4HZ), 4.20 (1H, m), 7.31 (1H, m), 7.54 (3H, m).

MS (CI) xn/e 344+.

b) K.n A.r)inxa-ft-nnprr4-Rp,>nn-8"Yl)"3'0?ciinidQ::

tto-i --nronvM 4-Wr\mfi\mvine.

The product from step a) (18g) was dissolved m dry toluene and cooled to -20°C under an atmosphere of nitrogen.

Potassium tert-butoxide (16.3g) was added and after 20 mm isoamyl nitrite (7.72ml) was added dropwise. The reaction WO 94/03437 PCT/CB93/01599 mixture was stirred at -20oC 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 organic layers were combined, dried (MgS04), filtered and concentrated under vacuum. The residue was triturated with diethyl ether to give the required compound (5.27g). mp 1970C. lB. NMR (360MHz, D6-DMSO) 5 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 (1H, m), 7.18-7.62 (4H, m), 9.95 and 10.17 (1H, 2 x s). MS (CI) m/e 373+.

c) N-rafR.<?V2.3-PihYdrft-s-(1i4-»-»-azasDirof4,51 PP3n.ft-v1V2-oxA-1-nrn-nvl-lK-1.4-henzQdia?gpin-3-Yll N'-ra-methvlphRnvll 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 60oC under 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 m-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 238-240oC. 'H NMR (360MHz, D6-DMSO) 8 0.70 (3H, t, J=7.5Hz), 1.26 (1H, m), 1.39 UH, m), 1.54 (2H, m), 1-73 (2H, m), 2.21 (3H, s), 3.25 (4H, m), 3.64 (1H, m), 3.88 (4H, s), 4.23 (1H, m)f 4.92 (1H, d, J=8.4Hz), 6.70 (1H, d, J=6.8Hz), 7.01-7.65 (8H, m), 8.82 (1H, s). MS (CI) m/e 492+. Anal.

Found C, 65.92; H, 6.61; N, 14.27. CNjA requires C. 65.97; H, 6.77; N, 14.25%.

to WO 94/03437 PCT/GB93/0I599 i-Yn--,-rrnrY1.1TT.i4-hPnZodia?oPiTi-Yl1 N'-r?-Tnfir.hvlphenYU urea To a solution of the product from Example 1c) (O.lg) m 1,4-dioxan (30ml) was added perchloric add (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 (Na2S04), 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. lH NMR (360MHz, De-DMSO) 6 0.70 OH, t, J=7.3Hz), 1-27 (1H, m), 1.41 (1H, m), 2.22 (3H, s), 2.26 (2H, m), 2.49 (2H, m), 3.52 (4H, m), 3.64 (1H, m), 4.23 (1H, m), 4 97 (1H, d, J.8.4HZ), 6.71 (1H, d, J=7.2Hz), 7.10 (3H, m), 7.17 (1H, s), 7.42 (1H, m), 7.68 (3H, m), 8.83 (1H, s). MS (CI) xn/e 448 mm+. Anal. Found C, 65.45; H, 6.49; N, 15.09.

C25H29N503. 0.6H2O requires C, 65.51; H, 6.64; N, 15.28%.

TJIXAMPT.F. 3- N-rafffffva ,s-r>ihydrn-?.-oyo-i-propyl-R-rLiOi Nr3-Tnpt.hvlnhpnvll 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 (Na2S04), filtered and WO 94/03437 PCT/CB9.V01599 concentrated in vacuo. The solid obtained was recrystallised from ethyl acetate/hexane to give the title compound (0.16g). mp 209-210oC. 'H mm (360MHz, D6-DMSO) 5 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 (1H, m, disappears on D20 shake), 2.65-2.83 (3H, m), 3.22 (2H, m), 3.60-3.67 (3H, m), 4.23 (1H, m), 4.92 (1H, d, J=8.4Hz), 6.70 (1H, d, J=6.8Hz), 6.99-7.12 (4H, m), 7.38 (1H, m), 7.54 (1H, d, J=7.6Hz), 7.64 (2H, m), 8.81 (1H, s). MS (CI) m/e 531+.

Anal. Found C, 61.48; H, 6.18; N, 15.82. CFgOs requires C, 61.12; H, 6.27; N, 15.84%.

TTYAMPT.F. 4- N-r3fR.,S)-2.3-Dihvdro-5-(414-(iimgthYlpiperidip- 1-vlV1-methvl-2-nvn-1H-1.4-hftTi7odiazepin-3-vll Nrindan-5-yll urea Intermediate 1: 4 -Dimethylpiperidine 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 Ih.

The mixture was then heated at reflux for a further 8h then cooled to 0oC. 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 (Na2S04) and evaporated. The pale yellow oil was distilled under reduced pressure to afford the title piperidine (12.3g). bp 440C/25mmHg. 'H NMR (360MHz, CDC13) 5 0.93 (6H, s), 1.29-1.32 (4H, m), 2.78-2.81 (4H, m).

a) Mftt.hvl 2-(N-bromo3cetvl-N-TTiPthylpTrnnp)benzQat<? 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 WO 94/03437 |»CIVGB93/01599 stirred at room temperature for 20h. The organic phase was separated and washed with 1M hydrochloric add (500ml), brine {300ml), saturated sodium hydrogen carbonate solution (400ml), dried (NaoS04) then evaporated to afford the required product (255g). lk NMR (360MHz, CDCI3) 5 3.23 (3H, s), 3.54 (1H, d, J=11HZ), 3.60 (1H, d, J=llHz), 3.90 (3H, s), 7.40 (1H, d, J=8Hz)) 7.51 (1H, dd, Ji = J2 = 8Hz), 7.65 (1H, dd, J1 = J2 = 8Hz), 8.04 (1H, d, J=8Hz).

b) 1-MpthvU.2.3.4-tetrahvrim-3H-1 4*nrm<WR7>>ViT\-?fr Wg Ammonia gas was bubbled through an ice-cooled solution of methyl 2N-bromoacetyl-N-niethylamino)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. NMR (360MHz, CDCI3) 5 3.42 (3H, s), 3.80 (2H, brs), 6.80 (1H, s), 7.24 (1H, d, J=8Hz), 7.32 (1H, dd, J, = J2 = 8Hz), 7.57 (1H, dd, J, = J2 = 8Hz), 7.90 (1H, d, J=8Hz). Found: C, 63.20; H, 5.25; N, 14.77.

C10H10N2O2 requires C, 63.15; H, 5.30; N, 14.73%.

c) l.-Dihydro-fi--Himfithvlpippridip-l-Y-l-nigthYl-.

To a solution of the product of part b) (lOg) 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 anhvdrous 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).

WO 94/03437 PCr/CB93/01599 The organic layer was dried (KXOg) and treated with decolourising charcoal and silica gel. After filtering, the solvent was evaporated in vacuo. The residue was redissolved in dichioromethane (300ml) and extracted with citric add solution (10%, 3 x 50ml). The combined aqueous layers were basified (4M NaOH solution) and extracted with dichioromethane (6 x 125ml).

These organic extracts were combined, dried (KCCV and evaporated m vacuo to give the title compound (7.5g). mp 143-145°C. 'H NMR (360MHz, CDClg) 6 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 (1H, d, J=12.0Hz), 4.24 (1H, d, J=12.0Hz), 7.21 (1H, t, J=8.3Hz)) 7.27 (1H, d, J=8.3Hz)J 7.46-7.53 {2H, m). MS (CI) m/e 286+.

d) il?-ni-hvriro-5-f4 4-diTnethvlr)iT)eridin-l-Yl)-methYl- 3-nximido-3IT-l,4-hpnzodiazeDin-2-Qne A solution of the product of part c) (7g) in anhydrous toluene (200ml) was cooled to -20oC under an atmosphere of nitrogen, and potassium te/t-butoxide (7.5g) was added portionwise over 5 min. After stirring at -20oC for 30 min, isopentyl nitrite (3.9ml) was added dropwise. The reaction mixture was stirred at -20oC 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 acid (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 (Na2S04) and evaporated in vacuo to give aa onmge solid. This was triturated with diethyl ether to give the title compound (6.92g). mp 215°C (dec). NMR (360MHz, D6-DMSO) 6 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 (1H, m), 7.44 (1H, d, J=7.9Hz)) 7.48-7.60 (2Hr m), 10.10 (1H, brs). MS (CI) m/e 315+.

WO 94/03437 1>CT/Gl$93/01599 e) 1 9.nihvAro-5-f4 -HimfithvlmPftridin-l-YD-l-Tngthvl-S- (O-Pt.hv1nminnrhn-nv1)0xinniHn-.?H-1.4-bPn7ndiaymP-3-Qne 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). 'H NMR (360MHz, CDC13) 5 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 (1H, m), 3.80-4.00 (1H, m), 6.36-6.42 (1H, m), 7.20-7.35 (3H, m), 7.46-7.52 (1H, m). MS (CI) m/e 386+.

f) K.f.?rR.,SV2.3-Pih-.4-diTnPthy1Pippridin-VY])- To a solution of the product of part e) (4.5g) in methanol (250ml) was added 10% palladium on carbon (Ig). 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 (3.5b) 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 0oC for 30 min a solution of the, amine (3.5g) in anhydrous tetrahydrofuran (20ml) was added dropwise. The mixture was stirred at 0oC 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 WO 94/03437 PCT/GB93/0I599 1320C (dec). lU NMR (360MHz, CDC13) 5 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=7,0H2), 3.16-3.26 (2H, m), 3.28-3.38 (2H, m), 3.42 {3H, s), 5.32 (1H d J=8.0Hz), 6.59-6.66 (lH,in), 6.95-7.13 (3H, m), 7.24-7.36 (SH, m), 7.51-7.58 {2H, m). MS (CI) m/e 460+. Anal.

Found C, 67.85; H, 7.11; N, 14.60. CfiO requires C, 67.90; H, 7.39; N, 14.66%.

An alternative procedure can be used for preparation of N-[3(JR,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: TTTlFn-R-v1 isoanate To a solution of 5-aimnoindane (25g) in anhydrous diethyl ether (1250ml), under an atmosphere of nitrogen, at 0oC was added triphosgene (18.3g). The mixture was stirred at 0oC for 2 min then triethylamine (64.7ml) was added until pH8. The mixture was stirred at 0oC 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 100oC/lmbar to afford the title compound <20g). NMR <360MHz, CDC13) 2.07 (2H, quin, J=7.5Hz), 2.86 (4H, m), 6.84 (1H, dd, J=7.9 and 2.0Hs), 6.94 (1H, s), 7.13 (1H, d, J=7.9Hz).

Step 2: N-r--DihY-4-4"1- yi-TnnrhvU9-nTn.1H-i4-hRn7ociiazepin-YnNMiTidan-5-Yn •yirea To a solution of l,2-dihydro-5-(4,4-dimethylpiperidin-l-yl)- l-methyl-3-(0-ethylaminQcarbonyl)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 hvdrogenated 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 WO 94/03437 PCr/GBM/OISW nitrogen, at room temperature, was added a solution of indan-5-vl 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.

Tmfl prai fipnBrtinn of N-r3fR.gV? MihYr1rQ-fi-(4.4- vll N--rindan-5-v11 UTa N-[3(jR,S)-2,3-Dihydro-5-(4,4-dimethylpipenclin-l-yl)-l- methyl-oxo'-lH-M-benzodiazepin-S-yl] N'-[indan-5-yl] urea (0 17g) was dissolved in 1:1 chloroform:methanol (4ml). 440pl of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., 5pm) per run using 95:5:1 l-chlorobutane:methanol:acetic add 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 (Na2S04) 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 180oC (dec). lB NMR (360MHz, D6-DMSO) 5 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), 30-5.38 (1H, m), 7.05-7.13 (2H, m), 7.29 (2H, brs), 7.56 (1H, t, J=7.5Hz), 7.71 (1H, d, J=8.2Hz), 7.83-7.92 (2H, m), 9-93 (1H, brs) 10 56 (1H. brs). MS (CI) m/e 460 [MHf. Anal. Found C, 61 67- H, 6.81; N, 13.67. CWHMNB08-HCU.5(H20> requires C, WO 94/03437 PCT/CB93/01599 62.00; H, 7.13; N, 13.39%.sD -241.1° (c=0.54, MeOH). Punty A'R - > 99 5*0 5.

" Peak B (67mg). mp 180oC (dec). lB NMR (360MHz, D6-DMSO) 6 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 (1H, m), 7.05-7.13 (2H, m), 7.28 (2H, brs), 7.56 (1H, t, J=7.5Hz), 7.71 (1H, d, J=8.2Hz)> 7.83-7.92 (2H, m), 9.33 (1H, brs), 10.46 (1H, brs). MS (CI) m/e 460+. Anal. Found C, 61.49; H, 7.06; N, 13.39. CHMN502-HC1.1.75(H20) requires C, 61.47; H, 7.16; N, 13.27%.26D +226.8° (c=0.63. MeOH).

Purity A:B = 1.7:98.3.

PIXMPT.F 6- -f??.9)-2.3-nibvriro-5-(ci,9-2,6-dimgthYl- rrprirfin-i.vivi-mpt.Tivi-2.oxo-iH-i A-bjim-yW N"-ra-inethvlphPnvn m-ea a) i.nihvrirn-fi-f-g.fi-dimethvlPippridin-l-YD-k Tr,Pt.hv1-a-nTimido-3F-''4-hflT":odiazepin-2::nn£ Prepared as in Example 4, steps c) and d), from 1-methyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (6g) and cts- 2!6-dimethylpiperidine (3.5ml). mp 240oC (dec). NMR (360MHz, D6-DMSO) 5 0.85-0.96 (3H, m), 1.20-1.92 (9H, m), 3,31 (3H, s), 3.97-4.09 (1H, m), 4.36-4.56 (1H, m), 7.25-7.34 <1H, m), 7.40 (1H, d, J=7.7Hz), 7.49-7.60 (2H, m), 9.88-10.16 (1H, m). MS (CI) m/e 315 [MHf.

v1V1-methvl-?-nTn.1H-1.4-bpn7.nr\fi7.rvm-$-Yl] „ liHSi TnftthvlnhfepvU nrea 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 60oC 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).

WO 94/03437 PCT/<;B93/015W The amine was redissolved in anhydrous tetrahydrofuran (20ml) and cooled to 0oC under an atmosphere of nitrogen.

m-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 (Na2S04) 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 2480C (dec). lH. NMR (360-MHz, CDCI3) 5 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 (1H, d, J=8.0Hz)> 6.42-6.50 (1H, m), 6.81 (1H, d, J=7.0Hz), 6.91 (1H, brs), 7.06-7.16 (2Ht m), 7.21-7.28 (2H, m), 7.32 (1H, d, J=7.8Hz)I 7.42-7.52 (2H, m). MS (CI) m/e 434 [MH1+. Anal. Found C, 68.07; H, 7.12; N. 15.98.

03.0.35(0) requires C, 68.27; H, 7.26; N, 15.92%.

kyatvtpt.f. 7- N-fP ™ •:!-r>ihvdro-1-methY]-5-(4- mPthv1niT>Pridin.l-yn.9..nTn-TH-14-bpn7;nfiia7;ppip-3-Yll N'-ra-methvlphenvll urea a) 1 9-r)ibvdro-1-Tpptbv1-5-(4-Tne.thvlpit?pridin-l-Yl)-3- nT7r1iHn-aH-i.4-bftn70Ttift7leT>in-8-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 4- methylpiperidine (10.9ml). mp 225-2280C. lB NMR (360MHz, D6-DMSO) 5 0.90-1.15 (4H, m), 1.20-1.36 (1H, 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 WO 94/03437 I»CI7(;B93/«!5W (1H, m), 7.38-7.43 (1H, m), 7.46-7.58 (2H, m), 9.93 and 10.16 (1H, 2 x s). MS (CI) m/e 301 [MET.

Tvr-r3--methvlrhpT1v11 urea In the same way as in Example 6b) from l?2-dihydro-l-methyl-5-(4-methylpiperidin-l-yl)-3-oximido-3H- l,4-benzodia2epin-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 Exampleb) and recrystallised from methanol, mp 1420C (dec). 'H NMR (360MHz, CDCI3) 5 0.95 (3H, d, J=6.3HZ)) 1.06-1.19 (1H, m), 1.24-1.36 (1H, m), 1.46-1.60 (2H, m), 1.65-1.76 (1H, m), 2.28 (3H, s), 2.62-2.82 (2H, m), 3.41 (3H, s), 3.48-3.58 (1H, m), 3.90-3.98 (1H, m), 5.28 (1H, d, J=8.6Hz), 6.54 (1H, d, J=7.9HZ), 6.82 (1H, d, J=7.3HZ), 6.95 (1H, s), 7.04-7.16 (2H, m), 7.21-7.32 (3H, m), 7.45-7.56 (2H, m). MS (CI) m/e 420+. Anal. Found C, 65.09; H, 6.79; N, 15.94. C24H29N502.1.25(H20) requires C, 65.21; H, 7.18; N, 15.84%.

flXAMPT/R 8: nvriral seiwation .of N-F3.>??)-2.3-(lihYdrp- -|.TT1otV1v1.F;-U.mPthv1rippriHin.1-vl)-?,-oxo-lH-l,4-T1ZndiRPin- a-yll N'-fR-metbYlphenvll urea N-[3(fi,S)-2,3-Dihydro-l-methyl-5-(4-methylpiperidin-l-yl) -2-oxo- lH-l,4-benZodiazorin-3-yl] N'-[3-methylphenyl] urea (0.6g) was dissolved in 1:24 methanol:dichloromethane (6ml).

The enantiomers were separated as described in Example 5.

Peak A (250mg). mp 1780C (dec). lH NMR (360MHz, CDCI3) 0.96-1.08 (3H, m), 1.30-1.44 and 1.64-1.86 (4H, 2 x m), 1.95-2.06 (1H, m), 2.28 (3H, s), 3.14-3.60 (5H, m), 3.62-3.76 (1H, m), 4.32-4.42 and 4.64-4.70 (1H, 2 x m), 5.67-5.76 (1H, m), 6.80 (1H, d, J=7.4HZ), 7.11 (1H, t, J=7.8Hz), 7.16-7.34 (3H, m), 7.38-7.64 WO 94/03437 l»Cr/GB9.V01599 (3H, m), 7.72-7.82 (1H, m), 8.07 and 8.50 (1H, 2 x bra), 11.85 and 11.96 (1H, 2 x brs). MS (CI) m/e 420 [MHT.

[a]23 -247.7° (c=0.50, MeOH). Purity A:B = > 99.5:0.5.

D Peak B (270mg). mp 180oC (dec). lB NMR (360MHz, CDCI3) 5 0.96-1.08 (3H, m), 1.30-1.44 and 1.64-1.86 (4H, 2 x m), 1 95-2.06 (1H, m), 2.28 (3H, s), 3.14-3.60 (5H, m), 3.62-3.76 (1H, m) 4 32-4.42 and 4.64-4.70 (1H, 2 z m), 5.67-5.76 (1H, m), 6.80 (1H, d, J=7.4Hz), 7.11 (1H, t, J=7.8H2), 7.16-7.34 (3H, m), 7.38-7.64 (3H, m), 7.72-7.82 (1H, m), 8.07 and 8.50 (1H, 2 x brs), 11.85 and 11.96 (1H, 2 x brs). MS (CI) m/e 420 [MHT. D +244.3° (c=0.50, MeOH). Purity A:B = 2.3:97.7.

1.v-1--mPthv1-2--1H-1.4-ben7oriiapin-3-yll N'-ra-methvlTihenvn urea The amine was prepared as in Example 6b), from l,2-dihydro-5-(4,4-dimethylpiperidin-l-yl)-l-methyl-3-oximido- 3H-l,4-benZodiazepin-2-one (7.5g). The title compound was prepared from the crude amine and m-tolyl isocyanate (S.lml) as described in Example 6b). mp 135°C (dec). NMR (360MHz, CDCI3) 5 0.95 (6H, s), 1.28-1.38 (2Hf 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 (1H, d, J=8.0Hz), 6.65-6.72 (1H, m), 6.82 (1H, d, J=7.0Hz), 7 06-7 19 (3H, xn), 7.22-7.35 (3H, m), 7.50-7.57 (2H, m). MS (CI) mJe 434 [MH1+. Anal. Found C, 66.76; H, 7.03; N, 15.60.

C25H31N8O2.0.9(H2O) requires C, 66.76; H, 7.03; N, 15.57%.

PtAMPT-Ff in- ™m1 PTtion of N-rarffVZ-dihydro- f;-r44iTrothviridi-i-vlvi-Tnet.hyl--nTn-1TT-1l4-nzodiaze pin-3- vl1 N'-rmRthvlphenyll urea N-[3(i?,S)-2,3-Dihydro-5-(4,4-dimethylpiperidin-l-yl)-l- methyl-2-oxo-lH-l,4-benzociiaZepin-3-yl] N'-[3-methylphenyl] urea (0.27g) was dissolved in 2:3 methanol:dichloromethane WO 94/03437 PCT/G B93/01599 {5ml). The enantiomers were separated as described in Example 5.

Peak A (103xng). mp 170oC (dec). 'H NMR (360MHz, D6-DMSO) 6 0.92-1.07 (6H, m), 1.27-1.40 (1H, m), 1.49-1.65 (3H, m), 2.23 (3H, s), 3.30-3.77 (7H, m), 5.30-5.38 (1H, m), 6.76 (1H, d, J=7.3Hz), 7.08-7.19 (2H, m), 7.23 (1H, s), 7.32-7.39 (1H, m), 7.56 (1H, t, J=7.6Hz), 7.71 (1H, d, J=8.1Hz), 7.82-7.92 (2H, m), 9.50 (1H, brs), 10.57 (1H, bra). MS (CI) m/e 434+. Anal.

Found Cf 62.00; H, 7.09; N, 14.11. CHCVHCIUSOO) requires C, 61.99; H, 6.99; N, 14.46%.22D-264.90 (c=0.61, MeOH). Purity A:B = > 99.5:0.5.

Peak B (89mg). mp 1720C (dec). 'H NMR (360MHz, D6-DMSO) 5 0.92-1.05 (6H, m), 1.25-1.40 (1H, m), 1.45-1.65 {3H, m), 2.23 (3H, s), 3.16-3.76 (7H, m), 5.26-5.37 <lHf m), 6.76 (1H, d, J=7.2Hz), 7.06-7.36 (4H, m), 7.50-7.60 (1H, m), 7.67-7.74 (1H, m), 7.78-7.94 (2H, m), 9.40 (1H, brs), 10.46 (1H, brs). MS (CI) m/e 434+. Anal. Found C, 61.83; H, 7.07; N, 14.03.

C25H31NB02-HC1-H20 requires C, 61.53; H, 7.02; N, 14.35%.

[a]22 +216.6° (c=0.65, MeOH). Purity A:B = 3.0:97.0.

D example ii: N-r3fB..9Va.ff-DiliyTlnvM4-mpt-hnT7Tipgridin- 1-v.i.mflthvl-2-oTo-lTT--t.4-bep70ftiazepin-3-Yll ttp-rfl-mPtfrvlphmyn m-ea a) 1 -Dihvdro-5-(4-methoyvpiperidin-1-Yl)-3H- 1 -Tncthvl-l 4-hen7:odiazeT)in-2-Qne Prepared as described in Example 4c), from 1-methyl-1,2,3,4-tetrahydro-3H- l,4-benzodiazepin-2,5-dione (4.6g) and 4-methoxypiperidine hydrochloride (3.6g). NMR (360MHz, CDClg) 6 1.43-1.86 (3H, m), 1.98-2.08 (1H, m), 2.91-3.18 (2H, m), 3.33-3.60 (9H, m), 3.63-3.75 (1H, m), 4.25-4.31 (1H, m), 7.20-7.32 (2H, m), 7.47-7.53 (2H, m). MS (CI) m/e 288 [MHT.

WO 94/03437 PCIVCBW/OISW b) 1 9-nihvciro-5-(4-f>ppriin-"1-vl)-:1-TT1ftr'hYl"3" Prepared as Example 4d), from 1,2-dihydro- 5-(4-methoxypiperidin-l-yl)-methyl-3H-l,4-benzodiazepin-2-one (2.3g) mp 1760C (dec). lK NMR (360MHz, D6-DMSO) 6 1.29-1.50 (1H, m), 1.53-1.65 (1H, m) 1.76-1.88 (1H, m), 1.90-2.04 (1H, m), 3.05-3.95 (11H, m), 7.25-7.32 (1H, m), 7.41-7.63 (3H, m), 9.97 and 10.21 (1H, 2 x brs). MS (CI) m/e 317+.

C) -faf7?.,<?V2.3-PvHrn-R.f4-TTlPthnT7PiPPridin-l-Yl)- -|.™pthv1-9-nTO--lF--' hpnTndiazenin-3-Yll NMS-mft-hYlPhenYll 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 compoxmd was prepared from the crude amine and m-tolyl isocyanate (0.57ml) as described in Example 6b). mp 145-1480C.

iH NMR (360MHz, CDClg), 5 1.45-1.58 (1H, m), 1.60-1.72 (1H, 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 (CI) m/e 436 . Anal.

Foukd C, 62.94; H, 6.63; N, 15.40. C24H29N603.1.25(H20) requires C, 62.93; N, 6.93; N, 15.29%.

flXATT/E 12: f.).N.r9 3-nihvriro-1-methYl-5-(4- fflpthvlTTinPridin-l -vlVg-mro-lH-l 4-bPTiyn<iin7eT?in-3-Yl1 Kz riTirinn-R-v11 nreg bydrochloride 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-aminomdane (2.53g) in anhydrous tetrahydrofuran (120ml), cooled to 0oC under an atmosphere of nitrogen, was added triphosgene (1.88g) in one portion. Triethylamine (5.3ml) was WO 94/03437 VCl/C,B93/01W) added dropwise. After stirring at 0oC for 20 min, a solution of the amine (5.4g) in anydrous tetrahydrofuran (20ml) was added dropwise. The mixture was stirred at 0oC 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 (Na2S04) and evaporated in vacuo. The residue was triturated with dichloromethane to give N-[3(72,S)-2,3-dihydro-l-methyl-5-(4-methylpiperidin-l-yl)- 2-oxo-lH-l)4-benzodiazepm-3-yl] N'-[indan-5-yl] urea (2.44g).

The title compound was separated foUowing the procedure of Example 5. mp 1850C (dec). iH NMR (360MHz, D6-DMSO) 0.87-1.04 <3H, m), 1.20-1.88 (5H, m), 1.97 (2H, quin, J=7.4Hz)5 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, bra), 10.52 (IH, brs). MS (CI) m/e 446+. Anal. Found C, 62.51; H, 6.93; N, 13.91. C2JI31Ks02-H.mV20 requires C, 62.45; H, 6.85; N, 14.01%.22D-245.40 (0=0.62, MeOH). Purity A:B = 99.0:1.0.

•p;XftM?T-F- N-r?rffll9V9 3-Dihvdro-5-(ds-2.6- HiniPt.hvlTOneriTiin-1-V'-methv1-?,-nxo-lH-1,4>T17ndiR?ifiPin-,> YnNj-ripan-s-v1}iirea a) i 9-rHhvdro-5-f-g.fi-rtiTnetbv1ntrpridm-l-vl)-l-metbL a.fo.ftt,hvinminocpr>intivnnxiTnirin-3H-l.4-ben7lT?dia2epin-2-one Prepared as described in Example 4e), from l)2-dihydro-5-(cis-2,6-dimethylpiperidm- l-yl)-l-methyl-3-oximido 3H-l,4-benzodiazepin-2-one (1.15g) and ethyl isocyanate (0.43ml). m NMR (360MHz, CDCI3) 5 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), WO 94/03437 l»Cr/GB93/01599 3 20-3.31 (2H, m), 3.44 and 3.46 (3H, 2 z b), 4.14.23 (1H, m), 4 58-4 67 and 4.72-4.80 (1H, 2 x m), 6.12-6.19 and 6.38-6.46 (1H, 2 x m), 7.20-7.38 <3H, m), 7.43-7.50 (1H, m). MS (CI) m/e 386 (MH)+. , , . ...

b) m?m «?v.3-PihTi-R-f-2 impthvlnirgnflin- 1 -rl) 1 TrrthYl-? iH-i.4.bPnriin7PpiTi-3-YT1 TT'-findan-g-Yll The amine was prepared as in Example 4 0, from l,2-dihydro-5-(cis-2I6-dimethylpiperidin-l-yl)-l-methyl-3- (0-ethyIaminocarbonyl)oximido-3H-l,4-ben2odiaZepin-2-one (1.41g).

The title compound was then prepared from the crude amine (1 Ig) and 5-aminoindane (0.73g) as described in Example 4f) mp 240oC (dec). iH NMR (360MHz, CDCI3) 5 0.84-0.94 (3H, m), 1.25 (3H, d, J=6.8Hz), 1.40-1.84 (6H, m)f 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-a.-THz), 7.03 (2H, s), 7.29 (IH s), 7.33-7.39 (IH, m), 7.48 (IH, d, J=8.0Hz)J 7.54-7.64 (2H, m) 8 74 (IH, s). MS (CI) m/e 460+ Anal. Found C, 69.83; H,'7.15; N, 14.82. CN.OSCEO) requires C, 69.88; H, 7.28; N, 15.09%.

v/fpj, id- ohirnl r" of N-rB.)-?-3-<1ihYdrQ-&- f-y1! N'-ra-tufthylrb1 xlTea- N-[3(i2,S)-2,3-Dihydro-5-(4-methoxypiperidin-l- yl)-l-methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-LS-methylphenyl] urea (Example 11) (0.32g) was dissolved m 4:1 chloroformrmethanol (4ml). The enantiomers were separated as described in Example 5.

Peak A (135mg). mp 165°C (dec). * NMR (360MHz, D6-DMSO) 5 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, ml, 5.26-5.38 (IH, m), 6.76 (IH, WO 94/03437 PCT/C;B93/01599 d J=7 OHz), 7.08-7.17 (2H, m), 7.22 (1H, brs), 7.28-7.38 (1H, m), 7,50-7.59 (1H, m), 7.70 (1H, d, J=8.5Hz), 7.78-7.83 (1H, m), 9.39 (1H, brs), 10.54 (1H, brs). MS (CI) m/e 436 .

[a]25 -265.2° (c=0.16, MeOH). Purity A:B = > 99.5:0.5.

D Peak B (125mg). mp 1650C (dec). W NMR (360MHz, D6-DMSO) 5 1.42 -1.60 (1H, m), 1.63-1.87 (2H, m), 1.94-2.08 (1H, m). 2.23 (3H, s), 3.14-3.86 (11H, m), 5.26-5.38 (1H, m), 6.76 (1H, d J=7 OHz), 7.08-7.17 (2H, m), 7.22 (1H, brs), 7.28-7.38 (1H, m), 7!50-7.59 (1H, m), 7.70 (1H, d, J=8.5Hz), 7.78-7.83 (1H, m), 9.41 <1H, brs), 10.54 (1H, brs). MS (CI) m/e 436+.

[a]25 +244.2° (c=0.18, MeOH). Purity A:B = 1:99.

D nypptn-a-vii N'-riTirtrni-fi-yll wea.

N-[3(/2,S)-2,3-Dihydro-5-(cis-2,6-dimethylpipendm-l-yl)-l- methyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[indaB-5-yl] urea (Example 13) (0.95g) was dissolved in 3:1 chlorofonmmethanol (20ml). The enantiomers were separated as described in Example 5.

Peak A (0.44g). mp 160oC (dec), m NMR (360MHz, D6-DMSO) 5 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 (1H, m), 7 02-7.30 (4H, m), 7.64-7.96 (4H, m), 9.30 (1H, brs), 10.18 and 30 (1H, 2 x brs). MS (CI) m/e 460+ Anal. Found C, 65.32; H, 7.14; N, 13.73. CHNA- HC1 ™es C' 65-38; H' 6.91; N, 14.12%. ta]25D-194.40 (c=0.50, MeOH). Purity A:B > 99 5*0 5.

Peak B (0.45g). mp 1590C (dec). W NMR (360MHz, D6-DMSO) 5 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 (1H, m), 7.02-7.30 (4H, m), 7.64-7.96 (4H, m), 9.39 (1H, brs), 10.20 and 35 (1H, 2 x brs). MS (CI) m/e 460+. Anal. Found C, WO 94/03437 I>CT/<;B9.V0I5W 65.14; H, 7.41; N, 13.52. CHO.-HCl-0.250) 0.15(0) requires C, 65.01; H, 7.17; N, 13.54%. [cOV183-50 (c=0-50' MeOH). Purity A:B = 0.7:99.3.

flxAMPT-F' ™' N-r3fff ,<?V2.3-DihYro-MCTg-2.fe ?-y]l r'-r3-TnethvirhPT1v11 ,irea a) i|?rrHhvrirn-fi-fp-?-fi-TnpninrDhn1in-4-vl)-l- Tnpthvi.aH-i.4-bPTi7ndin7RTTin-8-one Prepared as described in Example 4c), from 1-methyl- 12 3 4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (lOg) and cis- 2!6-diinethylmorpholine (S-Sml). >H NMR (250MHz, CDC13) 6 1 10 (3H, d, J=7Hz), 1.24 (3H, d, J=7Hi')l 2.40-2.76 (2H, m), 3.20- 3.88 (8H, m), 4.29 (1H, d, J=12HZ)) 7.19-7.39 <2H, m), 7.47-7.60 (2H, m)..

b) i 9-rHhvriro-M/-».«>-9. fl-riimethv1morpho1in-4-vl)-l:

Prepared as described in Example 4), from l,2-dihydro-5- (cis-2,6-dimethylmorpholin-4-yl)-l-methyl-3H-l,4- benzodiepin-2-one (4.8g). >H NMR (360MHz, D6-DMSO) 1 80 (6H, brs), 2.42-2.64 (2H, m), 3.80-4.20 <7H, brm), 7.30 (1H, dd, J=7.0 and 7.0Hz), 7.46-7.60 (3H, m), 10.10-10.42 (1H, 2 x brs). MS (CI) m/e 317+.

C) 1 frniVwriro-5-rrfg-2 fi-dimethvlmnrpholiTT-YD-X- matvU3.fn.flthTlnTrnnnvlv>Tr;do-3H-1,4-beM0diazBiaDz -one „ ... , .

Prepared as described in Example 4e), from l,2-dihydro-&- (cis-2,6-dimethylmorphoHn-4-yl)-l-methyl-3-oximido-3H-l,4- benzodiazepin-2-one (1.5g). W NMR (360MHz, CDC13) 5 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 (1H, brm), 6.39 (1H, m), 7.24-7.34 (3H, m), 7.53 (1H, dd, J=7.0 and 7.0Hz). MS (CI) m/e 388 [MH-]+.

WO 94/03437 PCT/(;B93/()1599 d) f3r7?.5?V2.3-rvr:irn.5-(r/.?-2.fi-dimethYlmnrphdin-4- yiyt-Ptiwi-a-nTo-iH-- 4-bPTi7,ndiazprin-?-Yll W-\d- Tripthvlnhenvll urea To a solution of the product of part c) (1.52g) in methanol (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 tetrahydrofuran (10ml) under an atmosphere of nitrogen, at 0oC, was added m-tolyl isocyanate (0.45ml) dropwise. After stirring at 0oC for 5 min the desired compound (1.45g) was collected by filtration and recrystalUsed from petrohethyl acetate (1:1). mp 253-2550C. m NMR (360MHz, CDC) 5 1.11 (3H, d, J=6.2Hz), 1.17 (3H, d, J=6.2Hz), 2.29 (3H, s), 2.41-2.47 (1H, m), 2.59-2.66 (1H, m), 3.41-3.45 (4H, m), 3.62-3.80 (3H, m), 5.34 (1H, d, J=8!oHz), 6.69-6.73 (1H, m), 6.83 (1H, d, J=7.lHz), 7.08-7.16 (3H, m), 7.24-7.35 (3H, m), 7.52-7.57 (2H, m). MS (CI) m/e 436+.

f.yample 17- N-rfff <?V2.3-Dihvdro-M4-rnptbYlpipmdm-l-.

v1V2-OTn--l-pr"Pv]-1H-l-4-bRn7:Qdia2:gpin'3'YllN>"" mPthvlnhenvll urea a) T-Prnpvlisat-"ift anhydride To a stirred solution of isatoic anhydride (lOOg) and propyl iodide (66ml) in dimethylformamide (600ml) at 0oC, under nitrogen, was added sodium hydride (28g of a 55% dispersion in mineral oil) portionwise. The mixture was allowed to warm to room temperature and stirred for 18h. The solvent was then removed in vacuo and the residue partitioned between ethyl acetate (1000ml) and water (500ml). The organic phase was separated, washed with bnne (2 x 500ml), dried (MgS04) and evaporated. The residue was triturated with anhydrous WO 94/03437 PCT/GB93/0I599 diethyl ether to give the title compound (57g). H NMR C360MHz, CDC13) 5 1.06 (3H, t, J=7.5HZ), 1.75-1.86 (2H, m), 4.01-4.05 (2H, in). 7.17 (1H, d, J=8.5Hz), 7.26-7.32 (1H, m), 7.73-7.78 (1H, m), 8.17 (1H, dd, J=7.9 and 1.7Hz). MS (CI) m/e 205+.

b) i-Pmpvi-i.2.3 4-t.rahvriro-SH-l l-hmtinzzvm- 2.5-dione N-Propyhsatoic anhydride (56g) and glycine (20.5g) were heated at reflux in glacial acetic add (375ml), under nitrogen, for 5h. The solution was concentrated in vacuo and the residue partitioned between dichloromethane (ISOOml) and saturated sodium bicarbonate solution (1000ml). The organic phase was separated, dried (MgS04) and evaporated to afford an orange gum. The gum was cooled to 0oC then triturated with anhydrous diethyl ether to give the bis-lactam (47g) as colourless needles.

iH NMR (360MHz, CDC13) 5 0.84 (3H, t, J=7.3Hz), 1.46-1.66 (2H, m), 3.52-3.64 (1H, m), 3.70-3.85 (2H, m), 4.18-4.28 (1H, m), 7.22- 7.36 (3H, m), 7.55 (1H, d of t, J=7.5 and 1.7Hz), 7.90 (1H, dd, J=7.8 and 1.7Hz). MS (CI) m/e 219+.

c .f??.,9V2.3--nihvrn-5-(4-mpthv1pippndin-l-vl)-2- nn-lranvMH-l 4-»3-1 N-TnPt.hYlphCTYH Prepared as described in Example 4, steps c)-f), trom l-propyl-l,2,3P4-tetrahydro-3H-l,4-benzodiazepin-2.5-dione(30g) and 4-methylpipericline (16.3ml). mp 133-136°C. H NMR (360MHz, CDCI3) 6 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 (1H, m), 4.23-4.36 (1H, m), 5.35 C1H, d, JSHz), 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 (CI) m/e 448+.

FyAMPT.F. 18: Cbirpl SRParation of N-FOT -?- -(tihydro-5-(4- r.otHlpinPridin-1-v1V2-oxa-l-PrnPYl-TH-l,4-bpn7,odiazgpii>-3-Yl] N'-ra-TnethYlphfinvll urea WO 94/03437 »'CT/(;B93/<)I599 urea N-[3(i?,S)-2,3-Dihydro-5-(4-inethylpiperidin-l-yl)-2-oxo-l- propyl-H-lr4-benzodiazepm-3-yl] N'-[3-methylphenyl] w (1.1 Ag) was dissolved in 9:1 chlorofonn:methanol (llml). 440pl of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20nmi i.d., Sim) per min using 95:5:1 l-chlorobutane:inethanol:acetic add as the mobile phase. Using a flow rate of 20miyimn and u.v. detection at 330nm, the two enantiomers were efficiently separated and isolated as described in Example 5.

Peak A: (0.68b). mp 167-170°C. W NMR (360MHzr D6- DMSO) 5 0.66-1.96 (13H, m), 2.22 (3H, s), 3.00-4.20 (9H, xn), 5.30-5.34 (1H, m), 6.74-6.76 (1H, m), 7.08-7.22 (2H, m), 7.22 (1H, s), 7.24-7.40 (1H, m), 7.56-7.62 (1H, m), 7.78-7.98 (3H, m), 9.46- 9.58 (1H, m), 10.52-10.64 (1H, m). MS (CI) m/e 448 [MH+].

[a]22 -211.3° (c=0.56, MeOH). Purity A:B = >99.5:0.5.

Peak B: (0'.71g) mp 164-1670C. W NMR (360MHz, D6- DMSO) 5 0.66-1.96 (13H, m), 2.22 (3H, s), 3.00-4.20 (9H, m), 5.30-5.34 (1H, m), 6.74-6.76 (1H, m), 7.08-7.22 (2H, m), 7.22 (1H, s), 7.24-7.40 (1H, m), 7.56-7.62 (1H, m), 7.78-7.98 (3H, m), 9.46- 9.58 (1H. m), 10.52-10.64 (1H, m). MS (CI) m/e 448 [MH+].

[a]22 +201.8° (c=0.57f MeOH). Purity A:B = 2:98.

.XA'M?T. 19- N-rfff.V? 3-DihvHro-1-TnPthv1-2-ft7to-{>4- tf|nnrnTnpthviniT)erTTi.i.vn-iH-1 4-bPTi7!ndia?eT>in-3-Yll NM3- PtViylphpnyll urea a) /|-Trifl""rnTTipvlPRridphvdro(:>" 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 Ih. The catalyst was filtered off and the filtrate evaporated in vacuo to afford 4- trifluoromethylpyridinium hydrochloride.

WO 94/03437 PCT/CB93/01599 The pyridium hydrochloride was dissolved in ethanol (70ml) and water (5ml), and hydrogenated at 40 psi at 60oC 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. H NMR (250MHz, D6- DMSO) 5 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 (CI) m/e 154+.

k i o.pm-i-TnRthvi-s-ro-ethvlaminpwrbpnYl) mrimido-5-f4-trifltioromet.hvlT)iperidin-Vvl)-3H-1.4.T enzodiazepin-2-one Prepared as described in Example 4 steps c)-e), from from l-methyl-l,2,3l4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (11.Ig) and 4-trifluoromethylpiperidine hydrochloride (10.63g).

m NMR (360MHz, CDCl3) 5 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 (1H, 2 x br s), 7.24-7.38 (3H, m), 7.53 (1H, d of t, J=7.2 and 1.5Hz). MS (CI) m/e 426 [MH1+ O N.r?tfff.t*?V2.3-nihvrfro-l-met.hvl-2-Q?tQ-5-(,4- trff1iinrnTriathvlpirPTHrlin-1-vl>-lH-1.4-benZQdin7Priri-3-y)1N'-f3- TTiphvlphenvl] 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 (4901) as described in Example 16d). mp 248-250oC. H NMR (360MHz, D6-DMSO) 8 1.30-2.24 (8H, m>, 2.40-3.00 (2H, brm), 3.04-4.20 (5H, brm), 5.22- 5.40 (1H, brs), 6.75 (1H, d, J=7.2Hz), 7.08-7.17 (2H, ml, 7.22 (1H, s), 7.24-7.46 (1H, brm), 7.50-7.60 (1H, m), 7.68-7.72 (1H, m), 7.80-8.00 (2H, m), 9.46 (1H, brs), 10.72 (1H, brs). MS (CI) m/e 474+.

WO 94/03437 PCT/GB93/0I599 f,XMPT, 20: Chn?} 'JParatinn of N-r3(R,f?)-g.3-dihYdrg-l- prKprPTvm-a-vn N--r3-mpthv1rheTiy1] wea N-[3(ii:,S)-2,3-Dihydro-l-methyl-2-oxo-5-(4-trifluoro methylpiperidin-l-yl)-lH-l,4-beii2odiazepin-3-yl] N'-[3- methylphenyl] urea (1.44g) was dissolved in 9:1 chlorofonnrmethanol (20ml). 1.5ml of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., 5m) per run using 95:5:1 l-chlorobutane:methanol:acetic add as the mobile phase. The two enantiomers were efficiently separated and isolated as described in Example 5.

Peak A (704mg) mp 185-188°. H NMR (360MHz, D6- DMSO) 5 1.30-2.24 <8H, m), 2.40-3.00 (2H, m), 3.04-4.20 (5H, brm), 5.22-5.40 (1H, brs), 6.75 (1H, d, J=7.2Hz), 7.08-7.17 (2H, m), 7.22 (1H, s), 7.24-7.46 (1H, brm), 7.50-7.60 (1H, m), 7.68-7.72 (1H, m), 7.80-8.00 (2H, m), 9.46 (1H, brs), 10.72 (1H, brs). MS (CI) me 474 [MH3+. [a}% -227.7° (teO.53, MeOH).

Purity A:B = >99.5:0.5.

Peak B (0.71g) mp 185-1880C. H NMR (360MHz, CDClg) 6 1.44-1.62 (1H, m), 1.66-1.98 (3H, m), 2.08-2.22 (1H, xn), 2.29 (3H, s), 2.58-3.40 (2H, m), 3.43 (3H, s), 3.58-3.68 (1H, m), 4.01-4.09 (1H, m), 5.30 (1H, d, J=7.9Hz), 6.59 (1H, d, J=7.8Hz), 6.95 (1H, brs)', 7.05-7.08 (1H, m), 7.14 (1H, dd, J=7.8 and 7.8Hz), 7.23-7.34 (3H, m), 7.52-7.56 (2H, m). MS (CI) m/e 474+.»D +211° (c»0.52, MeOH). Purity A:B = 2:98.

flXftTurpT.TC 9.11 N-rafff -2.3-DihvHrn-5-(2,2-dimet.bY)pipgndii)-.

i.y1Vl-mPt.hv1-2-ovn-1H-1.4-hen7nHinrepin-3-YllNr3- a) -PimfthYlripp-2-™6 To a solution of 2-2-dimethylcyclopenianone (2g) in formic acid (97%, 27ml) was added portionwise hydroxylamine-Q- sulphonic acid <3.02g) over a period of 10 mm. The mixture was WO W03437 I'CT/G 1*93/01599 heated at reflux for 5h. After cooHng, 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 (Na2S04) 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 128-1310C. H NMR (360MHz, CDCI3) 5 1.25 (6H, s), 1.64-1.68 <2H, m), 1.80-1.88 (2H, xn), 2.31 (2H, t, J=6.6Hz), 5.82 (1H, br s). MS (CI) m/e 128+ b) 9. 2-DimethYlpippridine 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 diethvl ether (120ml) portionwise over a period of 15 min. The mixture was heated at reflux under nitrogen for 5ht then cooled to 0oC. Water (2.5ml) was added dropwise, followed by aqueous sodium hvdroxide (2.5ml of a 4N solution) and water (7.5ml).

The resultant granular solid was removed by filtration, the filtrate dried (Na,S04) and evaporated. The pale yellow oil was distilled under reduced pressure to afford the title piperidine (2 7g) bp 70oC/60mmHg. NMR (360MHz, CDCig) 5 1.13 (6H, s), 1.36-1.50 (4H, m), 1.53-1.62 (2H, m), 2.83-2.87 (2H, m). MS (CI) m/e 114 (MH)+.

n\ 9-nihvdro-fi- 9.Tnfithvlpit)eridin-1-vn-1-Tnfithv1-3-{0- ylpminnrarhnnvUoxinurtn H 1 4-hPn7nHiR7Ppin-2-ong Prepared as described in Example 4 steps c) to e), from i-methyl-l,2,3,4-tetfahydro-3H-l)4-benZodiaZepin-2,5-dione (4 54g), and 2.2-dimethylpiperidine (2.7g). >H NIvIR {360MHz, CDCI3) § 1.20 and 1.25 (3H( 2 x t, J=7.3Hz), 1-43-1.44 (3H, m), 1 55-1 82 OH. m), 2.93-3.04 (1H, m), 3.19-3.30 (3H. m). 3.43-3.46 WO 94/03437 PCT/GB93/01599 (3H, m), 6.02-6.08 and 6.26-6.32 (1H, m), 7.18-7.34 (2H, m), 7.44- 7.52 (2H, m). MS (CI) m/e 386+.

r.qfR.q[V2.3-Pi-R-f2.2-dimPthv1pippridip-l-Y))-V tnpthvi-2-nxn-iF--''»riTi-3-v11 N-TnethYlphenvn 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 2350C (dec). H NMR (360MHz, CDCI3) 5 1.42-1.66 (9H, m), 2.29 (3H, s), 2.80-2.98 (2H, m), 3.42 (3H, s), 5.20 (1H, d, J=7.9Hz), 6.42-6.50 (1H, m), 6.70-6.86 (2H, m), 7.06-7.16 (2H, m), 7.18-7.28 (3H, m), 7.45-7.52 (1H, m), 7.69 (1H, dd, J=7.8 and 1.6Hz). MS (CI) m/e 434+. Anal.

Fotmd: C, 69.13; H, 7.23; N, 16.08. CN-A requires: C, 69.26; H, 7.21; N, 16.15% EXAMPLE 22: Hhiral senaration of N-f3(R,)-2,3-dihydrQ-5- f9 9.rtiTnfit.hvlT)ippri(3in-1-vl)-l-mPt,hv1-?.-OXO-lH-l,4- Pndiaze-nin-S-yll N,-r3-Tnethv1phenyll Wga N-[3(JR,S)-2,3-dihydro-5-(2,2-dimethylpiperidin-l-yl)-l- methyl-2.oxo-lH-l,4-benzodiazepin-3-yl] N'-tS-methylphenyl] urea (1.8g) was dissolved in 9:1 chloroform:methanol (12ml).

400 of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., 5m) 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 150oC (dec). W NMR (360MHz, d6- DMSO) 5 1.17-1.80 (12H, m), 2.23 (3H, s), 2.72-3.82 (5H, m), 5.10-5.28 (1H, m), 6.74 (1H, d, J = 7.0Hz), 7.06-7.36 (4H, m), 7.42-7.58 (1H, m), 7.61-7.98 (3H, m), 9.42 (1H, brs). MS (CI) m/e 434 [M+l]+.22D -423.1° (c=0.68, MeOH). Purity A:B = > 99.5:0.5.

WO 94/03437 PCT/O.B93/0I599 Peak B (0.8g). mp 150oC (dec). W NMR (360MHz, d6- DMSO) 5 1.12-1.83 (12H, m), 2.23 (3H, s), 2.83-3.70 (5Hf m).

5.08-5.30 (1H, m), 6.74 (1H, d. J « 6.9Hz), 7.04-7.31 (4H. m), 7.40-7.57 (1H, m), 7.62-7.96 (3H, m), 9.37 (1H, brs). MS (CD m/e 434+.22D +420.5° (c=0.67, MeOH). Purity A:B = 1.3:98.7.

RYAMPT.F, 23: N-fff <?.3-TObvHro-1-TnBthv1-g-P-i,?-(«S- 9 4 fi-tovlnirid-l-yn-IH-l-bPTizoriimn-a-vIl N'-Fg- methvlphenvn nrea a) 1,9-nihvrirn-l -mPthvl-3-(O-p.t.hvlaminocprbnnYl)QxipTid0- fi.c.9 4 R-trHPthvirirn-i-vivH-i 4-ben7.odiR7fiPin-g-ope Prepared as described in Example 4 steps c)-e) from 1- inethyl-lf2f3,4-tetrahydro-3H-l,4-beiizodiazepin-2,5-dione (5g) and dS-2,4)6-trimethylpiperidine (11.7g). NMR (360MHz, CDClg) 8 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 (1H, m), 4.54-4.76 (1H, m), 6.13-6.20 and 6.32-6.45 (1H, m), 7.18-7.38 (3H, m), 7.42- 7.50 (1H, m). MS (CI) m/e 400+.

b) N.r3(P.1(?)-2.-"nvdrn-l-metbvl-2-nxn-5-(r?-2,4,6- t.riTnPt.hviniperin-i-vlv-iH-1 A-brm.ottMmfr-Z-vW TTiPylphfT11 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 223-2250C. 'H NMR (360MHz, CDCI3) 5 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 (1H, m), 4.97 (1H, d, J = 8.3Hz), 6.71 (1H, d, J = 7.0Hz), 7.05-7.13 (3H, m). 7.16 (1H, s), 7.35 (1H, t, J = 7.0Hz), 7.55 (1H, d, J = 7.9Hz), 7.61-7.65 (2H, m), 8.85 (1H, s). MS (CI) m/e 448*.

Anal. Found: C, 70.00; H, 7.49; N, 15.45. CNA requires: C, 69.77; H, 7.43; N, 15.65%.

WO 94/03437 PCT/GB93/015W 60- F.YAAIPT.E 24: rrsl spnaratinn nf N-rSfffn-g.S-dihYdTPili mPthv1.9.nvo-S-frL'?-?,4lfi-TT>hvPri-1-v1)'lH':l14' hpnynHrpnin-S-vll N'-f-Pt-hvlphenYll urea N-[3CR,S)-2,3-Dihydro-l-inethyl-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 chloroformmethanol (20ml).

The enantiomers were separated as described in Example 5.

Peak A <0.59g). mp 170oC (dec). >H NMR (360MHz, D6- DMSO) 5 0.84-1.74 (11H, m), 1.80-2.32 (6H, m), 3.28-3.84 (4H, m), 4.14-4.48 (1H, m), 5.25-5.44 (1H, m), 6.75 (1H, d, J = 7.1Hz), 7.08-7.36 (4H, m), 7.50-7.62 (1H, m), 7.66-7.94 (3H, m), 9.45 (1H, brs), 10.16 (1H, brs). MS (CI) m/e 448+. Anal. Found: C, 60.42; H, 7.02; N, 13.35. CMH33N502.HC1.1.75 (H20) requires C, 60.57; H, 7.33; N, 13.58%. [aFD-138.8° (0=0.64, MeOH). Punty A:B = > 99.5:0.5.

Peak B (0.53g). mp 170oC (dec). W NMR {360MHz, D6- DMSO) 5 0.84-1.73 (11H, m), 1.80-2.30 (6H, m), 3.32-3.84 (4H, m), 4.16-4.46 (1H, m), 5.24-5.46 (1H, m), 6.75 (1H, d, J = 7.1Hz), 7.07-7.18 (2H, m), 7.20-7.34 (2H, m), 7.50-7.63 (1H, m), 7.66-7.94 (3H, m), 9.45 (1H, brs), 10.14 (1H, brs). MS (CI) m/e 448 [MHh.

Anal Found: C, 62.14; H, 7.10; N, 13.60. CNA.HCl.Hp requires C, 62.20; H, 7.23; N, 13.95%. [aPD +138.3° (c=0.65, MeOH). Purity A:B = < 0.5:99.5.

FYAMPLE 25: K-W* 92.3-Dihvdrn-5.f3,3-dimgt.hYlT>iperijin- l-vlVI-methvl 0 — -1TT-1 A.KPn7nHiPmn-3-vl1 NVrS-methYl phfinvll urea a) 1,9.-Dihvdro-M3,3-TnethvlDippriHin-1-Yl)-l-tngthYl-3- nYiTniHn-3H-1.4-hpn7.nriiazemn-2-one Prepared as described in Example 4, steps c) and d) from 1- methvl-1,2,3,4-tetrahydro-3H-1,4-benzodiazepin-2,5-dione (16.7g) and 3,3-dimethylpiperidine (lO.Og). NMR (360MHz, D6-DMSO) 5 0.69 (3H, s), 0.82 (3H, s), 1.28-1.45 (3H. m). 1.62- WO 94/03437 PCT/GB93/0I599 1 80 (1H, m), 2.75-3.00 (3H, m), 3.30 (3H, s), 3.50-3.60 (1H, m), 7.25-7.30 (1H, m), 7.40-7.60 (3H, m), 9.95 (1H, br s), 10.20 (1H, br s). TLC (10% MeOH/dichloromethane: siHca) Rf = 0.40.

b) -rfifp.<?.fl-nihvdm-f>-f3,3-dimptriYlPTP'ri'tin-1-Yl)-V TTltt.9.aTo.1H-l-honTna7.ftnin.3-vn Tr--TnylPhCTYll •urea l-Dihydro-S-O-dimethylpiperidin-l-yD-l-methyl-S-CO- ethylaminocarbonyDoximido-SH-l-benzodiazepm-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- dihydro-5-(3,3-dimethylpiperidin-l-yl)-l-methyl-3-(0- ethvlamino-carbonyl)oximido-3H-l,4-beiizodiazepin-2-one (HAg). The title compound was then prepared from the crude amine (8.5g) and m-tolyl isormate (4ml) as described in Example 6b). mp 213-215.°C. 1 NMR (360MHz, CDCI3) 5 0.71 (3H, s), 0.85 (3H, s), 1.30-1.47 (3H, m), 1.64-1.80 (1H, 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 (lH,m).

p.YAATPT.E 26: f>ra1 -narntinTi of y-r3(ff,.<?)-?l3-dihYdro-5- tnppin-s-vn N'-rs-TnpthYlPhPT)Yll vrea (.)-N-[2,3-dihy(iro-(3,3-dimethylpiperidin-l-yl)-l-methyl-2- oxo-lH-l,4-benzodiazepin-3-ylI N'-IS-methylphenyl] urea was prepared from the racemate analogously to Example 5. 'H NME (360MHz, D6-DMSC» 5 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), WO 94/03437 PC17GB9.V01599 9.26 (1H, s), 10.50 (1H, m). MS (CI) m/e 434+. Purity A:B 99.5:0.5. [aPD-86.30 (0=0.75, CIl2Cl.

EXAMPLE 27: N--2-':i-Dibvdro-f>-(4,4iTnPthYlpiperidill- 1.viv2-oxo-l-f?..2-t.rifluornpt.hvn-1H-1.4-hengodiazepiTi-3-Yl1 N'- f.q.-mPthvlphpnvl) urea a) Mftthvl 2-rN--hrnTnnacetvn-N-f2.2.2-lTifilroethYl)1 aTninflbenzQate A solution of methyl anthranilate (98.3g) and trifluoroethyl trichloromethanesulphonate (91.5g) 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 chromatography (silica gel, 10% diethyl ether/hexane) to give methyl 2-[N-(2,2,2-trifluoroethyl)]aminobenzoate, contaminated with trifluoroethyl trichloromethanesulphonate. To a solution of this mixture (35.8g) in dichloromethane (150ml), cooled to 10C under nitrogen, was added dropwise bromoacetyl bromide (10.1ml), keeping the temperature below +3°C. The reaction mixture was stirred at 0 ± 30G 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 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 (Na2S04) and evaporated in vacuo to leave a yellow oil.

This was purified by flash chromatography (silica gel, 20-25% EtOAc/petroleum ether) to afford the title compound (27.4g). W NMR (CDCI3) 5 3.58 (1H, d, J = 11.4Hz), 3.64 (1H, d, J = 11.3Hz), 3.83 (1H, m), 3.90 (3H, s), 4.79 (1H. m), 7.49 (1H, d, J = PC17GB93/01599 WO 94/03437 7 8Hz), 7.57 (1H, t of d, J = 7.6 and 1.3Hz), 7.68 (1H, t of d, J = 7.6 and 1.7Hz), 8.09 (1H, dd, J = 7.8 and 1.6Hz). MS (CI+. NH3) hPTi7ndin7RmTi-2,5-diQnS Ammonia gas was bubbled into a solution of the product ot part a) (27.3g) in anhydrous methanol (150ml) for 4h, keeping the temperature at +4 ± 9°C. The reaction mixture was allowed to stand open overnight then nitrogen was bubbled through the solution for Ih. The solvent was removed in vacuo and the residue stirred with 5% MeOH/CH2Cl2. The solid was filtered off, washed well with more 5% MeOH/CH2Cl2, and the combmed filtrates were purified by flat-h chromatography (silica gel, 3-5% MeOH/CH2Cl2) to give the title compound (15.2g). NMR (CDCI3) 5 3.87 (2H, m), 4.19 <1H, m), 5.03 (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+, NH3) m/e 259 .[MH]*.

c) 1 9.r>ihvdro-5-r4 4-riiTnethvlnipprifiiTi-1-viV3-(Q- 0Ylnr,nrbnTnvl)npn,n-1-(2.2.2-tllfhmiy,bYl)-3H-L4- V»p7ndiazeTrin-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).

m NMR (CDCI3) 6 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), 5.24-5.42 (IH, m), 6.16 and 6.33 (IH, 2 x br t), 7.31-7.56 (4H', m). MS (CI+, NH3) m/e 454+.

d) H-f?rff.9V2.3-rtihyro-5-(4.4-di-mpt}iYlpip?ridtn-l-Yl)-„2- nvn.i-r9 9. 9..t.rifl"T-nPt.hvi>-iH-l.4-bemnftin7,prip-3-vn N Following the procedure of Example 40, the product of part c) (450mg) was hydrogenated to give 3-aimno-l,2-dihydro-5-(4,4- WO 94/03437 PCT/«B9.V015«W 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) 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 236-2390C. lH mm (CDClg) 6 0.96 (6H, s), 1.30-1.50 (4H, m), 2.29 (3H, s), 3.30 (4H, m), 4.08 (1H, m), 5.23 (1H, m), 5.38 (1H, d, J = 8.2Hz), 6.46 (1H, br d, J = 7.9Hz), 6.84-6.88 (2H, m), 7.08-7.17 (2H, m), 7.21 (1H, s), 7.34-7.37 (2H, m), 7.53-7.58 (2H, m). MS (CI+, NH3) mJe 502+. Anal. Found: C, 61.21; H, 5.88; N, 13.19% 03302-0.620.0.1 C4H80 requires: C, 61.03; H, 6.21; N, 13.48%.

EXAMPLE 28: fWal Reparation of N-r3(/i>,)-2,3-dihvdrQ-5- (4i4.HiTnPt.hvlniperiiiTi-1-vlV2-oxo-T-(2.2,2-trifluoroRt-hvl)-lH-l,4- hpn*nHia7ftTriTv3-vn N'-ra-mpthvlphftnyll wea A solution of N-E3(B,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% CHCls/EtOH (5ml) was injected in 0.5ml volumes onto a dinitrobenzoyl leucine column (250 x 20.4mm i.cL, 5pm), eluting with 50% ethanol/hexane at 20ml/min. The fractions containing each enantiomer were separately evaporated in vacuo, the residues were rfedissolved in filtered dichloromethane (10ml) and ethereal hydrogen chloride (2ml) was added. The solvents were then removed in vacuo and the residues triturated with diethyl ether (5ml) to give:

Peak A. HC1 salt (134mg); mp 153-1580C; m mm (d6- DMSO) at 353K: § 0.98 (6H, s), 1.26-1.51 (4H, m), 2.23 (3H, s), 3.41-3.63 (4H, br m), 4.73 (1H, m), 5.15 (1H, m). 5.35 (1H, m), WO 94/03437 l»CT/GB93/01599 6 75 (1H, d, J = 7.1Hz), 7.06-7.20 (4H, in), 7.59 (1H, m), 7.78-7.85 <3H,xn),9.16(lH,brs). MS (CI% NH3) m/e 502*. [a3D = -195.5° (c=0.2, MeOH). Purity A:B= > 99.5:0.5. Anal. Found: C, 55.83; H, 6.04; N, 11.93%. C26H3oF3N502-HC1.1.42 H20 0.06 C4H10O. requires C, 55.48; H, 6.11; N, 12.33%.

Peak B. HC1 salt (128mg); mp 145-1510C; W NMR (d6- DMSO) at 353K same as for Peak A. MS (CI*. NH3) m/e 502*- [aFD = +204° (c=0.2, MeOH). ee = 99%. Anal. Found: C, 56.67; H, 5.86; N, 12.29%. C26H3oF3N502.HC1.0.8 H20: requires C, 56.53; H, 5.95; N, 12.68%.

EXAMPLE 29: N.raf7?..SfV2.3-rti>ivHro-R-(4.4-dimpthYlpipgridiii- 1-vn-1.pthvl-2-nvn.lH-1.4-bpn7ndiRzepin-3-Yl1 N,;-[3-TngthYl phgnvll vrea a) il9-nihvdro-M4-mRthv1pippridin-l-ylV1'ptPYl-3-(U- othylHTninnrflrhnnv1)»vimiHn-aH-14-bPTT7nftinyflriTTQne Prepared as described in Example 4, steps c) to e) from 1- ethyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (18g) and 4,4-dimethylpiperidine (lOg). NMK (360MHz, d6-DMSO) 5 0.9-1.20 (16H, br m), 2.94-3.03 (2H, m), 3.1-3.96 (5H, br m), 4.26 (lH,m), 7.2-7.7 (5H, m).

b) N.rarff,9vg.3-PiWrn.R.f4.4-diTnptbYlPippridiP-?-Yl)- otKY1.9.nvr>-R-f4.4-dim0YlrT-'i-V--1-4-gnZgdia2£mL a-vll N'-fH-metbYl pbpnvH urea The amine was prepared as in Example 40 from the product of part a) (5.2g). 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.

SAMPLE 30: rhiral sfiTmrafion of N-r3iff)-2.3-dihYfro-5- M i;mnty,Yrprin-l.vn-l-ethvl-2=flM=lIL1.4-h7.odia29Pin-.

a-vll N'-r.S-merbvlpbpnvll urea WO 94/03437 !>(T/GB93/0I59<> N-[3(i:2,S)-2,3-dihydro-5-(4,4-diinethylpiperidin-l-yl)-l- ethyl-2-oxo-lH-l,4-benzodiazepin-3-yl] N'-[3-methylphenyl] urea (2.4g) was dissolved in 9:1 chloroformimethanol (20ml). 1ml of this solution was injected onto a dinitrobenzoyl leucine column (250 x 20mm i.d., SyM) per run using 96:3:1 chlorobutane:

methanohacetic add as the mobile phase. Using a flow rate of 20mlAmn and u.v. detection at 330nmr 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 (MgS04), 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 (MgS04), filtered and evaporated to give a foam (0.45g). The foam was recrystallised from diethyl ether (0.28g).

mp 211-2130C. Found: C, 69.82; H, 7.24; N, 15.60. C26H33N502 requires C, 69.77; H, 7.43; N, 15.65. W NME (360MHz, CDCI3) 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 (1H, m), 4.33 (1H, m), 5.30 (1H, d), 6.74 (1H, d), 6.80 (1H, d), 7.07-7.37 (6H, m), 7.52 (2H, m).

jrcMPT.F HI: N.r3(R.SW*-r3.A7.a.hicvclor.3 ?. 21nonan-3-Yl)- ?3.Hi>ivdrn.1-tnet.hv1.9-n3cQ>1H-1.4-ben2odia7Ppin-3-YlVN'- ra-methvlphpnvn urea Mfithod A n} K.fa.Ay.flhirvHor3.?,?lnonRTi-3-Yl)-l,3-dihYdro-2H- i.Tr.Pt.hv1-3-nrimiHn.1.4-hep7,nHia7.Rpin-2-pne WO 94/03437 PCT/C.B93/0I599 Prepared analogously to Example 4, steps c) and d) from l.methyl-l,2,3,4-tetrahydro-3H-l,4-bexizodiazepm-2,5-dione (10 Og) and 3-azabicyclo[3.2.2]nonane (6.89g). mp 220-222oC.

'B. NMR (360MHz, CDCy 5 1.30-2.30 (10H, m), 3.32-3.40 (1H, m), 3.45 (3H, s), 3.47-3.54 (1H, m), 3.74-3.80 (1H, m), 4.66-4.73 (1H, m), 7.20-7.35 (3H, m), 7.49 (1H, ddd, J, = J2 = 7Hz, J3 - 1Hz). Found: C, 66.31; H, 6.93; N, 17.07. CN requires C, 66.24; H, 6.79; N, 17.17%.

i R.fiihvdro-i-m>ivi-2H-i 4-bpn7odinT?in-g-one The foregoing oxime (6.68g) was hydrogenated over 5% rhodium on carbon (6.7g) in methanol (670ml) at 40 psi and 60oC for 6.5 hours. The mixture was filtered then evaporated to give the crude amine which was used immediately in the next step.

c) N.rarT?RVR-f.S-irvnr3.2.?1noTn-3-Yl)-g,3- |1YHrn-1.Tnpt.hvl-2-nvn.lTT-1.4-beTlin7PTqn-n-N,-r3- jtfrvlphPTwll urea m-Tolyl isocyanate (3.17ml) was added to an ice cold soluticm of the foregoing amine (6.4g) in anhydrous tetrahydrofuran (70ml) then left standing at 40C 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 combined organics were dried (sodium sulphate) then evaporated and the crude product crystallised from dichloromethane to afford the title compound (1.55g). mP > 242°C (dec). 1H NMR (360MHz, CDC13) 5 1.54-2.04 (10H, m), 2.29 (3H, s), 3.26-3.40 (2H, m), 3.42 OH, s), 3.52-3,60 (2H, m), 5.28 (1H, d, J = 8Hz), 6.44 (1H, 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, m). Found: C, 63.39; H, 6.65; N 14.15. C H N O . 2H.O.0.15CH Cl2 requires C, 63.54; H, 7.20; N, 14.17%.

WO 94/03437 I»CI7(;B93/(H599 Method B a) fua-Asflhicvclnra 9. 2innnan-3-v1V1,3-dihydrQ-2H- i .mPthvi-R-fO-fethvTniTmcarbnnyDoximidoVI ,4-bPTi?;ndiazepm- 5-(3-Azabicyclo[3.2.23nonan-3-yl)-l,3-diliydro-2H-l-methyl -3-03dimdo-l,4-benzodiazepm-2-one (5.17g) and ethyUsocyanate (1.9ml) were heated at 60oC in anhydrous tetrahydrofuran (200ml) for 18 hours. The solvent was evaporated and the residue was purified by column chromatography on silica using dichloromethane _ 1% methanol/dichloromethane to afford a cream foam (5.53g, 90%, mixture of E/Z isomers), mp 1680C. H mm (360MHz, CDC13) 5 1.10 and 1.12 (3H, each t, J=7Hz)) 1.24-1.96 {9H, m), 2.16-2.28 (1H, m), 3.12-3.36 {3H, m). 3.38-3.52 (1H, m) overlapped with 3.44 and 3.45 (3H, each s), 3.58-3.70 (1H, m), 4.56-4.78 (1H, m), 6.13-6.22 and 6.36-6.44 (1H, each m), 7.18-7.52 (4H, m).

b) 3f7?...9VATmno-R-r3-azabicvHnr3 2l21nonan-3-yl)- 1 3.riihvriro-1-methv1-2H-1.4-beTi7ndiapi-n-2-QPe 5-(3-A2abicyclo[3.2.2]nonan-3-yl)-l,3-dihydro-2H-l-methyl- 3-(0-(ethylaminocarbonyl)oximido)-l,4-benzodiazepin-2-one (5.4g) was hydrogenated at 40 psi in methanol (500ml) 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 (4.45g) c) -i-.qfP.,9)-B-(3-Abvr1or3.2.21nonan-3-yl)-2,3- rlYrn-l-mfithvV.-nTn-lH-l-bRnzodiazgpin-a-yll-N'-fS- The foregoing amine (4.45g) in anhydrous tetrahydrofuran (15ml) was treated with m-tolylisocyanate (1.9ml). After 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.

WO 94/03437 PCI7GB93/01599 ,,,hirvrinr2.2.ilrtnTi-?-Ylv?-n-i-rrnryl-m-l,4- haTi7iHiR7pr-a-v •N'-ra-mpthvbhftPYll wea a) 1 ?.p|hvrtrn-R-fnP 4.qVf>-Tnfit.hv1-?..R-dia7,abiCYCl0 Prepared analogously to Example 4c) from l.propyl-l,23,4-tetrahydro-3H-lf4-benzodiazepiii-2f5-dione (5.0g) and (lS,4S)-2- methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (17.3g), J, OffT, ChCTP. 1990.55, 1684-1687).

b) 1 a.rHhvHro-5-lS 4RVfi-methv1-2.fi-diazabiCYClP [9 9 1 ibpnt-an-g-vD-TT-R-mriTnido-l-proPVl-1.4-beTi7iOdiazgpiy?.-.g.= Potassium t-butoxide (3.6g) was added in portions to a stirred, cooled (-20oC) suspension of l,3-dihydro-5-((lS,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl)-2H-l-propyl-l,4-benzodiazepm-2-one (2.0g) in anhydrous toluene (250ml) under a nitrogen atmosphere. After stirring at -20oC for 30 minutes isopentylnitrite (1.9ml) was added and the reaction mixture was stirred at -20oC for 1 hour then at room temperature for 3 days. The mixture was re-cooled to -20oC and further potassium t-butoxide (1.8g) and isopentylnitrite (1ml) were added. The mixture was stirred at -20oC 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) pfp giATnmn-l .3.hvdm-5-((lS.4lS)-S-mPthYl-g.5- Wr1nr2?11hPr,tpn.2.vn-?H-1-PrOPyl-l,4-ben7-odiapi2- one Trifluoroacetic acid (1.36ml) and activated zinc powder (Fieser and Fieser, 1967, Volume 1, 1276, 1.14g) were added to a WO 94/03437 !»CI7(;B93/01599 stirred solution of the foregoing oxime (0.6g) in glacial acetic add (70ml) at 40oC 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.

d) N.rafff..9V2.3-DihvHro-.'>-(f1S.4PVfi-TnPthYl-2.5- a7ifvvr1nr2.2.niiPrn.2-v1V2-nxo-1-nrnpvMH-1.4- niHTPrin.a.vn-Tsr-r3.TnpthvlphpnYnwea Triethylamine (0.3ml) was added to a stirred suspension of the foregoing amine trifluoroacetate in anhydrous 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 (50ml) and 1M citric acid (50ml). The organic layer was extracted with a further portion of 1M citric add (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 50ml). The combined organics were dried (sodium sulphate) then evaporated 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 (25mg) as a 1:1 mixture of diastereomers. mp 126-1280C. MS, CI*, m/z = 461 for (M+H)*. Found: C, 65.07; H, 7.08; N, 16,94. C H N 0o. 1.25H90 requires C, 64.64; H, 7.20; ' ' 26 32 6 «! i N, 17.39%.

f.yampt,e 33: (-yN-r5-(3-A7.3bicv<M3,2 ?lTwnan-3-Yl)-8,3- Hihvdro-1-metbvl.2-nxn-lH-1 4-bfinzodiazpp-3-Yll-N,-r3-n>ethYl pfrpfivn 1irea Hydrochloride The racemic compound (Example 31. 1.5g) was separated into its enantiomers using semi-preparative chiral HPLC on a WO 94/03437 PCI7GB93/U1599 Pirkle dinitrobenzoylleudne column (5p) [(250 x 21.4)mm] duting with 3% methanol in l-chlorobutane (including 1% acetic add). Flow rate 20ml/mmute, U.V. detection at 290nm.

Analysis was performed on an analytical Pirkle dinitrobenzoylleudne column (5p) [(250 x 4.6)mm] eluting with 5% methanol in l-chlorobutane (induding 1% acetic add). Flow rate Iml/minute, U.V. detection at 250nm.

The free base was liberated and obtained as a colourless solid (680mg). The hydrochloride salt had mp 188-190oC (dec.) (ethyl acetate/acetone (10:1). Rf 0.55 in dichloromethane/ methanol (9:1) on silica plates. MS, CI\ m/z = 446 for (M+Hf.

[a]23°c = -216° (c=0.2, methanol). Found: C, 63.75; H, 6.99; N, 13.98.DC H N O .HC1.0.5H2O requires C, 63.60; H, 6.77; N, 14.26%. HPLC: (Pirkle dinitrobenzoylleudne column, 5% methanol in l-chlorobutane (induding 1% acetic add)): > 99% ee (R = 5.6 minutes). HPLC: (Spherisorb 5pm 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.

F.YAMPT,E 34: U).N-r5-(3-AHrvdor.3.? ?,lTinnaTl-3-vl)-2.3- Hvrlrn-1-TnPthvl-2-nyn-1TT-1.4-her7,nrliH7Win-3-yll-N'-[3-niSthyl phpnvll urea ffvrirorhloride The title compound was obtained (660mg) using the procedure described in Example 33. The hydrochloride salt had mp 189-19rC (dee.) (ethyl acetate/acetone (10:1)). Rf 0.55 in dichloromethane/methanol (9:1) on silica plates. MS, CI , m/z = 446 for (M+H)+. [af3'cD = +222° (.c*0.2, methanol). Found: C, 63.59; H, 1.05; N, 13.86. COHCLCSH requires C, 63.60; H, 6.77; N, 14.26%. HPLC: (Pirkle dinitrobenzoylleudne column, 5% methanol in l-chlorobutane (including 1% acetic add)): 99% ee (R = 8.24 minutes). HPLC: (Spherisorb 5pm Phenyl column [(250 x 4.6)mm], 50% acetonitrile/50% of 0.2% WO 94/03437 PCI7G B93/01599 triethylamine in water and SOinM potassium phosphate, pH = 3):

> 99% chemically pure.

EXAMPLE 35: N-rnfR.RV5-f.c!-A7flbicvclor3.2.21nonan-3-vl)-2,3- dJhvdro-l-methv1-2-oxo-lH-1.4-bgnzQdiazffliP-3-Yl1-N'-r3- flm?rophenYll rea The title compound was obtained (450mg) from 3-fluorophenyl isocyanate and 3(R,S)-aiiiino-5-C3-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 196-1970C (dichloromethane/diethyl ether). MS, CH, m/z = 450 for (M+H)+.

'H NMR (360MHz, CDCy 6 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 (1H, d, J=8Hz), 6.62-6.67 {2H, m), 6.98 (1H, dd, JlHz, J2=8Hz), 7.10-7.55 (7H, m). Found: C, 67.23; H, 6.12; N, 15.46.

C H FNO requires C, 66.80; H, 6.28; N, 15.58%.

EXAMPLE 36- (VN-r5-(3-A73bicvclor3.2.21nonan-3-vl)-2.3:

dihvdn-)-l-methv1-2-oxo-lH-1.4-benzodiazPPm-3-Yll-N'-[3- flunronhenvll nrf« TTvrtrnRhloride The racemic compound (Example 35, 320mg) was separated into its enantiomers using semi-preparative HPLC on a Pirkle dinitrobenzoylleucine column (5p) [(250 x 21.4)mm] eluting with 5% methanol in 1-chlorobutane (including 1% acetic add).

The free base was liberated and obtained as a colourless solid (140mg). The hydrochloride salt had mp 208-210oC (acetone/ethyl acetate (1:1)).240CD = -235° (0=0.2, methanol).

1H NMR (360MHz, D20) 5 1.24-1.98 (9H, m), 2.28-2.36 (1H, m)» 3.50 (3H, s), 3.61 (1H, d, J=15Hz), 3.70 (1H, d, J=15Hz)) 3.76-3.84 (1H, m), 3.96-4.04 (1H, m), 5.58 (1H, s), 6.88 (1H, ddd, J -rlHz, JSHz), 7.07 (1H, d, J8Hz), 7.21 (1H, ddd, J1*J =lHz,2J =8Hz), 7.33 (1H, ddd, Jmz), 7.58 (1H, dd, WO 94/03437 PCIVGB93/01599 J =J =8Hz), 7.65 (1H, d, J=8Hz), 7.75 (1H, d, J=8Hz), 7.86 (1H, dd, ZJ=JdBRz). Found: C, 60.84; H, 6.15; N, 13.32.

C H FN20 HC1.0.5H O.O.SCH.COCH requires C, 60.74; H, 28 5 2 2 J » 6.35; N, 13.36% flXAMFT-rc 37: f+VTf-rK-f3-A»»hirvpTnr3 ?.21nonnn-3-Yl)-g.3- hvrirn-i-TnethvI-?-"-iTT-i.4-hPTi7;ndiazeT?in-?-Yn-N,-r3- fliTm-nnhenvll nrpn Hydrpchloride The title compound was obtained (115mg) using the procedure described in Example 36. The hydrochloride salt had mp 207-209oC (acetone/ethyl acetate (1:1)). D = +240° (c=0.2, methanol). Found: C, 60.87; H, 6.23; N, 13.44.

C H FN 0 .HC1.0.5HoO.0.5CH COCH requires C, 60.74; H, 28 5 2 2 J . " 6.35; N, 13.36%.

frXAMPT/F, 38: -f?(..RVS-f3-A7nhirvclor3.g11rtT)-3-v))-2,3- yT.n.1-Pt.hv1.2.07n-lTT.14-hRr.7nd7PPin-3-Yll-N'-[3-mgthyl rhpnyll urea a) fi-fa-AahirvrlP ?< 11nn-3-v1V1 3-dibydrO-2H-l- mPt.hv1-3-oxiTpidn-1.4-beT17,ndin7.eT?iT]-g-0ng The title compound was obtained from l-methvl.l,2,3,4-te.trahydro-3H-l,4-benzodiazepin-2,5-dione and 3-azabicyclo[3.2.1]octane fJ.Fhnrm, Sd, 1968, 51, 1785-1787) as described in Example 4, steps c) and d). mP 249-252°C (ethyl acetate/diethvl ether). MS, CI*, m/z = 313 for (M+H)*. Found: C, 62.28; H, 6.41; N, 16.54. COO requires C, 61.80; H, 6.71; N, 16.95%.

b) -r3fy?.,<?V5-(3-Ahicvr1nr3.2 11octon-3-yl)-2,3- Yrf>-1--mAthvl-9-nTo.1H-1.4-bPTi7ndiTOin-3-y11-N,-[3- TTiPthylphenvlT urea The title compound was obtained (1.75g) from the foregoing oxime as described in Example 31, Method A. mp 237-2390C. MS, CI*, m/z = 432 for (M+H)+. 1H NMR (360MHz, WO 94/03437 PCT/GB93/01599 CDC1 ) 5 1.46-1.49 (6H, m), 1.90-2.24 (2H, m), 2.28 (3H, s), 2.74-2.82 (1H, m), 3.06-3.12 (1H, m), 3.40-3.50 (2H, xn), 3.42 (3H, s), 5.35 (1H, d, J=8Hz), 6.66-6.78 (1H, m), 6.81 (1H, d, J=8Hz)1 7.06-7.58 (8H, m). Found: C, 69.38; H, 6.79; N, 15.92.

C H N O requires C, 69.58; H, 6.77; N, 16.23%.

hvHrn-VTnet.hvl-?-""--»TT-i.4-bPTi7ndiazepin-3-Yll-N'-r3-methYl phpnvll urea •prvdrnrhlnride 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 218-220oC (acetone/ethyl acetate (1:1)).23°cD = -215.5° (0=0.2, methanol).

MS, CI", mlz = 432 for (M+H)*. Found: C, 62.90; H, 6.46; N, 14.59. C H N O,.HC1.0.5H,O requires C, 62.95; H, 6.55; N, 29 5 2 ' 14.68%.

FYAMPT.F 40: f+l-N-rB--AzahJCYcMS.? nnr.tflTl-3-Yl)-2,3- pbenvll uren Fdrochlnride 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 190oC (dec.) MS, CI*, m/z = 432 for (M+Hf.23" = +182° (c=0.2, methanol).

Found: C, 62.77; H, 6.66; N, 14.07. CNp? HC1.0.6H2 O.0.1CH CO CELCEL requires C, 62.56; H, 6.61; N, 14.36%.

fiXAMPT.F, 41- f.vN-r5-(a-At!vor3 ? ?lTionan-3-Yl}-g.3- HibvHrn-i-methvl-?-nirn-iTT,-i.4-bPn7odia7,roin-3-Yn-N'-rf>-indapyl lurea a) ff..amino-N-(5-fa-nhirvclor3 ? ?1nnnan-3-Yl)-2,3- ihyrirn.1-metbv1-2-nyn-1.H-1,4-henzQdia?i9Pin-3-Yl) hpnzfiiiepropanamide WO 94/03437 PCT/GIWS/OISW To a stirred solution of 3(fl,S)-amino-5-(3-azabicyclo [3.2.2]nonan-3-yl)-l,3-dihydroa-inethyl-2H-lf4-benzodiazepin-2- one (2.22g) in anhydrous dimethylformamide (25ml) were added BOC-D-phenylalanine (2.072), 1-hydroxybenzotriazole (1.02g), i-O-dimethylaminopropyD-S-ethyl-carbodiimide hydrochloride (1.49g) and triethylamine (5ml). After stirring at room temperature for 30 mintues, the reaction mixtures was left standing at 40C for 16 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and 10% potassium carbonate solution. The organic layer was dried (sodium sulphate), evaporated to dryness, and the resulting oil purified by column chromatography on silica using dichloromethane-methanoydichloromethane (1:99). The product obtained (2.7g) was treated at 40C with ethyl acetate (15ml), saturated with hydrogen chloride gas and stirred at room temperature for 40 minutes. The solution was cooled down to 40C 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/methanoy dichloromethane (0.2: 2:98) (gradient elution) to afford diastereomer A (0.38g) HPLC (Spherisorb ODS2 column, 70% acetomtrile/30% of 0.2% triethylamine in water, pH to 3 with orthophosphoric add): Rt 6.8 minutes, and diastereomer B (0.51g, 23%), Rf 0.37 in methanoVdichloromethane (1:S) on silica plates, HPLC (same conditions as in diastereomer A): Rt 8.4 minutes.

fc) .fl.ATnino-S-'a-Arflhiftvclora ?! 21noT13Ti-3-vlH,3- rivHro-i-methyl-bdiarPTiiTi-oTieTrifliioroacgtatg Phenyl isothiocyanate (120pl) was added to a stirred soluction of the foregoing diastereomeric amide A (380mg) in anhydrous dichloromethane (10ml) then heated at 40oC (oil bath WO 94/03437 l»Cr/«H93/01599 temperature) for 3 hours. The reaction nnxture was evaporated and the residue purified fay colunm chromatography on sihca using dichloromethane _ methanoydichloromethane (5:95), to afford the thiourea (440mg). Anhydrous trifluoroacetic aad (16 8ml) was added to the solid thiourea (430mg) and ihe solution stirred at room temperature for 50 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 with toluene to afford the homochiral amine trifluoroacetate (218mg). Rf 0.30 in methanoydichloromethane (1:9) on silica plates,23*0. = -20.5° (0*0.2, methanol).

C) .rc-rK-fs-Azafri'TrHa 9.2inn--v1V? 3-riihvdrP- Vvi-s-nxn-iTT-i 4->—np-s-vn-N-rfi-innyll urea A stirred, cooled (0oC) solution of 5-aminoindan (81mg) m anhydrous tetrahydrofuran (15ml) was treated with triphosgene (60 4mg) and triethylamine (250]il). After stirring at 0oC for minutes a solution of (-)-3-amino-5-(3-a2abicyclo[3.2.2] nonan-3-yl)-l,3-dihydro.l-methyl-2H-benzodiaZepin-2-one trifluoroacetate (218mg) in anhydrous tetrahydrofuran (15ml) was added. After stirring at 0°C for 10 minutes the reaction nnxture was left standing at 4°C for 2 days. The reason nnxture was evaporated to dryness and the residue partitioned between saturated potassium carbonate solution and ethyl 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 (145mg, 60%). mp 2560C. D = -124° <c=0 1, methanol). 'H NMR (360MHz, DMSO-cU 5 1.5-1.66 (6H m), 1.76-1.87 (2H, m), 1.9-2.04 (4H, m), 2.76 (4H, dd, J =J =6 5Hz), 3.23-3.36 (2H, m), 3.32 (3H, s), 3.6-3.7 (2H, m), 41962(1H, d, J*7Hz), 6.79 (IH, d, J=7HZ)) 7.0-7.64 (7H, m), 8.78 WO 94/03437 PCI7CB9.V01599 (1H. s). Found: C, 71.59; H, 6.82; N, 14.73. C2BH33N502 requires C, 71.31; H, 7.05; N, 14.85%.

. v.YAvrPT,F. 42: TH?"? ffl-fi-fS-A7nhirvr1or3.2.g1nminn-3-Yl)-2tg- triflnnrnmethvl-rhPTiyn UTSS - The title compound was obtained (690mg) from 3(i2,S)-aiiiino-5-(3-azabicyclo[3.2.2]nonan-3-yl)-l,3-dihydro-l- methyl-2H-lf4-benzodiazepin-2-one and 3-trifluoromethylphenyl isocyanate as described in Example 31, Method A. mp 152-1540C (dichloromethane/diethyl ether (2:1)). MS, CI*, m/z = 500 for (M+H)*. Found: C, 60.58; H, 5.96; N, 12.91.

C H FNO H O requires C, 60.34; H, 5.84; N, 13.50%.

AMPT.F, 43- N-r3rffl,-?.l3-nihvHro-f!;-f8-TnPt.hYV3.S- H7pHrvrlnr3.2.11"rtnT1-Y-9-n1co-1-pr0T3vl'lH-L4' Prepared analogously to Example 32 from 1-propyl- l,2,3>4-tetrahydro-3H-lf4-ben2odiazepin-2,5-dione and 8-methyl- 3!8-diazabicydo[3.2.1} octane frT Md, Chem. 1974,11, 481-487).

mp 247-250oC. MS, CI% m/z = 474 (M+H)*. 'H NMR (360MHz, DMSOd) 5 0.70 (3H, t, J * 7Hz), 1.24 (1H, m), 1-39 (1H, m), 1.57 (1H, m), 1.79 (1HT m), 1.92 (1H, m), 2.15 (3H, s), 2.21 (3H, s), 2.62 (1H, m), 3.0 (4H. xn). 3.62 (1H, m), 4.42 (1H, m), 4.93 (1H, d, J = 8Hz), 6.71 (1H, d, J = 7Hz), 6.98 <1H, d, J = 8Hz), 7.06 (3H, m), 7.59 (4H, m), 9.80 (1H, s). Found: C, 67.99; H, 6.95; N, 17.54. 03402 requires C, 67.68; H, 7.26; N, 17.19%.

flXAMFTI* AJL- N-(?mRl.'Uft-Asiihirvrlnra 2,glnQnnTl-3-Yl)-2,3- im.T.mf>thYl-?.-nvn-iTT-i.4-hPT17f>difepin-3-yll-N,-[3-fluQro- A--mpthYlrhpnv11 u*** WO 94/03437 PCT/CBM/OISW Prepared as described in Example 31, Method B. mp 254- 255°C. Found: C, 65.87; H, 6.36; N, 14.54. CFN.O.SHP requires C, 66.08; H. 6.61; N, 14.829b.

TTCAMPLE AS- <.\-N---*™Kc.vc]oW ? ?lnnnan-3-Y])-2,3- HvHro-1-TnPt.hvI-9-"Tn.lH-1.4-hpn7ndia7ePin-3-Yll-N'-r3-flV0rP- 4-TnethvlphenYll rpa Hydrochloride The racemic compound (Example 44, 1.5g) was separated into its enantiomers using semi-preparative HPLC on a Pirkle dinitrobenzoylleudne column (5) [(250 x 21.4)mm] eluting with 3% methanol in 1-chlorobutane (including 1% acetic arid).

20nilvminute. X = 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 235-2360C (acetone/ethyl acetate). [aP0CD = -242° (c=0.2, methanol). 1H NMR (360MHz, DMSOd 5 1.50-1.80 (10H, m), 2.12 (3H, d, J = 2Hz), 3.10-3.38 (1H, m). 3.41 (3H, s), 3.44-3.58 (2H, m), 3.70-4.00 (1H, m), 5.28-5.36 (1H, broad d), 6.90-7.86 (8H, m), 9.46 (1H, broad s). Found: C, 61.65; H. 6.20; N, 13.49.

C2fiH30FN5O2.HC1.0.5H2O requires C, 61.35; H, 6.33; N, 13.75%.

F.XAMPLF 46- (.N-\F>-(Z™h\c.vcM3 ? ?.lnnnnn-3-vl)-2,3- riihvHro-1-TnetbvV9-oTn-1H-1l4-hP"7.ndia7Pmn-3-Yn-N'-F3-flwrp- 4--met.hvlphpnv11 nrfia 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 232-2340C (acetone/ethyl acetate).23' = +275° <c=0.2, methanol). Found: C, 61.54; H, 6.30; N, 13.23.

CaH30FNsO2.HC1.0.5H2O.0.lCH3CO2CH2CH3 requires C, 61.23; H.6.38;N, 15.527f.

WOW/03437 PC17C;B93/0I5W flXMPT.F - N-rafP PVP-f3-A7,nhi1nr3 ? ?lnoTinn-vP-2.3- 1-|1Yrn-i.TnPt.hvl-?-nn.m.i.4-bpn7ndinzgpin-3-v1l-N'-r3T incjnphenyll urea The title compound was obtained from 3(R,S)-aimno-5-(ci- azabicvclo[3.2.2]nonan.3.yl)-l,3-dihydro.l-methyl-2H-ll4.

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, 5.00; N, 11.86.

CaHalNsOHaO requires C, 52.18; H, 5.25; N, 12.17%.

mvrPT.K 4P: f.vN-rs-(3-7anr3-2 ?1nnTian-3-Yl)-g.3- iiv,Yfir..1.TT1Ptbv1--nxo-lH-14-hen7:0din7-3-v]l-N,-r3- The racemic compound was separated into its enanuomers using semi-preparative HPLC on a Pirkle dinitrobenzoylleudne column (51) [(250 x 21.4)mm] eluting with 4% methanol in 1- chlorobutane (including 1% acetic acid). 20ml/minute, X = 305nm.

The free base was liberated then recrystallised from ethyl acetate to afford a colourless solid (600mg). mp 219-221°C. [aP °cD = -132° (c=0.2, methanol). Found: C, 54.23; H, 5.03; N, 12.54.

CocHINsO;, requires C, 53.87; H, 5.06; N, 12.56%.

flyAMPT/E 4P- f+VN-r--AhicvclorSIlimin-a-YD-Z.S- iYirn.-|.mpthvi-2-oxo-lH-1.4-b?ninPin-3-y11-N,'f3- indonhenvll urea The title compound was obtained using the procedure described in Example 48. mp 220-222°C. i*W% * 4-132° (c=0.2, methanol). Found: C, 54.31; H, 4.99; N, 12.28. C2aH2BIN502 requires C, 53.87; H, 5.06; N, 12.56%.

WO 94/03437 PCT/G1193/01599 f.yampt:r 50: N-mrT? sv5-f3-AzaMcYdQr3.2.2]npnnn-3-YlV2.3- HihvHrn.i-mPthv]-2-nTn.iH-i.4-bPTi7ndin7Pi?in-a-v11-N'-fphenyn The title compound was prepared using the procedure described in Example 31 but replacing m-tolylisocyanate with phenyl isocyanate. mp 214-2150C (tetrahydrofuran). MS, CI*, m/z = 432 for (M+HK Found: C, 69.78; H, 7.29; N, 14.62.

02902.0.5 C4H80 requires C, 69.35; H, 7.11; N, 14.98%.

example 51- N-rafR.svR-(S-A7ahirYc1or2.2?.1nrtfln-2-vl)-g.3- rfihvHrn.i.methvi-9.-nTn.lH-1.4-henzodiazgrin-3-vll-N,-r3- mpthvlphpnyll urea a> 2-A7abirvclor2.2.2lQCtane Anhydrous diethyl ether {150ml) was added to a stirred solution of 1M lithium aluminium hydride in diethyl ether (57ml). Powdered S-isoquinudidinone (9g, OnraniC ftYIlthesis, 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 -20oC for 1 hour. 2- Azabicyclo[2.2.2]octane was isolated (4.80g) as a colourless solid, mp 175-180oC. 1H NMR (360MHz, CDCI3) 5 1.50-1.95 (9H, m), 2.84 (1H, s), 3.00 (2H, s), 3.38 (1H, broad s).

b) S-fg-Arahicvcln * 2im*.an-a-vlH.3-dihYdrp-2H.:.l- met.hv1-1.4-hen7odiazepin-2-Qnfi The title compound was prepared from 1-methyl-1,2,3,4- tetrahydro-3H-l,4-benzociiazepin-2,5-dione and 2-azabicyclo [2.2.2]octane as described in Example 31. mp 140-142oC (diethyl ether/n-hexane). MS, CI*, m/z = 284 for (M+H)*. Found: C, WO 94/03437 |»CI/<.IW/0I5<><> 70.62; H, 7.27; N, 14.41. C17H21N3O.0.25H2O requires C, 70.93; H, 7.53; N, 14.60%.

C) fi-f9-A7Bhirvrlpr? ? 21nrt.an-2-v1)-1 3-dihYdrO-2H-l- mpthvi-q-omido-i 4-bpn7odiazeDin-2-one The title compound was obtained from the foregoing benzodiazepine as described in Example 31. mp 264-2660C. MS, CI% m/z = 313 for (M+HK Found: C, 63.68; H, 6.44; N, 17.01.

C17H20N4O2.0.5H2O requires C, 63.53; H, 6.59; NT 17.43%.

d) N-rafT?..F8Vf>-f2-A>iWn1nr2.2.21nrt-?-v1)-?libYdrP- 1.TnPt.>iv1-2.n»o-1TT-1.4-hflnzodin7PT>in-3-Yn-N,-r3-mPt-hYlT?hgnYn The title compound was prepared from the foregoing oxime as described in Example 31, Method B. mp 242-2430C (dec) (ethyl acetate). MS, CI*, m/z = 432 for (M+HK Found: C, 69.95; H, 6.77; N, 16.25. CHNsO;, requires C, 69.58; H, 6.77; N, 16.23%.

FIXAMPT.F ss- N-r?fKlK--A?=ilnr3.2.21nnnpn'3-Yl)-2.3- j|ivHrn-i-TnRthYl-?-""-iH-l4-beT»iodi.az?rin-3-Yl)-N'-r4-flwpro- 3-methvlnhPTivn urea A stirred, cooled (40C) solution of 3(R,S)-amino-5-(3- azabicvclo[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 (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 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 160-162oC.

m NMR (360MHz, CDC13) 5 1.56-1.90 (8H, m), 1.94-2.02 (2H, wowimr it[/(;b9.voi5w 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 (1H, d, J = 8Hz)( 6.57 (1H, d, J = 8Hz), 6.85 (1H, dd, J1 = J2 = 9Hz), 7.00-7.05 (1H, m), 7.17 (1H, s), 7.21-7.32 (3H, m), 7.47-7.54 C2H, m). Found: C, 65.27; H, 6.58; N, 14.45.

C26H30FN5O2.0.75H2O requires C, 65.46; H, 6.66; N, 14.68%.

fiXAM-rc S3- f-VN-r5-(?-A7,pv ? ?1nnTinn-3-vl)-2.3- it1Yrn-i-nnPthvl-2-p-iH-i.4-bpn7,odiPDin-v11-Nl-r4-nuorQ- a-Pfipt.hvItthenYll "rRa Hydrochloride The racemic compound (Example 52, 620mg) was separated into its enantiomers using semi-preparative HPLC on a Pirkle dinitrobenzoylleucine column (5n) [(250 x 21.4)mm] eluting with 5% methanol in 1-chlorobutane (including 1% acetic add). 20mL/minute, X = 305mn.

The fractions from peak A were evaporated to dryness and the free base liberated (255mg). The hydrochloride salt had mp 221-2230C (acetonitrile/ethyl acetate). [aP°cD = -248° (c=0.2, methanol). MS, CI*, xa/z = 464 for (M+H)* of free base. Found:

C, 61.41; H, 6.22; N, 13.46. CFN.HCl.O.SH requires C, 61.35; H, 6.34: N, 13.76%.

FXAT'F 54: (+).N-r5-(3-A7abirYclnr3,2,21n0ETi-3-Yl)-2,3- ii.TnotV»vT-9-nT0.1H-1.4-hPTi7nf1inzCTin-3n-N,-f4-flv9rp- a-mRthvlphenyli nrfia HvdrochlQrid& Obtained using the procedure described in Example 53.

mp 221-2230C (acetonitrile/ethyl acetate). [aP°CD = •f2400 (0=0.2, methanol). Found: C, 61.73; H, 6.20; N, 13.60.

C28H30FNsO2.HC1.0.5H2O requires C, 61.35; H, 6.34; N, 13.76%.

mF. ** f-VN.rR-f3-A7ahirYglof3 ?,?lTinnn-3-Yl)-:

Yn-l-n1Pthvl-2-nXn.lH-1.4-hen7,odiazgpip-a.-jdIiHimi trif nnrnrnPthvlphpnyll urea Hydrochloride WO 94/03437 |'CT/<;H9.V(H5«W The racemic compound (Example 42, 400mg) was separated into its enantiomers as described in Example 53. mp 215-2170C (acetonitrile/ethyl acetate). [aWcD = -216° (c=0.2, methanol). MS, ClMn/z = 500 for (M+H)+ of free base. Found:

C, 57.76; H, 5.18; N, 12.79. CaHaF3N5O2.HC1.0.25H2O requires C? 57.78; H, 5.50; N, 12.96%.

fiYrn-1-Tr,Pf.hv1-2-"-1TT-1-4-benriin7Ppiri-3-vll-N'43- »rif»iinrrmiftt.hviT>hpnv11 nnjR Hvdrnchloride Obtained using the procedure described in Example 53.

mp 209-212oC (acetonitrile/ethyl acetate). [aWcD = +212° (c=0.2, methanol). Found: C, 53.25; H, 5.32; N, 11-86.

CaHaF3N5O2.HCl.3H2O requires C, 52.93; H, 5.88; N, 11.87%.

, / .

FXftMpT.rc 57: -rafR.SV?,.3-DihYciro-1-mp-tbYl-(ctg- mfithvlphenvll urea a) r.Qrtahvdmisoindolg Cis-4-cyclohexene-l,2-dicarboximide (10.9g) was hydrogenated over 10% palladium on carbon (Ig) in absolute ethanol (420ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give ds-cyclohexane-1,2- dicarboximide (10.6g). To anhydrous diethyl ether (200ml) was cannulated under nitrogen a 1M diethyl ether solution (200ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-l,2-dicarboxiinide (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 WO 94/03437 |'CI/<;BW/0I5«M filtrate dried (sodium sulphate) and evaporated to give a cream b) .nihvHro-l-Trvl-R-ts-nrtahYdTQiBgiTliPl-g-yD-gH.:

j-hRTizodiazenin-g-one A solution of phosphorus pentachloride (6.15g) m 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 40C 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 -4 10% methanoVdichloromethane (containing 1% ammonia) to afford the title compound (3.3g). mp > 1280C (dec). iH NME {360MHz, CDCI3) 5 1.16-1.72 (8H, m), 2.04-2.18 (1H, 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) 1ia.nihvriroO-r'pt.hvi-s-fcis-ort.qhYdroisQ.iTidol-g-vl)-2H- Potassium t-butoxide (2.94g) was added in portions to a stirred, cooled (-250C) solution of l,3-dihydro-l-methyl-5-(dS- octahydroisoindol-2-yl)-2H-l,4-benZodiazepm-2-one (3.2g) in anhydrous toluene (110ml) under a nitrogen atmosphere. After stirring at -250C for 50 minutes isopentylnitrite (1.6ml) was WO 94/0343- |»Cr/C;B9.VOI5»9 added. The reaction mixture was stirred at -250C for 6 hours, then isopentyhntrite (0.8ml) was added foUowed 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 -250C overnight. Whilst warming to room temperature the reaction mixture was treated with water (30ml) containing citric add (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. iH NMR (360MHz, CDCI3) 5 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 a.nvdro-i-r7Pt.hvi.f>-(cts-nrt.nhYdrpis?QiTifip1-?-Y))-3H- ?n.foty,YlRH""riYl)"yi>-T-4-bpn7nriinrepin-g-pne The foregoing oxime (2.3g), ethylisocyanate (2.8ml) and triethylamine (1ml) were heated at 65°C in anhydrous tetrahvdrofuran (150ml) for 18 hours. The solvent was evaporated and the residue was purified by column chromatography on silica using dichloromethane -> 3% methanoVdichloromethane to afford a white foam <2.8g, mixture of E/Z isomers), mp 175-180°C. H NMR (360MHz, CDCI3) 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) -Qy tninn-i -dihvHrn-l .methvl-Mrw-ortahYdro i cni prj pi .9-vl )-2H-1 4-hpn7.ndi a7epin-2-Qng The product of part a) (2.4g) was hydrogenated at 45 psi in methanol (160ml) over 10% palladium on carbon (Ig) for 3 hours at room temperature. The mixture was filtered then evaporated to dryness to afford the title amine (2g).

f) N.rafR.5;v2.3-r*vHro.i.methv1-f>-frtff-nctahYdro mnHnU2.vlV2-oxn-ni-l,4-benzQdin?priTi-3-vll-N,-r3- TpRthvlphenvll urea The foregoing amine (2g) in anhydrous tetrahydrofuran (5ml) was treated with m-tolylisocyanate (0.72ml). After standing for 5 minutes 1 drop of dichloromethane was added.

After ageing at 40C for 18 hours the predpitate was collected to afford the title compound as a free base (2.2g). mp > 1560C (dec), m NMR (360MHz, DMSO) 5 1.12-1.64 (8H, m), 1.96-2.09 (1H, m), 2.21 (3H, s), 2.30-2.36 (1H, m), 2.74-3.1 (1H, m), 3.27- 3.37 (1H, m), 3.31 (3H, s), 3.45-3.62 (2H, m), 4.94 (1H, d, J = 8Hz), 6.68-7.67 (8H, m), 6.91 (1H, d, J = 8Hz), 8.79 (1H, s).

Found: C, 65.40; H, 6.70; N, 14.83. CMH31N502.1.7H20 requires C, 65.57; H, 7.28; N, 14.70%.

fyamplf, 58: (,-'hN-r8.3-DihYdrn-1-mf?thYl-5-(«s- nhvdroisoindol--vlvg-nxo-lH-l-benzpdinPiTi--Yll-N'-rS- TriRthvlphenvllnrsa hvdrnchloride The racemic compound (Example 57, Ig) was separated into its enantiomers using semi-preparative chiral HPLC on a Pirkle dinitrobenzoylleucme column (5\i) [(250 x 21.4 tam] eluting with ethanol/hexane (1:1), flow rate 20ml/minute, U.V.

detection at 310nm.

The hydrochloride salt (350mg) had mp > 190oC (dec).

MS, CI+, m/z = 446 for (M+Hh. [aW% = .107.5° (c=0.2, methanol). Found: C, 61.65; H, 6.96; N, 13.33.

CNjAs.HCU.SHjjO.O.I C4H80 requires C, 61.42; H, 6.99; N, 13.57%. HPLC (spherisorb ODS2, 70% acetonitrile/30% of 0.2% triethylamine in water and orthophosphoric add to pH = 3):

98.5% chemically pure.

WO 94/03437 |»CI7GB9.V()I599 87- -tnhYirn-iri->--lH-14-n7,odin7Prin-3-v11-N'-f3- mpt.hvinhenvnnrpa hydrorhloride The title compound was obtained (360mg) using the procedure described in Example 58. The hydrochloride salt had mP > 190°C (dec). MS, CI*, m/z = 446 for (M+HK'cD = +109° (c-0.2, methanol). Found: C, 62.10; H, 7.02; N, 13.50.

CNAJHCUO requires C, 62.00; H, 6.88; N, 13.90%.

HPLC (spherisorb ODS2, 70% acetonitrile/30% of 0.2% triethylamine in water and orthophosphoric add to pH = 3): > 99% chemically pure.

mpt'tiYlphePYll \ffga a) -(H-vohexYl-N-meth-lino)-9-Oyn-T-propYl-L4- hpp7nHia7Jepine Prepared analogously to Example la) trom l-propyl-l,2,3,4-tetxahydro-3H-l,4-benzochaZepin-2,5-dione (10 Og) and N-methylcyclohexylaimne (15.6g) and purified by flash chromatography, eluted with' 2% methanoVO.5% 0.88 ammonia solution/dichloromethane. 'H NMR (DMSO) 5 0.68 (3H t I = 7.3Hz), 1.84-2.04 (3H, m), 2.72 (3H, s), 3.40 (1H, d, 1 = 12.2Hz), 3.54 (1H, m), 3.88 (1H, d, i = 12.2Hz), 4.22 (1H, m), 7.34 (1H, m), 7.50 (1H, d, J = 7.43Hz), 7.60 (2H, m).

pmpvl -l .4-bpn zodiazgpine.

Prepared analogously to Example lb) from product from step (a) (5g). The product was purified using flash sxhca chromatography, eluting with 0.5%. 0.88 ammonium solution/2% methanol/dichloromethane followed by chromatography on an alumina column, eluting with 2% methanol/dichloromethane WO 94/03437 PCI7GB93/01599 followed by 5% methanol/dichloromethane. lB NMR (DMSO) 0.52-2.06 (16H, m), 2.60-2.92 (3H, m), 3.60 (1H, m), 4.26 (1H, m), 7.22-7.66 (14H, m), 9.84 and 10.02 (1H, 2 x s).

n)N-rafR.S)-5-rN-fi-N-methYlarnin(>)-2,3-dihYdrQ:

9J.nyo.1-T)roT)vl-1TT.14-hfln7odia7eT)in-3-vI1-If-r?-TnPthYlphenYl1 urea The product from step b) (2.31g) was dissolved in acetic add (40ml), with activated zinc (8.83g) and trifluoroacetic add (5.21ml). The reaction was heated at 40oC for 8h with vigorous stirring, then cooled to room temperature, filtered through hiflo, and washed through with acetic add (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 (50ml), and 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 phase was reextracted with dichloromethane (2 x 25ml). The combined organic layers were washed with brine (50ml), dried (sodium sulphate) and the solvent was removed in vacuo to give a solid which was purified by flash column chromatography with 0 5% 0 88 ammonia solution/dichloromethane as the eluant on a Lobar column. Mp = 1180C (uncorr); "E NMR (DMSO) 5 0.70 (3H, t, si = 7.4Hz), 0.90-1.90 (13H, m), 2.23 (3H, s), 2.68 (3H, s), 3.64 (1H, m), 4.26 (1H, m), 4.90 (1H, d, si = 8.4Hz), 6.71 (1H, d, si = 8.0Hz), 6.92 (1H, d, si = 8.6Hz), 7.12 (2H, m), 7.16 (1H, s), 7.38 <1H, m), 7.51 (1H, d, J = 7.5Hz), 7.64 (2H, m); MS (CI) m/e 462 [MHf. Anal. Found C, 66.38; H, 7.72; N, 14.07.

C H N O .1.5Ho0, requires C, 66.37; H, 7.84; N, 14.33%.

27 35 5 2 WO 94/03437 PCI7GB93/().599 XAM131- fiV f-VB-fN-r'-vplnhfi1-N-TT1PthYlnmff)'2,s"- Yrn.9..nyn-1-T>rnH-1TT-1 4-hpTirnr!iR7PT?in';:t'Yl'N''[3" TTirthYlP1 urea The racemate (430mg) of Example 60 was separated using preparative chiral HPLC with a dmitrobenzoyl leudne column (250 x 20 mm i.d. 5pm) using 94:5:1 l-chlorobutane:methanol:acetic add as the mobile phase (with a flow rate of 20ml/mm and UV detection at 330nM). The two enantiomers were efficiently separated into Peak A (eluted first) 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 (MgS04), evaporated in vacuo and the residue obtained was triturated with diethyl ether and the resulting solid was collected by filtration to give: Peak A (127mg). Mp = 121-123°C; lH NMR (360MHz, D6-DMSO) 5 0.69 (3H, t, 1 = 7.4Hz), 0.9-1-90 <13H, m), 2.21 (3H, s), 2.66 (3H, s), 3 64 (IH, m), 4.25 (1H, m), 4.89 (1H, d, 1 = 8.4Hz), 6.70 (1H, d, J = 8 0Hz), 6.94 (IH, dU « 7.5Hz), 7.10 (2H, m), 7.16 (IH, s), 7.37 (IH, m), 7.50 (IH, d, J = 7.5Hz), 7.65 <2H, m), 8.80 (IH, s); MS (CI) m/e 462+. Anal. Found. C, 68.38; H, 7.74; N, 14.29.

C H N O .0.85 H20 requires C, 68.00; H, 7.76; N, 14.69.

[a]22 3-114°2(C=0.1, MeOH). Purity A:B = > 99%.

FYAMPLF, 62: M 5-(N-nYdqh9TYl-N-methYlaTniT)Q)-?i3- Peak B from Example 61 was treated in the same way as Peak A Example 61. Mp = 126-127°C; 'H NMR (360MHz, D -DMSO) 5 0.69 (3H, t, 1 - 7.4Hz), 0.9-1.90 (13H. m), 2.21 (3H, s)6 2 66 (3H, s), 3.62 (IH, m), 4.25 (IH, m), 4.89 (IH, d, I = 8 4Hz), 6.70 (IH, d, 1 = 8.0Hz), 6.94 (IH, d, I = 7.5Hz), 7.00 (2H.

m) 7 17 (IH, s), 7.38 (IH, m), 7.50 (IH, d, i = 7.5Hz), 7.65 (2H, WO 94/03437 PCI /C UW/01599 m), 8.80 (1H, s); MS (CI) m/e 462+. Anal. Found. C, 69.93; H, 7.54; N, 14.62. C! HN.0.2 H20 requires C, 69.71; H, 7.67; N, 15.05%. [arD+108o (C=0.1, MeOH). Purity B:A = > 96:4.

F.YAMPT,T? fi3- N-r3(ff.<?.fN-nvr1nheyv1-N-methYbTniT10)-2,3- Hihvriro-l-methv1-2-nTo-liy-1.4-henzodia7Pmn-3-vn-N'- ra-mgthYlphffnyllmea Prepared as for Example 60 parts a, b, and c, from 1- methyM,2,3r4-tetraliydro-3H-l,4-benzodiazepin-2,5-dione and recrystallised from methanol, water. Mp 145-147PC. NMR (360MHz, D6-DMSO) 5 0.99 (10H, m), 2.21 (3H, s), 2.65 (3H, s), 3.31 (4H, m), 4.92 (1H, d, J = 8.4Hz), 6.70 (1H, d, jl = 8.0Hz), 6.93 (1H, d, I = 7.5Hz), 7.09 (2H, m), 7.17 (1H, s), 7.36 (1H, m), 7.49-7.69 (3H, m), 8.80 (1H, s); MS (CI) m/e 434 [MHf. Anal.

Found. C, 67.22; H, 7.23; N, 15.29. CJIpO.lSBO requires C, 67.17; H, 7.33; N, 15.67%.

. EXAMPLE 64: M R-fN-nvr1oheyyl-N-mftthYlRminP)-g,3- dihvdro-2-oxQ-1 -methvl-lH-1.4-benzQdiazfiPin-3-Yl-N'- ra-methvlphenvn 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 after 5 minutes the solvent was removed in vacuo. The resulting oil was crystallised from dichloromethane/ether. Mp 193-1950C.

lH (360MHz, D -DMSO, trifluoroacetic arid) 5 0.95-1.95 (10H, m), 2.23 (3H, s), 3.12 (3H, s), 3.43 (4H, m), 5.39 (1H, m), 6.76 (1H, d, I = 7.2Hz), 7.11-7.90 (7H, m). MS (CI) m/e 434 [MHT Anal. Found. C, 60.45; H, 7.02; N, 14.05. CH NOHCl.

1.5H20 requires C, 60.41; H, 7.02; N, 14.35%.2 D-1950 (c = 0.1, MeOH). Purity A:B = >99%.

WO 04/03437 PCT/C.BW/01599 VAMPT.E 65: ri.)K.fK-r;vrlohpyv1-N-TT]ffthY]aTT]inQ)-g.3i ra-TnftthvlphenY1! "fl- Hydrochloride Separated from the racemate of Example 63 by chiral HPLC as for Example 61. Peak B (eluted second) was treated as in Example 64 to yield the desired hydrochloride OOmg). Mp 194-1960C. 'H NMR (360MHz, D6-DMSO + trifluoroacetic add) 0.95-1.95 (10H, m), 2.24 (3H, s), 3.12 (3H, s), 3.43 (4H, m), 5.39 (1H, m), 6.76 (1H, d, 1 = 7.5Hz), 7.06-7.86 (7H, m), 9.20 (1H, s); MS (CI) xn/e 434+. Anal. Found, C, 58.28; H, 6.82; N, 13 47 C H N O .HC1,2.35H20 requires C, 58.61; H, 7.22; N, 13 67% [aj+i'fC-O.l.MeOH). Purity B:A = > 95%.

D F.YAMPLE 66: N P pVR-fN.rvr1nheT)H-N-TnPthYlqTniTio)-2l3- hvriro-l-met-nxn-IH-lhPTiznfliazgpin-ajdHi f3-methvlDh?nvll urea Prepared analogously to Example 60 from N- methylcvcloheptvlamine. Mp = 1350C (uncorr); lB NMR (DMSO) 6 1.10 (1H, m), 1.20-1.50 (7H, m), 1.50-1.84 (4H, m), 1 91CIH, m), 2.22 (3H, s), 2.63 (3H, s), 3.31 (3H, s), 4.94 (1H, d, J = 8.0Hz), 6.70 (1H, d, il = 6.9Hz), 6.94 (1H, d, i = 8.4Hz), 7.09 (2H, m), 7.17 (1H, s), 7.37 (1H, t, i = 6.9Hz), 7.51 (1H, dd, J. = 7.8 and 1 3Hz), 7.62 (2H, m). 8.82 (1H, s); MS (CI) m/e 448. [MBT.

Anal. Found. C, 70.02; H, 7.41; N, 15.60. C26Ha3N602 reqmres C, 69.77; H, 7.43; N, 15.65%.

T?YAMPT,E 67: ' v-P.ynhpntvl-N-TnPthvlnmmoV.-bYdrQ rpa Hvdrnchloride a) The racemate (700mg) of Example 66 was separated using preparative chiral HPLC with a dinitrobenzoylleucme column (250 x 20mm i.d, 5 pM) using 89:10:1 \V(>«M/0J437 |'CI/(,Bl>3/0I5<>'> l-chlorobutane:methanol:acetic acid as the mobile phase, with a flow rate of 20inl/niinute and u.v. detection of 330nM.

Peak A was evaporated in vacuo and redissolved in the minimum 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=1740C; H NMR (360MHz, DDMSO, V.T. a 353K) 5 1.04-2.12 (13H, m), 2.24 (3H, s), 3.04 (SH, s), 3.38 (3H, s), 5.32 (1H, d, J = 7.6Hz), 6.72 (1H, d, J = 7.6Hz), 7.04-7.26 (4H, m) 7.52 (1H, t, si = 7.6Hz), 7.70 (2H, m), 7.82 (1H, t, si = 7.3Hz), 9.24 (1H, s(b)); MS (CI) m/e 448+. Anal. Found. C, 62.44; H, 7.29; N, 13.71.

C H N O .HC1 requires C, 62.20; H, 7.23; N, 13.95.

[a]22 L21O0 (c=lmgmA1, MeOH). Purity A:B > 99%.

D fiXAMPT.E 68; UVR-fN-Cvclohpptvl-N-mPthYlflTnmQVg.g-.

hYirn-i-Tnfit.hv1-9-nTn-lH.l.4-ben7odiazePin-3-Yl-N'- fa-Pthvlphenvli nrpa. Hydrochloride Peak B from Example 67 was treated in the same way as peak A to give the required product. Mp 173-1750C; NMR (360MHz, D6-DMSO, V.T. a 353K) 5 1.06-2.14 (13H, m), 2.24 (3H, s), 3.056(3Hf s), 3.38 (3H, s), 5.33 (2H, d, si = 7.6Hz), 6.74 (1H, d, J = 7.2Hz; 7.04-7.26 (4H, m), 7.54 (1H, t, J = 7.5Hz), 7.63-7.74 (2H, m), 7.82 (1H, t, si = 7.5Hz), 9.25 (1H, s(b)); MS (CI) m/e 448 [MHr. Anal. Found. C, 62.36; H, 7.26; N, 13.53.

C H N O .HC1 requires C, 62.20; H, 7.23; N, 13.95.

[a]622 +172° (c = ImgmfK MeOH). Purity B:A = 96.2% trample 69; N-r?fff R)-K-rN-nvdohppH-N-mpthYTnTnino)-2,3- ivHrmety-?-n.1p-4-bpnodi7Ppn-3-Yll-N,- ISjndanyTl urea a) f-HVNT-ra-aminn * fV ~r}V-K~™Pthv\Kmmo-2.?,- rn-l.mfit.hvl-9-nvn.l W-1 4-bRn2odiR7PPlT1P (TFA SSlO wo 04/03437 mvimvoisw To a solution of 5-(N-cycloheptyl-N-methylainino)- l-methyl-3-oxiinino-2-oxo-l)4-benzodiazepme (l.OOg,) in acetic add (40inl) was added activated zinc (3.99b) and trifluoroacetic add (3.48g). The reaction was stirred at 40°C for 30 minutes, cooled to room temperature, filtered through hiflo, and washed with acetic add (2 x 20ml). The solvent was removed in vacuo, and the resulting oil was azeotroped with toluene and dried under high vacuum.

b) .rr-RRV5-fN-Ynhpntvl-N-TnPthvlnmiTio)-g.3- jridanvll vtrea 5-aminoindane (0,41g) was dissolved in tetrahydrofaran (50ml) and cooled (0oC) under nitrogen. Triphosgene (0.31g) was added and the reaction stirred vigorously (2 minutes).

Triethylamine (0.92g) was added and the reaction stirred for a further 30 minutes.

A solution of the product from part a) and triethylamine (suffident to take solution to pH9) in tetrahydrofuran (25ml) was added dropwise and the reaction allowed to stir overmght.

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 combmed organics washed with brine (SOml). The solution was dned over sodium sulphate and the solvent removed in vacuo to give an oil that was purified by column chromatography with 0.2% 0.88 ammoma 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 183-185°C. 'H NMR (360MHz, D6-DMSO, V.T. a 353K) 0 80-1.80 (11H, m), 1.86-2.04 (3H, m), 2.65 (3H, s), 2.74 (4H, q, J.

= 7.0Hz), 3.30 (3H, s), 3.59 (1H, m), 4.94 (1H. d, 1 = 7.1Hz), 6.74 (1H, d, si = 8.4Hz), 7.02 (2H, m), 7.22 (1H, s), 7.34 (1H, t, 1 - WO 94/03437 PCI/(;H9.V<)I59«> 8.4Hz), 7.48 (1H, m), 7.52 (1H, m), 7.60 (1H, m), 8.60 (1H, s).

MS (CI) xn/e 474+. Anal. Found. C, 71.69; H, 7.86; N, 14.14. C H 5N6O2.0.3C6H4 requires C, 71.66; N, 7.91; N, 14.02% EXAMPLE 70: f-)-R-fN.nvfi1ohppt.v1-N-methYlRmino>2.3- HvHrn.i-TnP.t.hvV2-nTn-iH-i.4-ben7ndiazepin-3-Yl-N,-rf?-indanyn Vrfp Hvrnrhloride a) The racemate of Example 69 (600mg) was separated using preparative chiral HPLC with a dinitrobenzoylleudne column (250 x 20mm i.d, 5iim) using 707o 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 (5ml) was added and the resulting suspension was triturated with more diethyl ether (20ml). The product was collected by filtration. Mp 181-1870C dec; lU NMR (360MHz, DMSO) 5 1.20-2.12 (14H, m), 2.76 (4H, q, jl = 7.0Hz), 2.93-3.12 (3H, 2s, CH3 restricted rotation), 3.42 (3H, s), 3.62 and 4.18 (1H, 2m), 5.36 (1H, m), 7.05-7.90 (8H, m), 9.48-9.53 (1H, 2s) 10.17 and 10.32 (1H, 2br s); MS (CI) m/e 474+. Anal.

Found C, 62.83; H, 7.19; N, 13.07. CH NB02.HC1.1.5H20 requires C, 62.61; H, 7.32; N, 13.04%. -175° (c = 0.1, MeOH). Purity A:B > 99%.

eyampt/e 71: f4.vrR.(N.nvclDhpptv1-N-methYlaTnino)-g.3:

y1.otYi.9-nvn-iH-i.4-hen7odiR7,eT?in-3-vl1-N'-r5-indanYll nrp •prvdrochloride Prepared analogously to Example 70. m.p. 181-1870C dec; 'H NMR (360MHz, DMSO) 8 1.20-2.19 (14H, m), 2.76 (4H, q, 1 = 7.0Hz), 2.93 and 3.12 (3H, 2s, CH3 restricted rotation), 3.42 (3H, s), 3.62 and 4.18 (1H, 2m), 5.36 (1H, m). 7.05-7.90 (8H, m), 9.40 and 9.42 (1H, 2s), 10.10 and 10.26 (1H, 2br s); MS (CI) m/e 474 [MHr. Anal. Found C, 62,83; H, 7.20; N, 13.06.

WO 94/03437 I»CT/(;»93/0159V C H N O HC1.1.5H 0 requires C, 62.61; H, 7.32; N, 13.04%.

2Sl 35 6 2 2 [oT +197° (0=0.1, MeOH). Purity B:A > 99%.

example 72: -rp.Rvs-fN-Bpnzvl-N-methvlnmint))- rfihvdro-l.methYl-9-nTn-lH-l 4-heT7,odiafPi-3-Yll-N•- To a solution of 5-(N-benzyl-N-methylaimno)-3- oxiimno-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- lJ4-benzodiazepin-2,5-dione and N-methylbenzylamine) in methanol was added rhodium on carbon (600mg) and the resultant mixture was hydrogenated at 50psi at 60oC for 5h.

The reaction mixture was allowed to cool, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, cooled to 0oC 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. lE NMR (360MHz, D6-DMSO) 2 21 (3H, s), 2.74 (3H, s), 4.26 and 4.55 (2H, dd, si = 15.8Hz), 5.00 (1H, d, 1 = 8.4Hz), 6.70 (1H, d, I = 8.0Hz), 6.96-7.76 (12H, m).

8.81 (1H, s); MS (CI) m/e 442 (MH)+. Anal. Found C, 70.86; H, 6.39; N, 15.85% C26H27N502 requires C, 70.73; H, 6.16; N, 15.86%.

mMPT,F, 73: y-KM? RVRN-M-N-MpthYlPirmdiTivlVN- nott,ylnV2.3-dil1YiT"-T---n-1-"t-r>apip- a-vn.N'.ra-iPPt.hvlnhenvnurea Prepared analogously to Example 60 from 1-methyl- l,2,3.4-tetrahydro-3H-l,4-benzodiazepin-2.5-dione and N- methvl-(4-methylamino)piperidine. Mp = 1460C (uncorr); H WO 94/03437 I'CT/C;B93/01599 NMR (DMSO) 5 1.24 (1H, m), 1.60-1.90 {6H, m), 2.12 (3H, s) 2.21 <3H, s), 2.65 (3H, s), 2.75 (1H, m)f 2.82 (1H, m), 3.32 (3H, s), 4.92 (1H, d, I = 8.4Hz), 6.70 (1H, d, i = 7.1Hz), 6.95 (1H, d, J = 8.4Hz), 7.09 (2H, m), 7.17 (1H, s), 7.38 (1H, m), 7.51 (1H, dd, £ = 1.4 + 7.8Hz), 7.62 (2H, m), 8.82 (1H, s); MS (CI) m/e 449+.

Anal. Found: C, 63.37; H, 7.04; N, 17.46. CJlfif 1.3HaO requires C, 63.62; H, 7.39; N, 17.81%.

EXAMPLE 74: N.r3fR.RVR-fN-nvdnhPTrYlmf.thvl-N- mfit.hv1aininoV?,.vHrn.2-oyn.1-pmPVl-lH.14-bPn7,0diaggPin- a-vii-N'-rs-methvlphenvllurea Prepared as described in Example 60 from N- methylcyclohexylamine and l-inethyl-l,2f3,4-tetrahydro-3H.l,4- benzodia2epin-2,5-dione; mp 218-2250C. lH NMR (DMSO) 8 0.31 (1H, m), 0.66 (1H, m), 0.96-1.54 (9H, m), 2.21 (3H, s), 2.81 (3H, s), 2.92 (1H, m), 3.16 <1H, m), 3.30 (3H, a), 4.94 (1H, d, JL = 8.4Hz), 6.70 (1H, d, i = 7.0Hz), 6.91 (1H, d, J = 8.4Hz), 7.05-7.65 (7H, m), 8.81 (1H, s); MS (CI) m/e 448 [MHp. Anal. Found C, 65.59; H, 7.44; N, 15.46. C26HMN502 requires C, 69.77; H, 7.47; N, 15.65%.

EXAMPLE 75: N-OT SVR-fN.N-Di-rnpvlaTninp)- Yfirn-1.mPt.hv1.2-oyn.lTT.1.4-hRnZodnrppip.3-vn-N-r3-ipgthvl nhfinyllrea Prepared as for Example 60, using di-n-propylamine m place of N-methylcyclohexylamine and re crystallized from ethyl acetate and hexane. Mp 164-1660C. NMR (360MHz, D -DMSO-TFA) 5 0.60 (3H, t, 1 = 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 (1H, d, I = 6.3Hz), 6.78 (1H, d, 1 = 7.1Hz), 7.35-7.70 (8H, m), 9.30 (1H, s) MS (CI) m/e 422+. Anal. Found: C, 68.33; H, 7.44; N, 16.27%. C24H3 N502requires C, 68.38; H, 7.41; N, 16.61%.

WO 94/03437 VCY/iimVWW o o <1ihTn-Tnpt.hv1?-To-H-,4-hCT7f1inrTTl-P-Yn-N•- fa-ynPthvlnhpnyll urea Prepared as for Example 72, but using N-ethylcyclopentylamine in place of N-methylbenzylamine and recrystallized from ethyl acetate hexane. Mp = 252-2550C> H KMR (360MHz, D6-DMSO) 5 0.70-1.60 (11H, m), 2.21 (3H, s), 2 91-3.90 (6H, m), 5.37 (1H, d, J = 8.4Hz), 6.72 (1H, d, I - 8.0Hz), 6.92 (1H, d, 1 = 7.5Hz, 7.10 (2H, m), 7.29-7.63 (5H, m), 24 (lHr s). Anal. Found: C, 69.70; H, 7.21; N, 15.41%.

C H NO.0.15CHi4 requires C, 69.68; H, 7.47; N, 15.69%.

0thvinV2.3.dihYdiinpttiYl-?-o-lH-l,4-h7,odiaZepin -1 ? yII N'T?- TnothY1"hpT'v11urea a) Kpvi-4.4-dimpthvlfVVn>1pyvmine 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 (Ig). The reaction mixture was stirred for Ihr 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 Ihr 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 (SOOml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was distilled under reduced pressure Bpt 40-45°C at O.lmmHg. 'H NMR (CDCy 8 0.92 WO 94/03437 I'CI /(i 1*93/01599 (6H, s), 1.10-1.30 (5H, m), 1.30-1.50 (2H, m), 1.66-1.72 (2H, m), 2.26 (1H, m), 2.42 (3H, s).

b) F;.fN-r4.4-DimHvWr.lnhPxvl>-N-TnPthylaming)-3- PTriT1pii1n.i-inflt.hvi-a-oxo-l.4.-ben7;ndiazepine 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-dimethylcyclohexylamine.

C) -f.qrT?ffVR-fN-(4l-T)hvlovdohexY))-N- v1aTniT,nV9..a-dihvHT-VTT1RtMl-2-0Tn-1TT-14-bRTT7.QdiaWPiP- a-vll-N'-ra-methYlplvea 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 60oC 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 1-43% .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 (212vd) added. After 20mins diethyl ether (10ml) was added and the product collected by filtration and recrystailised from ethyl acetate, mp = 1720C (uncorr). lU NMR (DMSO) 8 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)f 3.31 (3H, s), 4.92 (1H, d, i = 8.4Hz), 6.70 (1H, d, I = 8.8Hz)r 6.94 (1H, d, i * 8.4Hz), 7.10 (2H, m), 7.17 (1H, s), 7.36 (1H, m), 7,50 (1H, dd, 1 = 1.3 & 7.7Hz), 7.60 (2H. m), 8.80 (1H, s); MS (CI) m/e 462+. Anal. Found: C, 69.48; H. 7.69; N, 15.18. CHO,. 0.2H O requires C, 69.71; H, 7.67; N, 15.05%.

WO 94/03437 PC1/GB93/0I599 ypy.-p 7B- -r?(,svR-fN-nvr1nhRyv1-N-ethYlnmino}-2,3- iYrp-i-mPthvi-oTn-lH-l.benrnriinrppin-ff-vll-N'-rs- mf thvlphffnYll urea Prepared as for Example 60 using N-ethylcyclohexylamine in place of N-methylcyclohexylamine and recrystallized from ethyl acetate. MP = 206-207oC. lB NMR (360MHz, DDMSO) 8 0.83 (3H, m), 0.83-1.9 (10H, m), 2.2 (3H, s), 3.0 (1H, m), 3.3 (4H, m), 4.9 (1H, d, J. = 8.9Hz), 6.7 (1H, d, i = 6.5Hz), 6.9-7.6 (8H, Aromatics), 8.8 (1H, s). MS (CI) m/e 448 (MH)*. Anal. Found:

G, 69.79; H, 7.6; N, 14.82%. CN requires C, 70.04; H, 7.49; N, 15.18%.

FXAHPT 79: N-rRVS-fN.r;vc1ohexYl-N-TTnPYlnTninft)-g.3- vHrn-1-Tnfithvl-9-nTn.lH.heilTnHiff7PpiTT3-Yn-N'-r3- mPftivlpVipnvllurea Prepared as described in Example 60 from 1-methyl- l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-l,5-dione and N- propylcyclohexylamine. Mp = 1460C (uncorr); NMR (360MHz, DMSO) 8 0.77 (3H, s), 0.86-1.18 (3H, m), 1.20-1.56 (6Hf m), 1.56-1.80 (2H, m), 1.88 (1H, m), 2.12 (3H, s), 2.82 (1H, m), 3.31 (3H, s), 3.43 (1H, m), 4.93 (1H, d, si = 8.3Hz), 6.70 (1H, d I = 6.9Hz), 6.89 (1H, d, 1 = 8.3Hz), 7.10 (2H, m), 7.18 (1H, s), 78 (1H, m), 7.48 (1H, dd, I = 1.3 & 7.9Hz), 7.61 (2H, m), 8.12 (1H, s); MS (CI) me 462 [MHT yampt.-R sn- N-rafR.RV5-n.Rpn?y1-N-CY1ot)e7tYlaiwnfl}Aai i>ixrn-1-mft>iv1-2-oxo-lH-14-benQdiPrppiP-'C'-Yll-N'- r-mpthvlthv11 urea a: N-Bpnzvlcvelolipxvlamine To a stirred solution of cyclohexylamine (9.34g) in methanol (300ml) was added benzaldehyde (lO.Og) followed by activated 3A molecular sieves. After Ih, sodium cvanoborohvdride (7.13g) was added followed by the dropwe WO 94/03437 I»aV<;B93/OI5W -100- addition of acetic add (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 under reflux in 5M potassium hydroxide solution for 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. 'H NMR (360MHz, D6-DMSO) 5 0.94-1.24 (5H, m), 1.48-1.88 (5H, m), 2.32 (1H, m), 2.32 (1H, m), 3.10 (2H, s(b)), 3.72 C2H, s), 7.14-7.40 (5H, m).

HitivHrn-i-TTifithvl-p-nTn-iH-i-bPTizofiiazemn-s-Yn-N'-r-S- methvlnhenvllurea Prepared as for Example 60 from l-methyl-1,2,3,4- tetrahydro-3H-l}4-benzodiazepin-2,5-dione and N- benzylcyclohexylamine and recrystallised from ethyl acetate/60-80 petrol, mp = 178-179BC, lB NMR (360MHz, D -DMSO, VT a 353K) 5 0.92-1.94 (10H, m), 2.21 (3H, s), 3.16 OH, s), 3.66 (1H, m), 4.22 (1H, d, 1 = 16Hz), 4.70 (1H, d, J = 16Hz), 4.92 (1H, d, J = 8.3Hz), 6.72 (2H, m), 7.02-7.24 (8H, m), 7.32 (1H, m), 7.44 (1H, m), 7.56 (2H, m), 8.62 (1H, s); MS (CI) m/e = 510 [MHT; Anal. Found: C, 73.08; H, 6.85; N, 13.74.

C H N O requires C, 73.06; H, 6.92; N, 13.74%.

fiXAMFTrF- "t N-r3fR.SVf>-(N-r>vr1oh7rykroiTio)-g,3-dihYdr9-,.i- mpt.hvT-9.-mrn-lH-14-heny.Qdia-?PT>ifi-3-Yll-N,-r3- mfthYlrp1,111""63 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 (0.50g).

The reaction mixture was heated under reflux for 2h then cooled NVO 04/03437 PCT/GBM/OISW - 101- to room temperature, filtered, washed with methanol (3 x 20ml) and the solvent removed in vacuo. The product was rediBsolved 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 = 153-155°C; 'H NMR (360MHz, D6-DMSO) 5 0.88 (1H, m), 1 06-1.34 (4H, m), 1.88-2.00 (5H, m), 2.22 (3H, s), 3.28 (3H, s), 3 58 (1H, m), 4.88 (1H, d, i = 8.6Hz), 6.54 (1H, d, si. = 7.7Hz), 6 68 (1H, d, 1 = 6.9Hz), 6.86 (1H, d, J = 8.6Hz), 7.08 (2H, m), 7.14 (IH, s), 7.34 (1H, t, JL = 7.8Hz), 7.60 (2H, m), 8.77 (1H, s); MS (CI); m/e = 420+. Anal. Found: C, 65.77; H, 6.97; N, 15.98. C2 H29H502.H20 requires C, 65.77; H, 7.14; N, 16.01%.

AXAmpt.f 82: .r.qfR.,svfN-Y''1pvi-N-mpthYlnTnino)-2.3- r-indanYllttrea Prepared as for Example 77c) and Example 69b) using 5-aminoindane. Mp = 232-234°C. lH NMR (360MHz, D6-DMSO) 1.01-1.98 (16H, m), 2.65 (3H, s), 2.76 (H, m), 4.92 (H, d, J = 8.46Hz), 6.88 (H, d, 1 = 8.46Hz), 7.23-7.65 (7H, m), 8.65 (H, s).

MS (CI) m/3 461 [MH*]. Anal Found: C, 68.78; H, 7.34; N, 13 26% C H N O . 0.7EtOAc. 0.7H2) requires C, 68.48; H, J-tJ- 27 33 5 2 7.71; N, 13.39%.

TRAMPLE 83: TWffi pyS-fN-CvrlonrH-N-mftthYlRmmP)- o|Mi|1rn.-TTlPt.hY-?-"-•TT--4-hpnrodppT-a-Yll-N,- Prepared as for Example 77 using N-methyl cydooctylamine in place of N-methyl-4,4- dimethylcyclohexylamine. mp = 221-222°C. 'H NMR (360MHz, D -DMSO) 6 1.1-1.6 (14H, m), 2.2 (3H, s), 2.66 <3H, s), 3.3 (3H, s)! 4.96 (IH, d, JL = 1.18H,), 6.7 (IH, d, JL = 6.6Hz), 6.9-7.6 (8H, m), 8.8 (IH, s).

WO 94/03437 I'CT/G II93/« 1599 - 102- f.yample 84: .N-r3fKlPV&g:PitiYrtro-lT-(2-(N.W- mPthvlnniTTio)ethYlnTnino>-1-mpthYl-8-07;o-lH-1.4- hPTinHinrftniTi-a-vn-T-ra. mRthvlpheTivllurea dihydrochlpride TnPthvl-3H-i.4-bpn?odin7PT>in-2-Qiie A solution of phosphorous pentachloride (8.10g) in anhydrous dichloromethane (350inl) was added dropwise to a stirred suspension of l.inethyl-l,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 40C and treated dropwise with a solution of N,N-dimethylaminoethylaiiime (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, CI*, xn/z = 262 for (M+H)+. lK NMR (CDCy 5 2.24 (6H, s), 2.46-2.60 (2H, m), 3.36 (s) and 3.32-3.47 (total 5H, m), 3.61 (1H, d, I = 12Hz), 4.20 (1H, d, 1 = 12Hz), 5.20 (1H, broad res.), 7.20-7.32 (2H, m), 7.46-7.59 (2H, m).

b) 1l2-r»ibvHro-B-f?.-fN.N-dimpthvlRTniT10)ethYl-(t' hn1nTvrarhopvlTTiiTioVl-mPthv1-?H-14-W7n(lJnTCPin-g-Qng Di-5-butyldicafbonate (4.33g) was added in portions to a stirred, cooled (40C) 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 Edmnina (Grade 3) using dichloromethane/methanol (50:1). Mp<350C. MS, CI\ m/z = 361 for (M+H)+. NMR WO 94/03437 PCI/C,B93/0.59<> - 103- (CDC1 ) 5 1.22 <9H, s), 2.45 (6H, s), 2.68-2.76 (1H, m), 2.79-2.87 (1H, m), 3.53 (3H, s), 3.7;- (IB, d, i = 11Hz), 4.02-4.09 (1H, m), 4.24-4.32 (1H, m), 4.65 (li:. \£= 11Hz), 7.35 (1HF dd, 1- 8Hz), 7.41 (1H, d, J = 8Hs.'. . .65 (1H, ddd, = 2Hz, = = 8Hz), 7.79 (1H, dd, J = 2Hz, = 8Hz).

c) ! ?.pfrm-K-(2.rN N-dimfthYlmninn)p-thYHt- vtYlnyYrprhnTivlTninnV1-mf?thYl--OTriTni-3H-1.4- |>pn7ndiazenin-2-Qne 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 105-109oC 'H NMR (360MHz, DMSO-d6) 5 1.02 (9H, s), 2.18 and 2.20 (6H, each s), 2.41-2.51 (1H, m), 2.82-2.88 (1H, 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 (1H, each broad s).

d) pv-Amitio-l o-iihyrtrn-S.f2.fN N-diTnethvlaiTOPg) ?fry] ~< t-bntvi oyyrnrbnn vi >ami n o)-1 -mgthy] -3H-1.4- hdinP-Z-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 amin, (0.462g). % 0.18m dichloromethane/methanol (5:1) on silica plates. H NMR (CDC1 ) 5 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 (1H, m), 4.10-4.18 (1H xn), 4.29 (1H, s), 7.19-7.29 (2H, m), 7.48-7.66 (2H, m).

WO 94/03437 PCI/(;B93/0I599 - 104- e) tj.rafT?.,S).2.3-nihvriro-R-(2-fN.N-dimethYlnTnino)ethYl- ft-hiitvlnTvcarbQT1vlTnino)-1-met,hv1-2-OyO-lH-1.4- h«»Ti7TT'iiFi7;"-«-v-N,-r3-mpt.hYlpbffnYllurea A stirred, cooled (40C) 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, CI*, m/z = 509 for (M+Hf.

Anal. Found: C, 63.82; H, 7.07; N, 15.60. CN. 0.1C6HM requires C, 64.09; H, 7.28; N, 16.24%.

f) N.mrR.R)-2.3-PibvHrn-5-f2-(NN-diTnethylaming) PtbvTnn)-l.metlivl-?o-lH-1,4-ben?;odiazppin--Yll-N'-f3- mPthvlhenvllnreR dihvdrnchloride A stirred, cooled (40C) solution of the foregoing benzodiazepine (0.18g) in ethyl acetate (5ml) was treated with ethyl acetate (20ml), pre-saturated with hydrogen chloride gas.

The solution was stirred at 40C for Ih foUowed by Ih at room temperature, then evaporated to dryness. The product was recrystallised from propan-2-oydiethyl ether (0.10g). mp 189-1920C. MS, CI+, m/z = 409 for (M+H)*. 'H NMR (D20) 8 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, J = 7.5Hz), 7.14-7.16 (2H, m), 7.27 (IH, dd, = = 7.5Hz), 7.55 (IH, dd, JI1 = J, = 8Hz), 7.62 (IH, d, i = 7.5Hz), 7.86-7.91 (2H, m). Anal. Found:

C, 53.89; H, 6.38; N, 16.89. CN. 2HC1. 0.6H2O requires C, 53.68; H, 6.39; N, 17.07%.

WO 94/03437 PCI/GB93/0159«» -105- RYAMPT.E 85: N-FB SV9.R-Dibvdro-5-fN-(2-N- n.TTh.liT1n0th-,.N-mPthv1aTninoVMnPtbYl-?-oP-lH-;,4- Prepared in the same way as Example 77 except using N-methyl-(2-aininoethyl)morpholme. Mp = 1740C (uncorr); lH NMR (DMSO) 6 2.10-2.38 <9H, m), 2.43 (1H, xn), 2.82 (3H, s), 3 12 (1H, m), 3.32 (3H, s), 3.48 (4H, m), 4.92 (1H, d, J = 8.4Hz), 6 70 (1H, df I = 7.1Hz), 6.96 (1H, d, J = 8.4Hz), 7.08 (2H, xn), 7.17 (1H, s), 7.37 (1H, m), 7.57 (2H, m), 7.63 (1H, xn), 8.81 (1H, s); MS (CI) m/e 465+. Anal. Found: C, 64.54; H, 6.66; N, 18 04 C H NO requires. C, 64.64; H, 6.94; N, 18.09%.

FXAMPT.E 86: N-PrF p)-N-nvr1ohpptv1VN-Tnfithy1PTninQ)-g.3- • Hihvdrn.1-metYl--nvn-1H-14-bPT17ndpin-Yll-"NT,-[3-(5- piPthvlTwridineVl urea a) -(N-nvdohertv1-N-methvlaTnino)-l-niPthy]-2-Q9- -lA-frPTynrKazetrine Prepared analogously to Example la) from l-methyl- 12 3 4-tetrahydro-3H-lJ4-ben2odiaZepin-2J5-dione and N-methyl ccloheptylamine. lU NMR (250MHz, CDCy 5 1.0-1.90 (12H, m), 1.96 (1H, m), 2.78 (3H, s), 3.36 (3H, s), 3.48 (1H, d, 12.2Bz), 4.23 (1H, d, J=12.2Hz)f 7.24 (2H, xn), 7.48 (2H, xn).

9-pTrft-l .4-hen7,ndiazepine Prepared analogously to Example lb).

C) .rafRR>.R-fI.riYr1nhRTitvlVN-Tnpt.hYmiPQ)-2,3- fjih-rrlm 1 yny1-9-"-1-1 -bennrlippin-a-YlVN'-f pPtbylpyridrnp)! 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 40oC with rapid stirrmg for 2hrS.

The reaction mixture was cooled to room temperature, filtered WO 94/03437 PC17G B93/01599 - 106- through hyfio, 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 I7hrs. 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 = 2350C (uncorr). H NMR DMSO 5 1.18 (1H, m), 1.40 (6H, m), 1.90 (1H, m), 2.21 (3H, s), 2.63 (3H, s), 3.32 OH, s), 4.93 (1H, d, S.SHz), 7.07 (1H, d, sS.SHz), 7.37 (1H, m), 7.50 (1H, dd, .1=1.4 and 7.8Hz), 7.61 (3H, m), 7.96 (1H, s), 8.29 (1H, d, J[=2.2Hz), 9.02 (1H, s). MS (CI) m/e 449 [MHf. Anal. Found C, 66.67; H, 7.19; N, 18.63. CN requires C, 66.94; H, 7.19; N, 18.74%.

TTCAMPT.F, 87: 3 pN-fR-fa-AhirvclorS.?. P,lnonRn-3-Yl)-2,3- dihvdro-l-mv'|-2-oxo-1'R-1-4-beri'ynd7PpiT1''':i'v'ndQ'2" rarhoxamide a) 5-/3-A7qhicvclor3.2.2]nQPap-3-YlV1.g-dihYdrQ-3H- 1.mPthvl-3-fQ-(pt.hvlaTninocrhnnvnnTimido)'1.4-ben?ffdia?ePin- 2-one The product of Example 31a) (17.5g), ethyl isocyanate (7.3ml) and triethylamine (4.6ml) were heated at 650C> 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). (20.8gJ. mp 1680C.

b) |,q)./fltTT1n-K.fa.H7ahirvclor3.2?.lnnnpn-3-Yl)-1.2- bvdrn-3H.l-Tnpt.hv1-1.4-bpn7,ndi7Ppin-2-one WO 94/03437 I'dVCIIM/OlSW -107- The foregoing oxinie derivative (ll.Og) was hydrogenated in methanol (ID 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 160-163oC (ethyl acetate), Found: C, 68.82; H, 7.67; N, 17.69. C18H24N40 requires C, 69.20; H, 7.74; N, 17.93%.

C) flfRVN-fS-ffrAgnhirvclora ? ?lnnnnP-3-YlK3,3- 4hvHrn-i-TnPt.hvl-2-pyp-iH-i.4-hen7,ndiazffffin-3-Yl)-1H-indQle-2z ffrhnxamide A solution of the foregoing amine (1.50g) in dimethylformamide (10ml) was treated with indole-2-carboxylic acid (852mg)> l-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 210-214oC (chloroform/diethyl ether). MS, CI*, m/z = 456 for (M+H)+. 'H NMK (360MHz, CDCy 5 1.44-1.95 8H, m), 1.95-2.08 (2H, m), 3.26-3.42 (2H, m), 3.44 (3H, s), 3.56-3.70 (2H, m), 5.46 (1H, d, J = 8Hz), 7.06-7.74 (10H, m), 9-22 (1H, broad resonance). Found: C, 69.11; H, 6.34; N, 14.74.

C HOQN O .0.66H O requires C, 69.36; H, 6.54; N, 14.98%.

27 2d 5 2 2 FYAMPLE 88: f-VN-fS-fa-AzaHrvr1or3,2,2lTiopfln-3-yl)-?,3- HiTivrirn.i-met>ivi-9-nvn-iH-i4-bpn7:pdia?erlT»-M)-1H-indple-2- rprHr|XnTnidfi hydrochloride The racemic compound (Example 87, 1.60g) was separated into its enantiomers using preparative chiral HPLC on a Pirkle dinitrnbenzoyleudne column (5p) [(250 x 21.4)mm] eluting with 2% methanol in 1-chlorobutane (including 1% acetic acid). Flow rate 20ml/minute, U.V. detection at SOSnm. Analysis was performed on an analytical Pirkle dinitrobenzoylleucine column WO 94/03437 I'd/CB93/01599 -108- (5)i) [(250 x 4.6)mm] eluting with 5% methanol in 1-chlorobutane (including 1% acetic add). Flow rate l.Sml/minute, U.V.

detection at 250nm.

The free base was liberated and obtained as a colourless soUd (780mg). The hydrochloride salt had mp 280-282oC (chloroform). MS, CI+, xn/z = 456 for (M+H)+.23' = -253° (csO.2, methanol). HPLC: > 99% ee. Found: C, 65.86; H, 6.15; N, 14.44; CI, 6.87. C H N O .HC1 requires C, 65.91; H, 6.14; N, 14.23; CI, 7.20%.

EXAMPLE 89: f4.VN.f5-(3-Azahirvr1pr3.g.81n"nnn-3-yl)-2.3- ihyrirn-1-TT1Pt.bvl-2-nYn.lH-1.4-bPn7odiRZgT?in--v1)-lTi-iT?d0k-2- rarbnyamide (JibvT-nrhloride The title compound was obtained (800mg) using the procedure described in Example 88. The dihydrochloride salt had mp 279-280oC (chloroform). MS, CI*, m/z = 456 for (M+H)+.

[a]23'0 = +222° (c=0.2, methanol). HPLC: 93% ee. Found: C, 59.73;DH, 5.60; N, 12.55; CI, 15.34. C27H29NB02.2.4HC1 requires C, 59.72; H, 5.83; N, 12.90; CI, 15.67%.

example 90: a'-R ?VN-r2.3-Dihvdro-5-(hoinnpireridin-l-Yl)-l- f9-TnPt.bv1nropvlVP-nTn.lH-1.4-bPTt70diaggPiT?-3-Yl)-1ff-ind0le-2- cnrbpamidg a) 1 DibvHro-SH--112-71 pmrvn-1.4-bprtyodinzeT?in-2-one The title compound was prepared from l-(2-methylpropyl)- l-tetrahydro-SH-l-benzodiazepin-dione, phosphorus pentiichloride and homopiperidine. mp > 210oC (dec). Found:

C, 71.88; H, 8.70; N, 12.95. C19H27N3O.0.25H2O requires C, 71.78; H, 8.72; N, 13.22%.

b) i|9.nihvdro-3TT.R-fbnmntriPPridin-l-vl>-Hf2- TnPtyTV,»rmTiv1Va-nTiTnido-1,-bf>Ti7ndia7.RPin-2-one WO 94/03437 PCI7GB93/0I599 - 109- The title compound was prepared from the foregoing benzodiazepine, potassium t-butoxide and isopentylnitrite in toluene.

C) ?fP SlAmiTio-1 -Hihvdrn-BH-R-fhOTTIQPiPSri'iiTI-VYi)-!- f9..mPt.hvlT)ropv1V1,4-benzQdin7iPPm-g-Qne The title compound was prepared from the foregoing oxime using previously described procedures.

d) fffff,9>.N-f2.3-Pihrn-s-fhomnT,iT1Pr'-1-Y1'<g" Tnpthv1nmnvn-2-oyo-lH-1.4-ben7oHin7PPin-3-YlV1H-idole-g- 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 > 2640C. Found: C, 71.47; H, 7.02; N, 15.14. CHNA requires C, 71.31; H, 7.05; N, 14.85%.

EXAMPLE 91: r.VN-f2.3-Dihvdrn-5-fhPTDTOirPridin-1-Yl)-l-(2- mpt>,v)prnnvn-2-oxn-1-1-bpnzndia7Ppin-3-yl)-lF-indC)k-2- rarhoxamide The racemate of Example 90 was separated into its enantiomers using a semi-preparative dinitrobenzoylleucine Pirkle column (5p) [(250 x 20)mm] eluting with 3% methanol in 1-chlorobutane (including 1% acetic acid). The free base was liberated and obtained as a colourless solid, mp 243-2460C.

[a]23°cD = -17° (c=0.2, methanol). Found: C, 71.56; H, 6.97; N, 14.80. CN-A requires C, 71.31; H, 7.05; N, 14.85%.

EXAMPLE 92; (tl-N-fr-hvdro-S-fhomopippndip-l-YD-Hg-.

rrptbvlnrnvj)-9-nvn-m-1.4-bPn7nr|7:f.piD-3-Yl).:lF-indplg-2- parhnxamide WO 94/03437 PCr/C;B93/015W - 110- Obtained as for Example 91. mp 240-241oC. [a)*'cD = +15° (c=0.2, methanol). Found: C, 65.91; H, 6.77; N, 13.36.

CsbHjbNbOHsO requires C, 66.25; H, 7.35; N, 13.80%.

FXAMPLE 93; &* <?VN-r2.3-Dihvdro-5-fh9PnnpipRriiin-l-Yl)-l-.

r9..TnPt.}ivinmnvn-2-nTn.iH-i.4-bpn7odTn?ieT?iT)-3-y1)-fg'S)-indQlme-.

?-r3rbnxamide Prepared analogously to Example 87 from 3(i2>S)-amino- l>2-dihydro-3H-5-(homopiperidin-l-yl)-l-(2-methylpropyl)-lI4- benzodiazepin-2-one and (S)-(-)-indoline-2-carboxylic add. mp 105-106oC. Found: C, 70.26; H, 7.24; N, 14.14.

CfflH35N502XUH=0 requires C, 69.94; H, 7.51; N, 14.57%.

FXAMPLE" 94: 3f)?1.<?VN-(2.3-r>vdro-5-fhnmnpiTiRriain-l-vl>l:

f9-mftt.hvlT>ropvlV9-nTn-TH-l,4.hPTi7ndiazenin-3-Yl)-lP-TnJ9l9-3-, flcetamide Prepared analogously to Example 87 from 3(J?,S)-annno- l,2-dihydro-3H-5-(homopiperidin-l-yl)-l-(2-methylpropyl)-l,4- benzodiazepin-2-one and indole-3-acetic add. mp 178-180oC.

Found: C, 72.11; H, 7.10; N, 14.45. C29H35N502 requires C, 71.72; H, 7.26; N, 14.4270.

EXAMPLE 95; ?fff,-f2.3-Dihvdro-5-f4-m-gtbYlpirRndin-?-Yl)- i-r9..TnPtbvlnropv1V2-nxo-lH-l,4-hRn2odia7Pnin-3-Yl)-1H-indolg- 9-prhnxHTmde a) l-nibvdro-F---"161"1'"1'12' ppthv1prnnv1V1.4-b»n7nf1Pin-2-Qne 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, ClMn/z * 314 [M+H]*.

y,\ -[ |9.piV,Yrlrn.3H-5-f4-mPthv1pineridiTi-1-v1)-3-9ximid0-l- P.Ti7nrliazepir>-2-one WO 94/03437 IWCB93/01599 -111- Prepared from the foregoing benzodiazepine, potassium t- butoxide and isopentylnitrite in toluene, mp 188-1910C (ethyl acetate/n-hexane). MS, CI*, m/z = 343 [M+H]+. >H NME (360MHz, CDCI3) 5 0.81-1.10 and 1.20-2.00 (14H, each m). 2.80- 3.00 (1H, m), 3.10-3.35 (1H, m), 3.34 (1H, dd, J, = 6Hz, J2 = 14Hz), 3.60-3.90 (2H, m), 4.34 (1H, dd, Jj = 9Hz, J2 = 14Hz), 4.44-5.00 (1H, m), 7.12-7.48 (4H, m).

C) 1 9.r>vHro-3-.(otlivinnrhonyl)-oyiTnido)-3H-5:.B- m7lri-i-vivi-f2-TnpthvlProPYlV1,4-h>'Ti7nn7;TOm-g- The foregoing oxime (SOOmg) was treated with triethvlamine (0.2ml) and ethyl isocyanate (0.37inl) m 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+H3*. ._,. 1 ., T o-KylpT-rvpyiyi .4-ben7nriip7PP1P-g-ong 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) ?rff.-N.f2.3-DYn--(4-methylpiPfridip-l-YlKH2z TT1othvirmTiv1V2--iF-iTirodn'>ppiTf3-YlVlH-iTTd02- A stirred solution of the foregoing amine (725mg) in dimethylformamide (10ml) was treated with W 3- dimethylaminopropyD-S-ethyl-carbodiimide hydrochlonde (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 WO 94/03437 PCr/CB93/01599 -112- filtration. The solid was purified through a short silica column using dichloromethane/'methanol (20:1) then recrystaUised from ethyl acetate/n-hexane (455mg). mp 248-2490C. MS, CI*, mlz = 472 [M+H]+. Found: C, 71.79; H, 7.01; N, 14.58. 03362 requires C, 71.31; H, 7.05; N, 14.85%.

F.YAMPLE 96: N-f? pva-PihYn-l-mPthvl-M •-f3.rN-mPthvl-N'-piPPrn7inv1)phnYllur,s.a iO a) 1 -Dihvdro-1 -mPthv1-5-(4-mPt.hy)pipgrin-1 -vD-3-O- 0f|7ylnn1irnnar>,oTivl)oyimido-aH-l14-bPTirnriif.pin-2-png 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). lH NMR (360MHz, CDC1) 5 1.00 (3H, bra), 1.13 (3H, t, J = 7.2Hz), 1-22-1.42 (2H, m), l!54-1.90(3H, m), 2.78-3.30 (4H, m), 3.44 (3H, s), 3.56-3.78 (1H, m), 4.54-4.86 (1H, m), 6.37-6.45 (1H, m), 7.21-7.38 (3H, m), 7.46-7.54 (1H, m).

M f-Mpt.hvl-N'-T)ipernTiyl V itrnbenzene A mixture of N-methylbis (2-chloroethyl)amine hydrochloride (9.8g) and 3-mtroaniline (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 0oC and filtered. The solid was collected, washed with anhydrous ether then partitioned between dichloromethane (200ml) and sodium hydroxide solution (1M, 150ml). The organic layer was separated and the aqueous phase washed once more with dichloromethane (200ml). The combined organic layers were dried (KCOg) and evaporated in vacuo. The resultant residue was chromatographed on silica gel, using dichloromethane:methanol (96:4) as the eluant, to afford an WO 94/03437 h-i/ui>/-u - 113- orange oil. The oil crystallised on standing and the resultant piperazme (5.64g). >H NMR (360MHz, CDCl,) 8 137 (8H. .).

2.58 (4H, t, J = 5Hz), 3.30 (4H, t, J = 5H*>, 7.18 (1H, dd J- 9 and 3Hz), 7.35 (1H, t, J = 8H.X 7.64 (1H, dd, J = 9 and 2Hz), 7 71 (1H, d, J = 2Hz). MS (CI, NH,) 222 (M+l).

vftminn.a-fN-ninth"l IT TiiPT-tTinYDnzme A solution of 3-(N.methyl-N-piperazmyl)-l-nitrobenzene (117g) in ethanol (40ml) was hydrogenated at 25 psi for 20 rmn in the presence of a palladium on carbon catalyst (200mg, 17% (w/w)) The catalyst was filtered off and the solvent evaporad in vacuo. The residue was chromatographed on silica gel using a gradient elution of Petrol:ether (1:1) followed by dichloromethane.methanol (95:5) to give a colourless oU, which was azeotroped with toluene (20ml) then left at CC overnight After this time the oil had crystallized, and after trituration w,th solid 'H NMR (360MHz, CDCl,) 6 2.34 (3H, s), 2.55 <4H, t, J = 5Hz), 3.18 (4H, t, J = 5Hz), 3.60 (2H, brs), 6.20 (1H, dd,J = 8 and 2Hz), 6.25 (1H, t, J = SB.). 6.36 <1H, dd, J - 8 and 2Hz), 7.04 (1H, t, J = 8Hz). MS (CI, NH,) 192 (M+l).

d) w \?mKv?. ,s.rei1.l.iri-mrtbvl-5..(4-Tn'-tlivlripmdin-l:

11 r n-rn ITT 1 1 1™""*'*«*«*-™ WiMN-mPtbTl-y-.

pir>fira7nnv1)pfrpTwl1 urea To a sdution of ttie product of part a) (0.62g) in methanol (30ml) was added 10% palladium on carbon (0*. 32% (w/w)).

The mixture was hydrogenated at 40 psi for 2h. Fisher 10% palladium on carbon (O.lg, 16% (w/w)) was added and the Lture hydrogenated at 40 psi for another Ih. 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 tetrahvdroftiran (30ml) cooled to WO 94/03437 PCI7CB93/01599 -114- 0oC under an atmosphere of nitrogen was added triphosgene (0.25g). Triethylamine (1.0ml) was added dropwise. After stirring at 0oC for 30 min a solution of the amine (0.48g) in anhydrous tetrahydrofiiran (lOml) was added dropwise. The mixture was stirred at 0oC 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 solid 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 160oC (dec). >H NMR (SSOMHz, CDCI3) 0.95 (3H, d, J = 6.2Hz), 1.05-1.21 (1H, m), 1.28-1.37 (1H, m), 1.46-1.62 (2Hf m), 1.64-1.74 (1H, 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 (1H, m), 3.86-3.96 (1H, m), 5.26 (1H, d, J = 7.8Hz), 6.52-6.58 (2H, m), 6.65 (1H, d, J = 7.9Hz), 6.98 (1H, brs), 7.11 (1H, t, J = 8.1Hz), 7.16-7.20 (1H, m), 7.21-7.33 (2H, m), 7.47-7.55 (2H, m).

WO 94/03437 PC17CB93/01599 - 115 - r.XAMPLE 97A Tbit. copfnina i-?*Tm of compound Amount toq Compound of formula (I) Microcrystglline cellulose Modified food corn starch Lactose Magnesium Stearate 1.0 2.0 25.0 20.0 20.0 20.0 20.0 20.0 20.0 58.5 57.5 34.5 0.5 0.5 0.5 EXAMPLE 97B T„h1 P.ts conninq ?6-100liq of CQTnpound Amount mq 26.0 50.0 100.0 80.0 80.0 80.0 Compound of formula (1) Microcrystalline cellulose Modified food corn starch 80.0 80.0 80.0 213.5 189.5 139.5 Lactose xj.s Magnesium Stearate 0*5 0*5 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, 2.0mgf 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet.

EXAMPLE 98 Parenteral injection Compound of formula (I) Citric Acid Monohydrate 3 0 Sodium Phosphate Sodium Chloride Water for Injections The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The WO 94/03437 PCT/GB93/01599 - 116 - compound of formula (I) is dissolved or suspended in the solution and made up to volume.

EXAMPLE 99 Topical formulation Amount mq Compound of formula (I) l-10 Emulsifying Wax :30 Liquid paraffin 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 125I-CCK from rat pancreas (CCK-A) or guinea pig brain (CCK-B). The data in Table 1 were obtained for compounds of the Examples.

WO 94/03437 F'cr/GBW/oisyv - 117 - TMSLE I CCK RECEPTOR BINDING RESULTS ICsoW Compound of Ex # (enantiomer A) (enantiomer B) 8 (enantiomer A) 8 (enantiomer B) (enantiomer A) (enantiomer B) 14 (enantiomer A) 14 (enantiomer B) 15 (enantiomer A) (enantiomer B) 18 (enantiomer A) 3 0 2 0 (enantiomer A) 2 0 (enantiomer B) 2 2 (enantiomer A) 24 (enantiomer A) 24 (enantiomer B) 125I-CCK 125I-CCK Pancreas Brain 724 14.8 871 2.02 544 11.6 1.19 738 0.49 7.8 14.8 235 10.9 7.74 1.64 981 0.35 2.61 23.2 8.97 0.21 421 0.76 0.42 12.6 25.2 4.22 2180 0.28 496 1.53 3220 11.6 11.4 174 1902 3.47 2650 19.1 27,2 0.2 765 0.64 3294 1.52 3670 32.9 2250 0.927 WO 94/03437 1»CT/GB93/01599 - 118 - 26 >3000 0.27 28 (enantiomer A) 239 27.8 2 8 (enantiomer B) 3.97 281 347 0.36 31 20 0.53 32 >3000 22 33 1604 0.10 34 6.46 2 6.7 39.6 0.82 36 1400 0.32 38 7.93 0.71 39 4010 0.17 8.8 36.3 41 >3000 0.37 42 80.4 1.79 43 >3000 48.3 44 70.2 0.52 >3000 0.42 46 23.7 20.1 47 26.6 1.01 48 2418 1.11 49 9,65 82.7 10 3.9 51 28.5 5.49 52 18.5 0.25 53 3760 0.18 54 8.4 68 >3000 0.73 57 12.3 4.6 58 2260 2.0 59 9.7 144 WO 94/03437 PCT/GB93/01599 - 119 - 186 2.56 704 0.22 114 35.2 304 1.36 2065 0.22 138 13.7 83.6 0.79 1999 0.10 53.4 26.6 469 2.82 >3000 0.61 17 6 10.3 >3000 1410 192 7.3 314 46.9 760 3.12 135 81.1 891 4.5 1700 13.4 1135 32.4 14.9 23.2 815 0.47 283 3.67 >3000 1900 >3000 785 831 31.3 0.87 509 0.26 653 8.7 225 11.6 161 WO 94/03437 l'CT/«B93/0IS99 - 120 - 94.1 148 WO 94/03437 PCT/GB93/015W 121 -