CA2129990C - Benzodiazepin derivatives useful as cck-receptor antagonists - Google Patents

Abstract

A benzodiazepine derivative of formula (1), or a pharmaceutically acceptable salt thereof, wherein (a) R1 is -CH2CHOH(CH2)a R4 or a ketone group -CH2CO(CH2)a R5 in which a is 0 or 1 and R4 and R5 are selected from alkyl and cycloalkyl groups and saturated heterocyclic groups optionally substituted at a hetero-atom; (b) R2 and R3 are independently selected frown aromatic carbocyclic and heterocylic residues; and (c) W and X
are selected independently from halogen and hydrogen atoms and alkyl and alkoxy groups. These compounds are gastrin and/or CCK-B receptor antagonists.

Description

~ ~r~s_ !NO 93/ 16999 "' . '' ~ ~ PCT/G B93I00404 _1_ Benrodia~epin derivatives usefui as CCiC°receptor antagonists This invention relates to benzodiazepine derivatives which are useful as drugs exhibiting antagonism at the gastrin and/or CCK-B
receptor, and to their production.
May benzodiazepine derivatives have been described in the course of development of psychotropic drugs which act as agonists at the "benzodiazepxne receptor" in the central nervous system. More recently benzodiazepine derivatives have been described which act as antagonists at the CCK-A (cholecystokinin-A) and GCK-B
receptors: It was further reported that those compounds which were selective antagonists for the CCK-B receptor were able to reduce the secretion of gastric acid in response to the administration of pen~agastrin (V. J. Lotti &, R.S.L. Chang, Eur.J.Ph~rmacol. I6Z, 273-280; 1989). Examples of benzodiazepine derivatives which act as antagonists at the CCK-B receptor are disclosed in, for example, U.S:Patent No.4,820;834.
The compounds of the present invention are novel. They differ from the compounds described in U,S.Patent Plo.4,820,834, particularly in the nature ~f the substituent at position 1 of the benzodiazepine nucleus The present invention includes compounds of better pharmacological ch~ract~ristics than those described an U.S.Patent No.4;820,834; preferred compounds of the invention have a higher affinity for the CCK-B receptor and/or discriminate more selectively between the CCK-B and CCK-A receptors than the previously described compounds.
The present invention provides a benzodiazepine derivate of formula I, or a pharmaceutically acceptable salt thereof ~:

t W R O
N
htHCONH-Ft~
N
f R
wherein ( a ) R1 i s - CHZ CHOH ( CHZ ) aR4 or a ke tone group -CHzCO (CHZ} aRs in which a is 0 or 1 and R4 and RS are selected from alkyl and cycloalkyl groups and saturated heterocyclic groups optionally substituted at a hetero-atom;
(b) Rz and R3 are independently selected from aromatic carbocyclic and heterocyclic residues; and (c) W and X are selected independently from alkyl and alkoxy groups and halogen and hydrogen atoms.
According to an aspect of the present invention, there. is provided a benzodiazepine of formula I, or a pharmaceutically acceptable salt thereof:
R' O
NHGt?NI-t-R2 N

R
wherein (a) R1 is -CHZCHOH (CHZ) aR4 or a ketone group -CHZCO (CHz) aRs in which a is 0 or 1 and R4 and RS are selected from alkyl groups of up to 8 carbon atoms; C3 to -2a-C$ cycloalkyl groups; C3 to Ca cycloalkyl groups substituted with one or more alkyl groups of up to 8 carbon atoms; adamantyl and saturated heterocyclic groups of formulae II and III:
v CH~b CH2~b O
~s IL
in which R6 is one of H, C1-C3 alkyl, and C1-C3 acyl and b is 1 or 2;
(b) RZ and R3 are independently selected from unsubstituted or substituted phenyl and pyridyl, the substituents being selected from halogen atoms and hydroxy, amino, nitro, carboxylic acid, carboxamido, cyano groups, alkyl, alkoxy, alkylamino and dialkylamino groups, wherein the or each alkyl group is of up to 8 carbon atoms;
(c) W and X are selected independently from halogen and hydrogen atoms and alkyl and alkoxy groups of up to 8 carbon atoms.
According to another aspect of the present invention, there is provided a medicinal composition comprising a compound as described above and at least one of a carrier and an excipient.
According to another aspect of the present invention, there is provided a medicinal composition as described above wherein the composition is a gastrin or CCK-B receptor antagonist.

-2b-According to another aspect of the present invention, there is provided a medicinal composition as described above wherein the composition is the treatment of diseases induced by the failure of a physiological function controlled by gastrin.
According to another aspect of the present invention, there is provided a medicinal composition as described above wherein the physiological function is selected from the group consisting of gastric and duodenal ulcers, gastritis, reflux esophagitis, gastric and colon cancers, and Zollinger-Ellison syndrome.
According to another aspect of thc~ present invention, there is provided a medicin<~.1 composition as described above wherein the composition is for the treatment of diseases induced by the failure of physiological function controlled by the central CCK-B receptor.
According to another aspect of the' present invention, there is provided a medicinal composition as described above wherein the composition is for the reduction of anxiety or for the appetite regulation.
According to another aspect of the present invention, there is provided a process for the production of benzodiazepine of general formula I, or pharmaceutically active salt thereof, as defined above ' Jun-ZB-05 05:Z3wn Fr~rn-511r~AS LTD 416595 1306 T-593 P.004/005 F-634 _~c_ wherein R1 is -CHaCO (CT-Iz) aR~, the process comprising the reaction of 3-aminobenzodiazepine V with organic isocyanate R~~NCO:
R' N O w i'N ~!%' NHz + ~1 HCD -a f ' l~'"...ON'rF: s"~
J
~~N
x R3 7C u3 v x According to another aspect of the present invent~.on, there is provided a process for the production of benzodiazepine of general formula I, or pharrnaceutica~.ly acceptable salt thereof, as defined above wherein R1 is -CHZCQ (CkIz) aRs, the proce$s compri:~ing the reaction of 3-p- nitrophenyloxycarbon~rlamino benzodiazepins vI with amine R2-NH2:
il_o ~ ~tc?~ - :z ~z --~ '' ~l _.-X ~ A3 ~~r.
AcGOrd~ng ro another aspect of the~presenC
invention, there is provided a process for the production of a Y~enzodiaz~:pine of general formula I, or pharmaceutically active salt thereof, as defined above whereixz R1 is -CHzCHOH(CHz)aR4, the process comprising reaction of the benzodiazepine of formula I wherein Ri is CH~CO(CH2)aRs with a reducing agenC_ -2d-According to another aspect of the present invention, there is provided use of a compound as described above for the preparation of a medicament for the prevention or treatment of disease induced by failure of physiological function controlled by gastrin or central CCK-B receptor.
According to another aspect of the present invention, there is provided use of a compound as described above for the prevention or treatment of disease induced by failure of physiological function controlled by gastrin or central CCK-B receptor.
Herein all "alkyl, "cycloalkyl~~, "acyl" and "alkoxy"
groups are preferably of up to 8 carbon atoms, and "halogen" may for example be fluorine, chlorine, bromine or iodine. The aromatic residues herein (R2, R3) may be substituted; they are preferably monocyclic, usually of 5 or 6 ring atoms; when heterocyclic they may for example have 1, 2 or 3 hetero ring atoms. Preferably at least one of R2 and R3 is unsubstituted, monosubstituted or disubstituted phenyl or unsubstituted, monosubstituted or disubstituted 2-, 3-, or 4-pyridyl. Preferably one (most preferably each) of W and X is a hydrogen atom.
Preferably R4 is alkyl (e. g. C4 - C~, linear or branched);
or is cyclo- or polycycloalkyl (which may be unsubstituted or substituted with one or more alkyl groups) and contains e.g. from 3 to 8 carbon atoms; or is of Formula II or III:
~'w~~ b O N
~s iti 2~?~~ ~~

in which R6 is H, alkyl (e.g. C1 - C3) or -CO-alkyl (where the alkyl is e.g. C,. - Cue) and b is 1 or 2. Preferably RS is alkyl (e.g. C1 - C3) or as defined for R°.
Examples of alkyl and cycloalkyl groups include tart-butyl, cyclopentyl and cyclohexanemethyl.
Examples of saturated heterocyclic groups include pyrrolidyl and tetrahydropyranyl. Examples of substituents at the heteroatom inchade simple alkyl and acyl groups (e.g. of up to 3,4,5 or 6 Carbon atoms, such as formyl, acetyl, etc).
Examples of substituents on the aromatic residues (R2, R3) include halogen atoms (e. g. fluarine, chlorine, etc); hydroxy amino, vitro, carboxylic acid and cyano grougs; and alkyl, alkoxy, alkylamino and dialkylamino groups in which the or each alkyl component is preferably of up to 6 (e. g. up to 3) carbon atoms (methyl; ethyl etc.); for substituted RZ, mete-substitution is preferred.
Most preferably Rz is unsvabstituted phenyl; phenyl having a mete !
substitu~nt chosen from F; CI, Br, OH, OCH3, NHS, NMez, NOz, Me, -(CH2)~-COZH, CN, NHMe, NMeEt, NEt2. CHZNMez, NHCHO and -(CH~)C-803H where c is 0-2; or 2-, 3- or 4-pyridyl optionally with a substituent selected from F, Cl, CH3 and COZH.
Most preferably R3 is ghenyl or 2-, 3- or 4-pyridyl.
GJ acnd X are greferably~ both H, but when either is alkyl or alkoxy it ~.s preferably of 1 to 3 earbon atoms.
The compounds of this invention all have at least one stereogenic centre and so can exist as optical isomers. It should be understood that these isomers, either separately or as maxtures, are included within the scope of this invention. In addition, the ;, ~.:::; . .., :.,. ; ...:; .: ._ ..: . , . . .. . _:., _ . , WO 93/16999 PCT/GB93/OOaOa compounds of this invention can form salts with inorganic or organic acids or, in some cases, bases. Examples of such salts would include chlorides, sulphates and acetates, or sodium and potassium salts. These salts should also be understood to be included within the scoge of this invention. In preferred compounds according to the invention, the absolute configuration at tlae 3-position of the benzodiazepine ring is R (as shown in IV).
W I
j -~~ Ni-°tCONH-R~ ~' Compounds according the ~rwention act as CCK-B and gastrin receptor antagonists. They may be used as drugs for the treatment of w diseases induced by the failure of a physiological function controlled by gastrin, such as gastric and duodenal ulcers, .
gastritis, reflux esophagitis; gastric and colon cancers, and Zollinger-Ellison syndrome; there may be no side effects arising from CCK-A receptor interaction. They may be used as drugs for the treatment of diseases induced. by the failure of physiological function Controlled by the central CCK-B receptor (e.g. for the reduction of anxiety or for appetite regulation).
~,ongst preferred compounds according to the invention are those listed b~:~ow and salts thereof: Some of the compounds are exemplified hereinafter as indicated against the individual compounds concerned.
SUBSTITUTE SHEE°i' 1~ ~~'~i~

1. N-((3RS)- 1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 2); w 5 2. N-((3RS)-1-Diethylmethylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 3);
3. N-((3RS)-1-Cyclobutylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 1);
4. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2 oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 4);
5. N-((3RS)- 1-Cyclohexylcarbonylmethyl-2,3-dihydroi2-oxo-5-phenyl-lH-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example ?);
N-((3RS)-l-Cycloheptylcarbonylmethyl-2,3-~.ihydro-2-axc~-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 5);
7. N-((3RS)-Cycloheptylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-N'-(3-chl.orophenyl ) urea (Example 6 ) ;
8. N-((3RS)- 1-Cyclop~ntylcarbonylmethyl-2,3-dihydro-2 oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl-N'-(3 methylphenyl) urea (Example 14);
9. N-((3RS)- 1 -Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-(3-pyridyl)-1H-1,4-benzodiazepin-3-yl}-N'-(3-methylphenyl) urea (Example 21);
U~~TITU'~E S~EE°~' Ziz~~~~~
i~0 93116999 P~I'/G~93/00404 10. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-(4-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 15);
11. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yI)-N'-(3-carboxyphenyl) urea (Example 16);
12. N-((3R)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 17);
13. N-((3S)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 18);
14. N- ( (3RS) -2, 3-Dihydro-2-oxo-5-phenyl-1- ( (2R) -2-pyrrolidylcarbonylmethyl)-1H- 1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 10);
~.5. N-((3RS)-2,3-Dihydro-2-oxo-5-phenyl-1-((2S)-2-pyrrolidylcarbonylmethyl)-IH-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 3);
16: N - ( ( 3 R S ) 1 - ( ( 2 R ) - 1 - A c a t y 1 _ 2 -pyrrolidylcarbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example ~1 ) ;
17: N - ( ( 3 R S ) _ 1 - ( ( 2 S ) - 1 - A c a t y 1 - 2 -pyrrolidylcarbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 18. . N- ( (3RS) -1-- ( (2RS) -2-Cyclopentyl-2-hydroxyethyl) -2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 12);
~U~STITUT~ ~H~E'C

W(7 93/16999 ~ ~ ~ j ~ ~ t PCT/GB93/00404 19. N-((3RS)-1-((ASR)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 13);
20. N-((3R)-1-((2R)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-S-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 19);
21. N-((3R)-1-((2S)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-S-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 20);
22. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2 oxo-~5-phenyl-IH-1,4-benzodiazepin-3-yl)-N'-(3-cya nophenyl ) urea ( Exatripl a 4 9 ) ;
23. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-cyanophenyl) urea (Example 50);
24. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-S-phenyl-1H-1;4-benzodiazepin-3-yl)-N'-(3-carboxymethylphenyl) urea (Example 31); .
25. N-((3RS)-1-(1-Adamantyl)carbonylmethyl-2,3-dihydro-2-oxo-S-phenyl-1H-2,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example S1);
26e N-((3RS)-1-Cy~~.oPentylcarbonylmethyl-2,3-dihydro-2 oxo-5-phenyl-1H-1,4-benzodiazepin-3--yl)-N'-(3-pyridyl) urea (Example 30);
27. N-((3RS)~1-Cyclopentylcarbonylmethyl-2,3-dihydro-2 oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(6-methyl-2 pyridyl) urea (Example 29);

2~.~u~~~
WO 93li6999 ~CT/GB93/00404 28. N-((3RS)-1-(3-Cyclohexyl-3-methyl-2-oxobutyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-E3-methylphenyl) urea (Example 52);
29. N-((3RS)-1-Cyclohexylmethylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 32);
30. N-((3RS}-1-Cyclopentylmethylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 33};
31. N-((3RS)-l-((1-Methylcyclohexyl)carbonylmethyl)-2,3 dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3 methylphenyl) urea (Example 34);
32. N-((3RS)-1-((1-Methylcyclopentyl)carbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl }urea (Example 46);
33. N-((3R)-1-~Cyclopentylcarbc~nylmethyl-2,3-dihydro-2- .
oxo-S-phenyl-1H-1,4-benzodiazepin-3-yl}-N'-(3-carboxyphenyl) urea (Example 23);
34. N-((3RS)-1-Cyclopentylcar~onylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4y-benzodiazegin-3-yl)-N'-(3- ;
carboxyphenyl) urea (Example 22);
35. N-((3R)-1-((2RS)-2-Cyclopentyl-2-hydroxyethyl)-2,3- ..
dihydro-2-oxo-5-phenyl--1H-1,4-benzodiazepin-3-yl}-N'-(3-carboxyphenyll urea (Example 24);
36. N-((3R)-1-((2R)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H- 1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea (Example 25);
SLJ~~T'I~T~1~'E SH~~"t' i,.r Hr :~ ,Y t tl WO 93/ ~ 6999 PCT/GB93/004~4 37. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxam-idophenyl) urea (Example 35);
38. N-((3R)- 1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 26);
39. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2 oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3 methylphenyl) urea (Example 27);
40. N-'(3RS)-1-test-Butylcarbonylmethyl-2,3-dihydro-2 axo-5-phenyl-~H-Z,4-benzodiazepin-3-yl)-N'-(3 carbaxyphenyl) urea (Example 28);
41. N-((3RS)-1-tart-~.mylcarbonylmethyl-2,3-dihydro-2-r~xo-5-phenyl-1H-~., 4-benzodiazepin-3-yl) -N' - (3-methylphenyl) urea (Example 36);
42. N-((3RS)-1-tart-Amylcarbonylmethyl-2,3-dihydro-2-. ,.
oxo-5-phenyl-ZH-~,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea (Example 37);
43. N--((3RS)-1-tent-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H,-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea (Example 38);
44. N-((3RS)-I-tart-Butylcarbonylmethyl-2,3-dihydro-2-3a oxo-5-(2-pyridyl)-2H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea (Example 39);
45~ N-((3RS)-1-C'yclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-ber_zodiazepin-3-yl)-N'-(3-d~.methylaminophenyl) urea (Example 40);
~U~~TITUTE S>-~EET

WO 93! 3 6999 PCT/G B9310~404 46. N-((3RS)-1-tent-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea (Example 41);
5 47. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin~-3-yl)-N'-(3-methoxyphenyl) urea (Example 42);
48. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-10 oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl}-N'-(3-methoxyphenyl) urea (Example 43);
49. N-((3RS)--1-C~rclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-nitrophenyl) urea (Example 44); .
50. N-((3RS)-l.-tart-Busylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-nitrophenyl) urea (Example 45);
51.. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)--N'-(3-formylaminophenyl) urea (Example 47);
52. N-((3R}-1-((2R)-2-Hydroxy-3,3-dimethylbutyl}-2,3-dihydro-2-oxo-5-phenyl-IH-1,4-benzodiazepin-3-y1)-N'-(3-methylphenyl) urea (Example 48);
53. N-((3R)-Z-((2S}-2-Hydroxy-3,3-dimethylbutyl)-2,3 dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3 methylphenyl}urea;
54. N-((3RS}-1-(1-Methylcyclopropyl)carbonylmethyl-2;3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 53);
S~JSSTITIJTE Si~EET

~~?~;~
WO 93tI6999 PCT/G~3931OOQ04 55. N-((3RS)-1-tent-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 54);
56. N-((3RS)-1-Isopropylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 55);
57. N-((3R)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-~5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylaminophenyl) urea (Example 56);
58. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylaminophenyl) urea (Example 57);
59. N-((3R)-1-tart-Butylcarbonylmethyl-2,3-dihyd'ro-2 oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-(N-ethyl-N
methylamino)phenyl) urea (Example 58);
60. N-((3R)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1;4-benzodiazepin-3-yl)-N'-(3-diethylaminophenyl) urea (Example 59);
61: N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-o~co-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminomethylphenyl) urea (Example 60);
62. N-((3RS)-1-tart-Butylcarbonylmethyl-2,'3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(N-ethyl-N-methylamino)phenyl) urea (Example 61);
63. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminomethylphenyl) urea (Example 62);

c ,.; ~1 Lc L~ J O
WO 93/16999 P~I'/GB93/00404 64. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl-N'-(3-diethylaminophenyl urea (Example 63);
65. N-((3R)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea (Example 64);
66. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(4-methylphenyl)-1H-1,4-benzodiazepin-3-yl)-N°-(3-methylphenyl) urea (Example 65);
67. N-((3R)-1-tent-Butylcarbonylmethyl-2,3-dihydro-2-axo-5-phenyl-1H-1,4-benzodiazepin-3.-yl)-N'-(3-aminophenyl) urea (Example 66);
68. N-((3R)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodazepin-3-yl)-N'-(3-methylphenyl) urea;
69. N-((3R)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3- '~v aminophenyl) urea;
7Q. N-((3R)-1-test-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N°-(3-methylaminophenyl) urea;
71. N-((3R)-1-tent-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea;
72. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2 oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N°-(3 aminoghenyl) urea;

~~r0 93/16999 PCT/GB93/OOa04 .

73. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylaminophenyl) urea;
?4. N-((3RS)-1-tent-Butylcarbonylmethyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 67);
75. N-((3RS)-1-tart-Butylcarbonylmethyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea (Example 68);
.76. N-((3RS)-1-tart-Butylcarbonylmethyl)-?-chloro-2,3-dihydro-2-oxo-5-(2-chlorophenyl)-1H-2,4-benzodiazepin-3-35 yl?-N'-(3-methylphenyl) urea (Example 69);
77: N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-8-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea (Example 70)~
78. N-((3RS)-~.-tart-Butylcarbonylmethyl-2,3-dihydro-2-a~co-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-(N-ethyl-N-methylaminophenyl) urea;
79. N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-diethylaminophenyl) urea.

SUBSTfTUTE SH~~"

.. ,...i..;: ~ .~.:..~~::... v,.a::. . ,,~~r , ....:..'. .. .':~;:1' ;'::.~ ,.
. ;~'-,', :....:..s;':. , :.;";. . 1~~.~. ~;.~.~.;' ~:.......:..;..:.......:.
... .. .;,. .,~.:....., ....
>r .~r ~ » ~ ~ e~ V
W'O 93/ 16999 PCT/G B93/00404 1, 4 The compounds of the invention can be prepared according to the route autlined in Scheme I below. , Scheme 1 R~
H O
~,~ ~ O w O
~0 N N
~ ( ~
. ~ r N NHZ Step (i) ( - N NHZ
'~ R3 X Ra Step (ii) c.d i RT
OH O
w O w O
N ~ N O
' ~( NH~ NH-RZ -~- ~ - I NH~ (~.j_ R
N Step (iii) r.-- N
Ra . . X Ra Reagents : (a) NaH, DMF; (b) R,COCHZBr; (c) Ha, Pd-C
or HHr;
( d) RZNCO ; ( a ) NaBH4 -(R' represents Ra (CHa) a, or RS (CHz) a) When R' = Ph, the starting material 1_ is a known compound [M.G. Bock et al. J'. O~g. Chexrz. 52, .232°239, 198?] .
For other examples of R', such as pyridyl, the starting , material 1 can be prepared in a manner analogous to that described by Bock et a1. For simplicity, in the specific examples which follow, the compound 1 (R' - Ph) is St9~~TiTU'TE ~i~IEE"r' ~,. ~~ : ! ~ ~~
W'() 93/16999 ~'CTfGB93f0040~1 referred to as the Bock benzodiazepine.
In step (i) the compound 1 is deprotonated with a strong base (typically sodium hydride) and then reacted with a 5 bromomethyl ketone R'COCH2Br. In general, these ketones are not commercially available, but can be prepared from commercially available carboxylic acids or carboxylic acid chlorides by the route outlined in Scheme 2.
ZO Scheme 2 R~-C02H f ~- R'COC1 -- ° -~- ~~N ~°--:-°~.- ~8r Step (i) . Step (ii) R 2 Step (izi) R' 1. 5 Reagents: (f) SOC~.a; (g) CHzN2; (h) HBr The alkylated benzodiazepines 2 (Scheme ~.) are then deprotected. Scheme 1 illustrates the case when the amino-group is protected by a Z group (Z -benzyloxycarbonyl) which can be removed by catalytic hydrogenolysis or acidic hydrolysis.
When a protecting group other than Z is used the deprotection step tray need to be changed appropriately.
The deprotected benzodiazepine is then treated with an aryl isocyanate (R~I~CO) . When R2 -- 3-methylphenyl for example, this leads directly to compounds 3 which are l~:st~d above (e.g. compounds 2 - 10, etc). When Ra contains a protected functional group (e. g. a carboxylic acid protected as an ester) this group must be unmasked to give the listed compound. The ketone 3 can be reduced by, for example, sodium borohydride to give the corresponding alcohol 4 (e. g. compounds 18 - 21, etc).

In some cases it is preferable to prepare the urea by an altenate route This is outlined in Scheme 3.
~U~ST(TU'T~ SHE~'T

1V0 93/16999 P(_'T/GB93/0040~

Scheme 3 Rr R~
p O
w O W O O \ NO2 N N
NHZ ~', ~ ~ NN O
~. N Step (i) s N
1. 9 x R X R3 k Step (ii) . R~
W ~ O
l5 , O
N O
Rz N!-!~ NH"i 2~ 3 Reagents ; ~( j ) p° ~J~rIC6H,OC0C1. ; (k) R2NHa The protected benzodiazepine derivative ~ is protected as before (Scheme 1; step (ii)} but is then treated with p ~5 nitropherayl chloroformate to dive the p-nitrophenyl ~arbarnate S. In step (ii) this is reacted with an amine Ra~2 tca give the urea 3. This route is particularly useful when the isocyanate RzNCO is not commercially available but the amine RaNH2 is .
These general methods will now be further illustrated with specific, n~n-limiting examples.
~PLE 1 N- -1- lobut 1 ar n lmeth 1-2 ~-dih d -2- x -5-hen -1H-1 4-be zodia~e in-3- 1 -N' 3-m th 1 hen 1 W'19E3~t'lTllZ'E SI~E~1"

~~r.~~tyJu urea. Compound 3 1A Bromomethyl cyclobutyl ketone (Scheme 2, Steps (i) -iii To an ice-cold solution of cyclobutanecarboxylic acid (1.5 g, 15 mmol) in Et20 (10 ml) was added N,N-diisopropylethylamine (2.9 ml, 16 mmol) followed by thionyl chloride, (1.24 ml, 17 mmol). The mixture was stirred at O°C for 45 min. then poured into an ice-cold solution of CH2N2 (prepared from Diazald~, 14.1 g, 66 tnmol) in Et2O, and the resulting mixture was allowed to warm to room temperature over 2 hrs. A saturated solution of HBr in EtzO was added dropwi5e until no more nitrogen was evolved. The resulting ethereal solution of bromomethyl ketone was washed successively with satd. KHC03, water and brine, filtered (Whatman° 1 PS phase separator), and concentrated ia~ vaeuo. The crude product was purified by bulb-to-bulb distillation (100°C, 5 mm Hg), to give the title Icetone as a colourless, mobile oil (1.13 g, 440).
NMR (CDC13) 8 3.86 (2H, s); 3.57 (1H, quintet, J
8 .5 Hz) ; 2 .5 - 2 .2 (6H, m) ; 2.2-1 . 8 (2H, rn) .
1B 3RS -3-Benz lox carbon lamino-1-a elobut lcarbon 1 meth 1-2 3-dih dro=5- hen 1-1H-1 4-benzodiaze in-2-one Scheme 1; step (i)~
To a stirred solution of (3RS)-3-benzyloxycarbonyl--amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one [M.G. Bock et al. J. Org. C~aem. 52, 3232-3233, 1987.) (57~ mg, from 605 mg of monohydrate azeotroped with DMF
x 3, 1.5 mmol) in DMF (5m1), cooled to -10°C under N2,was ~~i~~~~~~~~ ~~

- ..' '. . , ,~.:,~, .;. -~ ' ~.:. ... .. ...
., ~ , ,... .. .. .t ,;.. . ',' : ... . .. .... n . . . . ~.~_.. ~ '~: ~~
..~~. , dV0 93/16999 PCT/GB93/00404 added sodium hydride (63 mg of 80o dispersion in oil, 2.1 mmol) . The mixture was stirred at -10°C for 30 min, when a solution of the bromomethyl ketone of Example 1A (398 mg, 2 . 25 mmol ) in DMA' ( 2 ml ) was added. The resulting mixture was allowed to warm to room temperature with stirring over 1 hr, then poured into dilute aq. HC1 (100 ml). The mixture was extracted once with EtOAc, and the organic layer was washed with water and brine, filtered (Whatman~ 1 PS phase separator), and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 60-8o pet.
ether 40:60 v/v) to give the title benzodiazepine as a glassy-solid (490 mg, 68%).
Rf (EtOAc: 60-80 pet. ether 50:50) 0.54.
NMR (CDC13) b 7.8 - 7.2 (14H, m) ; 6.70 (1H, d, J = 8 Hz); 5.47 (1H, d, J = 8 Hz); 5.18 (2H, s); 4':69 (H,; d, J = 7.5 Hz); 4.60 (1H, d, J = 7.5 Hz);3.36 ~(1H, quintet, J = 8 Hz); 2.5 - 1.8 (6H, m).
1C N- ( C3RS~ -1-Cyclobut~lcarbon,~rlmethyl-2 3-dihvdro-2-oxo-S-phen~rl-1H-1 4-benzodiazepin-3-yl)-N'-(3-methyl-phenyl ) urea ( Scheme' 1, step ( ii ) ) To a deoxygenated solution of the benzodiazepine of Example IB (490 mg, 1.02 mmol) in glacial acetic acid (25 ml) was added 5o palladium-on-carbon catalyst (ca. 200 mg) . Hydrogen gas was bubbled through the suspension for 4 hrs, and the x'eaction was terminated by nitrogen degassing. The mixture was filtered, and the catalyst residue was washed with methanol. The combined filtrates were evaporated in vacuo, and traces of solvent were finally removed by co-evaporation with toluene. The residue was taken up in CHzCl2 (25 ml) and stirred at room temperature. To this solution was added m-talyl isocyanate (0.13 ml, 1.02 mmol), and stirring was VV!O 93/ 16999 continued for 2 hrs. The solvent was evaporated in vacuo, and the crude product was purified by flash chromatography on silica gel (eluant EtOAc: 60-80 pet.
ether 40:60 v/v). Finally the product was taken up in acetic acid and lyophilised to give the title benzodiazepine as a white powder (203 mg, 410, >95o pure by HPLC ) .
Rf (EtOAc: 60-80 35:65) 0.12.
pet. ether NMR (CDC13) b 7.82 (2H, d, - 7 Hz); ?.8 - ?.2 J

(11H, m) ; ?.09 (1H, d, = 8 Hz) ; 6.99 (1H, d, J

J = ? I-Iz) 5.83 (1H, d, = 8 Hz) ; 4.78 (2H, ; J

s) ; 3 .44 1H, quintet, = 8.5 Hz) ; 2.43 (3H, ( J

s) ; 2 . 4 1. 9 ( 6H, m) - .

M.S. (FAB, +ve ion) m/e 481.8 (M+H).

N-((3RS? 1-pert-ButYlcarbonylmethyl-2,3-hvdro-2-oxo-5-hen l-1H-1 4-benzodiaze in-3- 1 -N'- 3-meth 1 hen 1 urea . Compound 1 2A tert Butyl bromomethyl ketone (Scheme 2, steps ii _~iiiW

To an-ice-cold solution of CH2N2 (prepared from Diazald~, 10:4 rg, 49 mmol) in Ft2O was added pivaloyl chloride (2 ml, 16 mmol}. The solution was allowed to warm to room temperature with stirring over 3 hrs, when a saturated solution of HBr in EtOAc was added until no more. nitrogen was evolved. The salution was washed with brine, filtered (Whatman° 1 PS phase separator), and concentrated in vacuo to give the title ketone as a mobile, pale brown oil (3.47 g, 82% pure by NI~fR, remainder EtOAc, 990).
NMR (CDC13) b 4.15 (2H, s) ; 1.20 (9H, s) .

21~~~~~ .
l~V~ 93/ 1 b999 PC'~'/GB93/~0404 2B ~3RS)-3-BenzyioxYcarbonvlamino-1-tert-butvlcarbonylmethyl-2,3-dihydro-5-mhenyl-1H-1,4-benzodiazepin-2-one, (Scheme 1, step (i) 5 This was prepared following the method of Example 1B
using the Bock benzodiazepine (578 mg, 1.5 mmol), sodium hydride (63 mg of 80o dispersion in oil, 2.1 mural) and the bromomethyl ketone of Example 2A (491 mg, 82% pure 2.25 mmol). The crude product was purified by flash 10 chromatography on silica gel (eluant EtOAc: 60-80 pet.
ether 50:50 v/v) to give the title benzodiazepine as a glassy, solid (700 mg, 97%).
Rf (EtOAc: 60-80 pet. ether 50:50} 0.56.
15 NMR (CDC13) b 7.8 - 7.2 (14H, m); 6.74 (1H, d, J = 8 Hz} ; 5.53 (1H, d, J = 8 Hz) ; 5.23 (2H, s} ; 5. 05 (1H, d, J = lB Hz; 4.77 (IH, d, J = 18 Hz); 1.33 (9H, s) .
20 2C N-(j,3RS)-1-tern-Butvlcarbonylmethvl-2.3.-dihvdro-2-oxo-5-phen~,rl-1H-1 '4-benzodiazepin-3-yl,~ -N' - (3-methylghenyl ) urea Scheme 1, step ( ii ) ) This was prepared following the method of Example 1C
using the benzodiazepine of Example 2B (700 mg, 1.45 mmol), 5% palladium-on-carbon (ca. 300 mg), and m-tolyl isocyanate (0.19 ml, 1.5 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 60-80 pet, ether 40:60 v/v), taken up in acetic acid, and lyophilised to give the title benzodiazepine as a white powder (233 mg, 330, >97% pure by HpLC).
Rf (EtOAc: 60- 80 pet. ether 40:60) 0.31.
NMR (CDC13) b 7.72 (2H, d, J = 8 Hz); ?.7 - 7.0 (12H, m) ; 6.87 (1H, d, J = 7 Hz) ; 5.73 (1H, d, J = $
Hz); 4.92 (1H, d, J = 18 Hz); 4.82 (IH, d, J = 18 Hz}; 2.32 (3H, s}; 1.25 (9H, s).
SUE~T~TIJTE SHEET

2~?~~~~~~
'vVO~ 93/16999 ,.., :~ .-i r :% P(:T/GB93l~DO~tO~

M.S. (FAB, +ve ion) m/e 483.2 (M-~H) .

N-((3RS)-1-Diethylmethylcarbon~rlmethvl-2,3-dihvdro-2-oxo-5-phenyl-1H-1,4-benzodiaze~in-3-yl)-N'(3-methylphenyl) urea. Compound 2 3A Bromomethyl dieth r~lmethyl ketone (Scheme 2j, steps (1) - (3.3.1.) ) To 2-ethylbutyric acid (2.09 g, 18 mmol) at O°C was added thionyl chloride (5.2 ml, 71.5 mmol) and the resulting mixture was allowed to warm to room temperature and stirred for ~5 min: The mixture was diluted with dry THF
then concentrated in vacuo at ambient temperature, azeotroping with further dry THF to remove last traces of SOC12. The residual oil was taken up in dry THF (20 ml) poured onto an ice-cold solution of CHZN2 (prepared from Diazald~ , 9 g, 42 mmol) in Et20 and the resulting mixture allowed to raarm to room temperature and stirred for 90 min., The reaction was quenched with AcOH (x 5), basified (5a KHC03) and extracted with EtOAc (x 3). The combined organic phases were washed with water, then sat .
brine, filtered (Whatman° 1 PS phase separator) and concentrated in vaauD. The crude oil was purified by flash chromatography ors silica gel (eluant EtOAc: 40-60 pet: ether, 5:95 v/v) to give diazomethyl diethylmethyl ketone as a pale yellow liquid (261 mg, 1.86 mmol). To a solution of this diazoketone in EtOAc (10 ml) at room temperature was added a saturated solution of HBr in EtOAc portionwise until no more nitrogen was evolved.
The reaction was basified (5o KHC03) and extracted with EtOAc (x 2). The combined organic phases were washed with water, sat. brine, filtered (Whatman° 1 PS phase separator) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel ~U~STITtJTE SHEET

W~ 93f16999 P~'T/G893/04404 (eluant gradient of EtOAc: 40-60 pet. ether, 4:96 to 10:90 v/v) to give the title ketone as a pale brown mobile oil (268 mg, 7.70).
NMR (CDC13) (for the major rotamer 88.8%). b 3.95 (2H, s); 1.56 - 1.46 (4H, m); 2.75 - 2.65 (1H, m); 0.91 - 0.85 (6H, m).
3B (3RS)-3-Benzvloxycarbonylamino-1 diethylmethylcarbonylmethyl-2,3-dihydro-5-ohenyl-1H-1,4 benzodiazepin-2-one (Scheme 1, step (i)) This was prepared following the method of Example TB
using the Bock benzodiazepine (3.56 mg, 0.925 mmol), sodium hydride (39 mg of 80% dispersion in,oil, 1.3 mmol) and the bromomethylketone of Example 3~i (268 mg, 1.4 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 40-60 pet.
ether 25:85 vJv) to give the title benzodiazepine as a colourless ail (351 mg).
Rf (EtOAc: 40-60 pet. ether 40:60) 0.35.
NMR (CDC13) b 7.64 - 7.13 (14H, m) ; 6.67 (1H, d, J =
8.25 Hz) ; 5.43 (1H, d, J - 8.25 Hz) ; 5.27 (2H, s); 5.15 (1H, d, J = 18 Hz); 4.78 (1H, d, J = 18 Hz) ; 2.45 - 2.35 (1H, m) ; 1 .76 - 1.42 (4H, m) ;
0.90 - 0.85 (6H, m).
3C_- N-((3RS)-1-Diethylmethvlcarbanvlmethvl-2,3-dihvdro-2-oxo-5- hen 1-1H-1 4-benzodiaze in-3- 1 -N'- 3-methylphenvl) urea. (Scheme 1, std (ice ) This was prepared following the method of Example 1C
using the benzodiazepine of Example 3B (351 mg, 0.68 mmol), 5% palladium-on-carbon (350 mg) and m-tolyl isocyanate (87 ~.1 0.71 mmol) . The crude product was purified by flash chromatography on silica gel (eluant ~U~~TITUTE SHEET

PtT/ G 893100404 1~~ 93/ Z 6999 ~ ~ ~ .' ~ ~ ~ ii EtOAc: 40-60 pet. ether 35:65 v/v) to give the title compound as a white solid (229 mg, 680, >99o pure by HPLC ) .
Rf (EtOAc:40-60 pet. ether 40:60) 0.24.

NMR (CDC13)b 7.66 - 6.80 (15 H, m); 5.66 (1H, d, J =

8 Hz) 4.73 (1H, d, J 18 Hz) ; 4.64 (1H, d, J
; =

-- 18 ) ; 2.49 - 2.31 m) ; 2.26 (3H, s) ; 1.?1 Hz (1H, - 1.39 (4H, m) ; 0.86 81 (6H, m) .
- 0.

M.S. (FAB, (M+H).
+ve ion) m/e 497.3 N- 3RS -1- c1o ent lcarbon Imeth 1-2 3-di.h dro-2-oxo-5 phen~rl-1H-1.4-benzadiazenin-3-yl)-N'-f3-methyl~henyl) urea. Compound 4 4A ~3romomethvl cvclopentyl ketone (Scheme 2, stns i) - (iii) ) This was prepared following the method of Example 3A.
The intermediate diazoketone was prepared from cyclopentanecarboxylic acid (2.05 g, 18 mmol), thionyl chloride (5.2 ml, 72 mmol) and CHZNZ (generated from Diaz~ld~ 9g, 42 mmol) and purified by flash chromatography on silica gel (eluant EtOAc: 40-60 pet.
ether 15:85 v/v). The diazoketone was subsequently treated with a saturated solution of HBr in EtOAc . Flash chromatography on silica gel (eluant gradient EtOAc: 40-60 pet. ether 4:96 to 10:90 v/v) afforded the title ketone as a, pale brown mobile oil (1. 29 g, 3°7 0 ) .
NMR (CDC13) b 3 . 99 (2H, s) , 3.18 (1H, q, J = 8 Hz) , 1.93 - 1.56 (8H, m).

WC3 93/16999 ~CT/GB93/00404 4B (3RS)-3-Benzvloxvcarbonylamino-1-cyclopentylcarbonylmethvl-2 3-dihydro-5-phenyl-1H-1 4=
benzodiazebin-2-one. (Scheme 1 step (i)) This was prepared following~the method of Example 1B, using the Bock benzodiazepine (578 mg, 1.5 mmol), sodium hydride (63 mg of an 80% dispersion in oil, 2.1 mmol) and the bromomethylketone of Example 4A (431 mg, 2.25 mmol).
The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 40-60 pet. ether 30:70 v/v) to afford the title compound as a colourless crystalline solid (682 mg, 88.5%).
Rg (EtOAc: 40 - 60 pet. ether, 40:60} 0.25.
NMR (CDC13) b 7.64 - 7.17 (14H, m} ; 6.60 (1H, d, J =
8.25 Hz) ; 5.42 (1H, d, J = 8.25 Hz) ; 5.14 (2H, s) ; 4.78 (1H, d, J = 17.8 Hz) ; 4. 63 (1H, d, J =
17.8 Hz); 2.92(1H, q, J - 8 Hz); 1.85 - 1.55 ( 8H, m} .
4C N-((3RS)-1-Cyclopentylcarbonylmethyl-2 3-dihydro-2 oxo-S-phenyl°1H-1 4-benzodiazepin-3-girl) -N' - (3 methwlphenyl) urea. (Scheme 2 step (ii)) This was prepared following the method of Example 1C
using the benzodiazepine of Example 4B (680 mg, 1.32 mmol), 50 palladium-on-carbon (600 mg) and m-tolyl isocyanate (169 ~1, 1:39 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc; 40-60 pet: ether 35:65 v/v) to give the title compound (463 mg, 71%).
The title compound was re-crystallised from hot methanol to give 161.8 mg of crystalline solid (>99% pure by HPLC) .

~V~ 93/ 16999 (EtOAc: 40-60 pet. ether, 40:60) 0.16.
~R _(CDC13) b 7.66 - 6.80 (15H, m); 5.65 (1H, d, J - 8 Hz) ; 4.74 (1H, d, J - 18 Hz) ; 4.67 5 (1H, d, J - 18 Hz); 2.95 - 2.83 (1H, m);
2.28 (3H, s) ; 1.90 - 1.53 (6H, m) .
M.S. (FAB a-ve ion) m/e 495.2 (M+H) .

N- 3RS -1- clohe t lcarbon lmeth 1-2 3-dih dro-2-oxo-5-hen l-1H-1 4-benzodiaze ine-3- 1 -N'- 3-meth 1 hen l urea Compound 6 5A Bromomethyl cyclohept~l ketone (Scheme 2, steps (i) ..
(iii)) This was prepared following the method of Example 3A.
The intermediate diazoketone was prepared w from cycloheptanecarboxylic acid (3g, 21 mmol), thionyl chloride (6:24 ml, 84 mmol) and CHZNZ (generated from Diazald° 12 g, 56 mmol) and purified by flash ch~~matography on silica gel (eluant EtOAc: 40-60 pet.
ether, 10:90 v/v). The diazoketone was subsequently treated with a saturated solution of HBr in EtO~lc . Flash chromatography on silzca gel (eluant gradient EtOAc: 40-60~pet: ether, 5:95 to 10:90 v/v) gave the title ketone as a brown oil (1.8 g, 8.22 mmol, 390).
~R (CDC13) b 3:98 (2H, s); 2.95 - 2:85 (1H, m); 2.93 - 1.SO) (12H, m).
5B (3RS)-3-Benzyloxycarbonylamino-1~
cycloheptylcarbonylmethvl- -2 3-dihydro-5-~henyl-1H-l.4-benzodiazepin~2-one (Scheme 1, stets (i)) This was prepared following the method of Example 1B, using the Bock benzodiazepine (578 mg, 1.5 mmol) , sodium hydride (63 mg of an 80o dispersion in oil, 2.1 mmol) and WO 93l1b999 PCTlGB93IOOa04 ..
the bromomethylketone of Example 5A (493 mg, 2.25 mmol).
Reaction was complete after 30 min.
The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 40-80 pet. ether, 40:60 v/v) to afford the title compound as a colorless crystalline solid (764 mg, 930).
Rf (EtOAc: 40-60 pet. ether 40:60) 0.3.
NMR (CDCl~) b 7.64 - 7.13 (14H, m) ; 6.64 (1H, d, J =
8.25 Hz) ; 5.42 (1H, d, J - 8.25 Hz) ; 5.14 (2H, s) . 4 .79 (1H, d, J = 17.5 Hz) ; 4.63 (1H, d, J
17.5 Hz); 165 - 2.65 (1H, m); 1.93 - 1.28 (12H, m) .
5C N-((3RS)-1-Cycloheptylcarbcnylmethyl-2.3-dihydro-2-oxo-5-:phenyl-1H-1,4-benzodiaze~in-3 =yl)-N'- (3-m~thylphen~rl ) urea . (Scheme 1, step ( i~. ) ) This was prepared following the method of Example 1C
using the benzodiazepane of Example 5B (787 mg, 1.5 ;.
mmol), 5% palladium-on-carbon (600 mg), and.m-tolyl isobyanate (0.20 ml; 1.58 mmol). The crude product was purified by flash chromatography on silica gel (eluant 2S EtOAc: 40-60 pet. ether 30:70 v/v) to afford the title compound as a white solid (53.6 mg, 10%, >98o pure by HPLC) .
R~ (EtOAc: 40-60 pet. ether 40:60) 0.27.
M.S: (FAB, +ve ion) m/e 523.3 (I~i+H) .

N-~ 3RS)-1-Cycloheptylcarbonylmethyl-2,3-dih~ydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'~s3-chloro~he~l) urea. Compound 7 (Scheme 1, step (ii)) r SugSTtTUTE SHEET

hCT/G B93100404 This was prepared following the method of Example 1C
using the benzodiazepine of Example SB (764 mg, 1.41 .
mmol), 5o palladium-on-carbon (600 mg) and m-chlorophenyl isocyanate (180 ~cl, 148 mmol). The crude product was purified by re-crystallisation from hot EtOAc to give the title compound as a white crystalline solid (379 mg, 69 . 8 0 ) ( >99% pure by HPLC) .
NMR (CDC13) b 7.68 - 6.89 (15H, m) ; 5.64 (1H, d, J =
$.Hz); 4.74 (1H, d, J=18 HZ); 4.66 (1H, d, J = 18 Hz); 2:60 2.52 (1H, m); 1.92 - 1.22 (12H, m).
M.S. (FAB +ve ion) m/e 543.1 (M+H).
EXAMPLE ?
N- (3RS)-1-Cyclohexvlcarbonvlmethyl-2.3-dihydro-2-oxo-5-phenyl-1H-1 '4-benzadiazepin-3-~l) -N' - (3-meth~,rlt~henyl) urea. Compound 5.
7A Bromometh 1 c clohe 1 ketone Scheme 2 ste s i -(iii)) Thzs wa.s prepared according to the method of Example 3A.
The diazoketone wasprepared from cyclohexane carboxylic acid (1.92 g, 15 mmol), thionyl chloride (4.46 ml, 60 mmol) and diazometha:ne (generated from Diazald~ 7.16 g, 33.4 mmol). Without purification the diazoketone was treated with a saturated solution of HBr in ethyl aeetate until nitrogen ceased to be evolved. Chromatography on sil~,ca gel (eluant Et~Ac: pet. ether 5:95) provided the title compound as a yellow oil (0.91 g, 30%).
NMR (CDC13) b 5 4.00 (2H, s); 2.75 (1H, m); 1.95 1.20 (10H; m) .
~ ~S~°'~~~~

. ,.s,. .
.., .'...,:. - -.:. ". ,.. t~~ ., ;.; . :' ::... , ., ~,-~< . '.'...,: . ~:.n ~~.~ ~~~~ . , W~ 93116999 PCT/GB9311)U404 ?B (3RS)-3-Benzyloxycarbonylamino-1-c~rclohexylcarbonylmethyl-2.3-dihydro-5-phenyl-1H-1.4=
benzodiazepin-2-one. (Scheme 1. step (i~
This was prepared following the method of Example 1B
using the Bock benzodiazepine (385 mg, 1.0 mmol) , sodium hydride (42 mg, 80o dispersion in oil, 1.4 mmol) and the bromomethyl ketone of Example ?A (308 mg, Z.5 mmol). The 20 product was purified by flash chromatography (eluant EtOAc: 40-60 pet. ether, 35:65, v/v) to give the title compound as a colourless solid (490 mg, 96%)., Rf (EtOAc: 40-60 pet. ether 40:60) 0.3.
NMR (CDC13) b . 7. 8 - 7.2 (14H, m) ; 6.65 (3.H, d, J =
8.2 Hz) ; 5.42 (1H, d, J = 8.2 Hz) ; 5.18 (2H, s) 4.72 (2H, d, J -- 7.5 Hz) : 4.61 (2H, d, J = 7.5 Hz) ; 2.40 (1H, m) ; 1.9 - 1. 0 (1C7H, m) .
7C N-((3RS)-1-Cyclohexylcarbonymethyl-2.3-dihydro-2-oxo-5-ahenyl-1H-1.4-benzodiazepin-3-vl)-N°-(3-methylphen_yl ) urea . Scheme 1, step ( i i ) ) This was prepared fo~.lowing the method of Example 1C
using the benzadiazepi.ne of Example 7B (480 mg, 0.945 mmol), 5o palladium-on-carbon (ca. 400 mg) and m-tolyl isocyanate (O.I30 ml, l mmol). The crude product was purified by flash chromatography (eluant EtOAc: 40-60 petrol, 35:65, v/v) and by crystallisation from ethyl acetate/petrol to provide the title benzodiazepine as~,a colourless solid (245 mg, 52%, >98o~pure by HPLC).
Rf (EtOAc: 40-60 pet. ether 40:60) 0.32.
NMR (CDC13) b 7.? (2H, d, J = 8 Hz) ; 7.65 - ?.00 (12H, m); 6.88 (1H, d, J = 7 Hz); 5.62 (1H, d, J = 8 Hz) ; 4.67 (2H, s) ; 2.39 (1H, m) ; 2.21 (3H, s) ;
SU~S"f I'~UTE SHEET

WO 93/16999 P(.'T/GB93/Ofl404 1 . 9 - 0 . 8 ( lOH, m) .
M.S. (FAB +ve ion) m/e 509 (M+H).

N-((3RS)-2,3-Dihydro-2-oxo-S-phenyl-1-((2S)-2-pyrrolidylcarbanYlmethyl)-1H-1.4-benzodiaze~in-3-yl)-N'-(3-meth~'lphenyl) urea hydrochloride. Compound 15 1.0 8A (2S) -1-tent-Butyloxvcarbon~l-2 pyrrolidyl diazomethyl ketone (Scheme 2, steps (i) - (ii)) To a solution of Boc-L-proline (5.5 g, 25.6 mmol) and N-' methylmorpholine (3.1 ml, 28.2 mmol) in dry THF (80 ml) at -20°C was added isobutyl chloroformate (3.5 ml, 27.~
mmol) . The mixture was stirred at -10°C for Z hr and then poured into an ice-cold solution of CHZN~ (prepared from Diazald° , 18 g, 84 mmol) in Et2o, and the resulting mixture was allowed to warm to room temperature over 2 hrs. Excess CHaN2 was quenched with glacial AcOH and the resulting solution then basified with 5% aqueous KHCO~
solution and extracted with EtOAc. The organic phase was ' separated, washed with water and brine, filtered (Whatman~ 1 PS ,phase separator), and concentrated in vacuo. '.Che crude product was purified by flash chromatography on silica gel (eluant EtOAc: 40-60 pet.
ether 35.65 v/v) to give the title compound used immediately in the next stage.
Rf (EtOAc: 40-60 pet. ether 30:70) 0.22.
8B (2S)-1-tert-Butyloxycarbonvl-2=pvrrolidyl bromomethyl ketone. (Scheme 2, step (iii)) To a stirred solution of the diazoketone of Example 8A in EtOAc was added a saturated solution of HBr in EtOAc dropwise until no more nitrogen was evolved. The e~l.~~~T'~~~~ ~H~~

,,., , , ; :-~: -:.. .. .. ..: ,.. . , . . :: , . .:..: . : :; ,.;::_. .,.., ;
.
WO 93/16999 P~ T/GB93/0040n resulting solution of bromomethylketone was washed successively with saturated KHC03, water and brine, filtered (Whatman° 1 PS phase separator), and concentrated az~ vacuo. The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 40-60 pet . ether 15 : 85 v/v) to give the title ketone as a brown oil (1.25 g, 17s far two steps).
Rf (EtOAc: 40-60 pet. ether 20:80) 0.2.
NMR (CDC13) $ 4 .66 - 4.49 (1H, broad m) , 4.1 - 4 .0 (2H, broad m), 3.73 - 3.50 (2H, broad m), 2.40 _ 1.67 (4H, m), 2.46 and 1.44 (9H, 2 singlets).
8C (3RS) -3-Ben~loxycarbonylamino-1- ~ (2S) -tent butyloxycarbonvl-2-xayrralid~lcarbonvlmethyl)-2 3-dihydro 5~tahenvl-1H-1,4-benzodiazepin-2-one. (Scheme 1 step (i)) This was prepared following the method of Example 1B
using the Bock benzvdiazepine (1.2 g, 2.97 mmol) , sodium hydride (125 mg of an 80% dispersion in oil, 4.2 mmol) and the bromometh~.~lketone of Example 8B (1.25 g, 4.46 mmol ) .
The product was purified by flash chromatography on silica gel (eluar~t EtOAc: 40-60 pet. ether 35:65 v/v) to give the titl a compound (798 mg, 450).
NMR (CDC13) b 7.62 - 7.18 (14H, m) , 6.65 (1H, d, J =
8 Hz), 5.42 (lH, d, J = 8 Hz), 5.14 (2H, s), 4.95 - 4.72 (1H, m), 4.64 - 4.40 (1H, m), 4.38 - 4.28 (1H, m) , 3. 60 - 3.44 (2H, m) , 2.23 - 1.82 (4H, m) , 1.44 (9H, s) .
8D N- ( (3RS) -1- ( (2S) -tert-Butyloxycarbonyl-2-rrolid lcarbon lmeth 1 -2 3-dih dro-2-oxo-5- hen 1-1H-1,4-benzodiazex~in-3-yl)-N°-(3-methylphenyl) urea.
(Scheme 1~ Step (iii) Pc~lcB93looao4 W~ 93!16999 This was prepared following the method ofExample 1C
using the benzodiazepine of Example 8C (798 mg, 1.33 mmol), 5% palladium-on-carbon (ca 600 mg) and m-tolyl isocyanate (180 ~1, 1.4 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 40:60 pet, ether 45:65 v/v) to give the title compound as a colourless oil (559 mg, 71.1 %).
NMR (CDC13) b 7.65 - 6.81 (15H, m), 5.66 (IH, d, J =
9 Hz), 4.97 - 4.56 (2H, m), 4.40- 4.25 (1H, m), 3.56 - 3.38 (2H, m), 2.27 (3H, s), 2.21 -1.86 (4H, m), 1.44 and 1.42 (9H, 2 singlets).
8E N-((3RS)-2.3-Dihydro-2-oxo-5-phenyl-1-((2S)-2-'t~Yx'rolidylcarbonylmethy_1-1H-1,4-benzodiazet~in-3-yl) -N' -S3-methylphenyl) urea hydrochloride The Boc-protected compound of Example 8D (559 mg, 0.95 mmol) was dissolved in HCl-dioxan (4M, XS) and stirred at roam temperature for 30 min. The solution was concentrated in vac~ao, azeotroping twice with dry toluene to remove last traces of dioxan. The residue was ~;
crystallised from chloroform/ether to provide the title salt as a white solid (245 mg, 48.50, > 98% pure by 2 5 HPLC ) .
Rf (CHC13: MeOH: AcOH, 12:2:1) 0.32.
M. S . - (FAB, +ve i~an) m/e 495 . 2 (M+H) .

N- 3RS -1- 2S -2-Acet 1-2- rrolid !carbon !meth 1-2 3-dih~dra-2-c~xo-5-phenyl-IH-1.4-benzodiazepin-3-yl)-~T'-(3-methyl~phenyl) urea. Compound 17 To a solution of the benzodiazepine salt of Example 8E
(166 mg, 0.32 mmol) in CHZC12 at O°C under an atmosphere E,~~STiTUTE SHEET .

. .
WO 93/16999 PCZ'/GB93/00404 of nitrogen was added DIEA (0.11 ml, 0.63 mmol) followed by acetylchloride (22 ~.1, 0.32 mmol). Reaction was complete after 10 mires. The mixture was concentrated in vacuo and the residue partitioned between CHZC12 and 0.3 M KHS04. The organic phase was separated, dried (NaZSOg}, filtered (Whatmanp 1 PS phase separator) and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (eluant EtOAc . AcOH, 100:2 v/v) to give a white solid which was taken up in acetonitrile/water and lyophilised to give the title compound as a white powder (148 mg, 89%, >99% pure by HPLC } .
NMR (CDC1~) b 7.91 - 6.95 (14H, m} , 6.76 (1H, m} , 5. 68 - 5.62 (1H, m)~ 4.94 - 4.43 (3H, m), 3.48 - 3.35 1S (2H, m) , 2 .35 (1H, s) , 2.23 (3H, s) , 2 .1 - 1 . 79 ( 6H, m) .
M. S . (FAH, -ws ion) m/e = 538 . 3 (M-~H) .

N- ( l3RS)~2.3-Dih~ro-2-oxo-5-ghenyl-1- f~2R) -2-p~rrrolidvlcarbonylmeth_.yl) -IH-1.4-benzodiazepin-3-yl) -N°(3-methyl-phenyl) urea hydrochloride. Compound 14 10A (2R) -1-tert-But~,rloxycarbonyl-2 pyrrolidyldiazomethyl ketone. (Scheme 2, steps (i) iii This was prepared following the method of Example 8A
usiazg, Boc-D-proline (4 g, 19.4 mmol}, NMM (2.1 ml, 19.4 mmol) and isobutyl chloroformate (2.7 ml, 20.5 mmol).
Flash chromatography on silica gel (eluant EtOAc: 40 - 60 pet. ether 35:65 v/v) afforded the title compound as an oil (1.68 g, 38%).
NMR (CDC13} b 5.45 (1H, d, J = 23 Hz) , 4 .24 (1H, d, J
- 23 Hz}, 3.51 - 3.43 (2H, m), 2.19 - 1.83 (4H, a~ l~
WO 93/16999 PCI'1~893/00404 m), 1.47 and 1.43 (9H, 2 singlets).
10B (2R) -1-tart-Butyloxycarbonyl-2-pyrrolidyl bromomethyl ketone. (Scheme 2, step (iii)) This was prepared following the method of Example 8B
using the diazoketone of Example 10A (1.68 g, 7.4 mmol).
The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 40-60 pet. ether 20:80 v/v) to give the title ketone as a brown oil (986 mg, 47.5%).
Rf (EtOAc: 40-60 pet. ether 20:80) 0.19.
lOC (3RS) -3-Benzyloxycarbonylamino-1- ( (2R) -1- tart- ...
butyloxycarbonyl-2-pyrrol~.dylcarbonylmethyl-2,3-dihydro-5-phenyl-1H-1~4-benzodiazepin-2-one. (Scheme 1, step This was prepared following the method of Example 1B
using the Bock benzodiazepine (950 mg, 2.35 mmol) , sodium hydride (99 mg of an 80% dispersion i2 oil, 3.29 mmol) and the bromomethylketone of Example lOB (986 mg, 3.57 mmol). The product was purified by flash chromatography on silica gel (eluant EtOAc: 40-60 pet. ether 40:60 v/v) to give the title compound (1.3 g, 92%).
NMR (CI?C13) b 7.62 7.18 (14H, m) , 6.68 (1H, d, J
8 Hz) , 5.43 (1H, d, J - 8 Hz) , 5.14 (2H, s) , 5.09 -- 4.8 (1H, m) , 4 .65 - 4 .4 (1H, m) , 4.37 4.27 (lH, m), 3.49- 3.44 (2H, m), 2.22 - 1.85 (4H, m) , 1.43 (9H, s) .
lOT7 N- ( (3RS) -1- ( (2R) -1-tart-Butyloxycarbony,l-2-rrolid lcarbon lmeth 1 -2 3-dih dro-2-oxo-5- hen 1-1H-1~4-benzodiazeoin-3-yl)-N'-(3-methylphenyl~, urea.
(Scheme 1 step (ii)) SiJE3STlTUTE SHED t' WO 93f 16999 PC'1'/GB93I00404 This was prepared following the method of Example 1C
using the benzodiazepine of Example 10C (394 mg, 0.65 mmol), 5% palladium-on-carbon (ca 200 mg) and m-tolyl isocyanate (88 ~1, 0.68 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc: 40-60 pet. ether 40-60 v/v) to afford the title compound as a crystalline solid (175 mg, 65%).
NMR (CDC13) b 7.63 - 7.0 (13H, m) , 6.97 - 6.78 (1H, l0 m) , 5.64 (1H, d, J = 10 Hz) , 4. 8 - 4 .7 (2H, m) , . 4 .37 - 4.08 (1H, m) , 3.48 - 3.37 (2H, m) , 2.24 (3H, s), 2.05 (3H, s), 2.2 - 1.76 (4H, m), 1.49 - .
1.34 (9H, 2 singlets).
10E N- ( (3RS) -2 3-Dih>rdro-2-oxo-5-phenyl-1- ( (2R) -2-~yrrolidylcarhonylmethyl)--1H-1 4-benzodiazepin-3-,~1)-N'-(3-methvlphenvl) urea hydrochloride This was prepared following the method of_- Example 8E
using the benzodiazepine of Example lOD (175 mg, 0.3 mmol). ~ The crude product was taken up in AcOH and 2yophilised to give the title compound, without purification, as a white powder (125 mg, 780, >99% pure b~, HPLC ) .
M.S. (F'AE, kve ion) m/e = 496.2 (M+H) .

N- 3RS -1- 2R -J.-Acet 1-2- rrolid lcarbon lmeth 1 -2.3-dihvdro-2-oxo-5-phenyl-1H-1 4-benzodiaze°nin 3 yl) N' ( 3 -meth~phen~rl ) urea . Compound 16 This was prepared following the method of Example 9 using the benzodiazepine salt of Example l0E (244 mg, 0.46 3S mmol), DIEA (0.16 ml, 0.92 mmol) and acetyl chloride (32.7 ~.1, 0.46 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc: AcOH, ~S~~S'TITUTE ~H~E'T

w'O 93/16999 PCT/GB93/00404 100:2 v/v) to give the pure product which was then taken up in glacial AcOH and lyophilised to give the title compound as a white powder (173 mg, 700, >99% pure by HPLC} . ..

M.S. (FAB, +ve ion} m/e = 538.3 (M+H). , N-((3RS)-1-((2RS)-2-Cyclopentyl-2-hvdroxyethyl)-2.3 10 dihydro-2-oxo-5-phenyl-1.H-1.4-benzodiazep~.ne-3-yl)-N'-(3 methYlphen~rl) urea. Compound 18 and N- 3RS -1- 2SR -2-C clo ent l-2-h drox eth 1 -2 3-dihydro-2-oxo-5 :,phenyl--1H-2 , 4-benzodiaz~ine-3 yl) -N' - (3-methZrlphenyl ~, urea . Compound 19 20 To a solution of the benzodiazepine of Example 4C d240 mg, 0.49 mmol) in ethanol at C3°G was added sodium ,w , borohydride (29 mg; 0.76 mmol) . The resulting mixture was stirred at O°C fox 30 minx and then at roam temperature for a further 90 minx. The mixture was concentrated in 25 vacuo and the residue flash chromatographed on silica gel (eluant EtOAc: 40-60 pet. ether 35:65 v/v) to afford two compounds. Each was taken up in acetonitrile/water and lyophilised to give the title compounds.
30 Less polar ~raduct: 66 mg, 260 >98o pure by HPLC
R~ (EtOAc: 40-60 pet. ether 35:65 ) 0.14 NMR (CDC13) b 7.74 - 6.90 (14H, m}, 6.78 (1H, d, J
- 8 Hz), 5.62 (1H, d, J = 8Hz), 4.41 - 4.34 35 (1H, m), 3.65 - 3.55 (2H, m), 2~22 (3H, s), 1:67-1.13. ( 9H, m) .
M.S. (FAB, +ve ion} 497.2 (M+H}
~UB~~~~U~E ~

it~t.~JusJ'~
W~ 93/ i 6999 PCT/G 893/00404 More polar t~roduct: 95 mg, 380, >96a pure by HPLC
Rf (EtOAc: 40-60 pet. ether 35:65) 0.10 NMR (CDC13) cS 7.73 - 7.0 (14H, m) , 6.87 - 6.78 (1H, m) , 5.59 - 5.56 (1H, d, J = 8 Hz) , 4. 05 - 3 .70 (3H, m), 2.24 (3H, s), 1.76 - 1.14 (9H, m).
M.S. (FAB, +ve ion) 497.0 (M+H) ' EXAMPLE 7.4 N- 3RS -1- clo ent lcarbon lmeth 1-2 3-dih dro-2-oxo-5-(2-~avridvl) -1H-1, 4-benzodiazegin-3-girl) -3~1' - (3-meth~rlphenyl ) urea. Compound 8 .
14A (3RS)-3-Benzvloxvcarbonylamino-1 c~rclo7~entylcarbon~lmethyl-2 3-dihydro-2-oxo-5- (2 pYridyl)-1H-1,4-benzodiazenin-2-one. (Scheme 1 stet To a stirred solution of (3RS)-3-benzyloxycarbonylamino 2,3-dihydro-5-(2-pyridyl)-aI3-1,4-benzodiazepin-2-one (R. M. Freidinger e~ a~. Eur. Pat. No. 0 434 364 A2) (388 mg, ~. mmol) ~.n DMF (5 ml) , cooled to -10°C under N2, was added sodium hydride (42 mg of 80o dispersion in oil, 1.4 mmol). The mixture was stirred at -10°C for 30 min, when a solution of the bromomethyl ketone of Example 4A (250 mg, 1.4 mmol) wad added. The resulting mixture was allowed .to warm to room temperature over 1 hr with st~.rring, then poured ,into dilute aqueous HCI (100 ml) .
The mixture was extracted twice with EtOAc and the organic extracts washed with brine, filtered (Whatman° 1 PS phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluant EtOAc/40-60 pet. ether 90:10 v/v) to give the title compound as a colourless solid (426 mg, 86~).
R~ (EtOAc) 0.35 NMR (CDC13) b 8.62 (1H, d, J = 8 Hz) , 8.17 (1H, d, J
~UE~~TITLJT~ ~H~~T

~ fj i ~. ?.i ~ cl ~ ~i WO 9:3/16999 PCT/GB93/00404 8 Hz) , 7.78 (1H, t, J = 8 Hz) , 7.50 (1H, t, J
8 Hz), 7.4 - 7.15 (9H, m), 6.76 (1H, d, J = 8.5 HZ), 5.51 (1H, d, J = 8.5 HZ), 5.16 (2H, m), 4.80 (1H, d, J - 17.5 Hz) , 4.42 (1H, d, J=17.5 Hz) , 2.92 (1H, m) , 1.9 - 1.5 (8H, m) .
14B N-((3RS~-1-CYclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5- (2-pyridyl) -1H-1, 4-benzodiazepin-3-yl) -N' - (3-meth~rlphenvl ) urea . ~ Scheme 1, step ( ii ) L
The benzodiazepine of Example 14A (426 mg, 0.86 mmol) was treated with 40% HBr in acetic acid (6 ml) and the mixture stirred at room temperature for 2 hrs. The mixture was azeotroped twice with toluene and the residue partitioned between EtOAc and 1 M NaOH: The organic portion was filtered (Whatman° 1 PS phase separator), evaporated, taken up in GH2Clz (5 ml) and treated with m-t~lyl isocyanate (130 ~,1, 0.95 mmol) at room temperature with stirring for 2 hrs. The mixture was evaporated and chromatographed (eluant EtOAcj40-60 pet. ether 70:30 v/v) to provide a yellow solid which was recrystallised from . ~' acetonitrile to give the colourless product (73 mg, 17%).
Rf (EtOA.c/Hexane, 60:40 v/v) 0.38 NMR (CDC13) b 8.6 (1H, d, J = 6 Hz, 7.95 (1H, d, J =
6 Hz), 7.6 - ?.0 (lOH, m), 6.80(1H, d, J = 8.5 Hz), 5.78 (1H, d, J = 8.5 Hz), 5.10 (1H, d, J =

14 Hz) , 5: 00 (1H, d, J = 14 Hz) , 2. 82 (1H, m) , 2.14 (3H, ~). 1.90 - 1.50 (8H, m).
. 30 M.S. (FAB, +ve ion) m/e. 496.3 (M+H) N-((3-RS)-1-Cyclot~entylcarbonylmethvl-2,3-dihydro-2-oxo-5-(4-pyridvl)-1H-1,4-benzodiazepin-3-vl)-N'-(3-methy~henY,l ) urea . Compound 10 .
~l.~~S'TIT~.!'TE SHED t' ~1~J~J~i.~
~~ 93/ i 6999 PCT/GB93/00404 38 , 15A (3RS)-3-Benzyloxycarbonylamino-1-~clopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-(4-pyridyl)-1H-1~4-benzodiazepin-2-one (Scheme 1, step (i)) A solution of (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(4-pyridyl)-1H-1,4-benzodiazepin-2-one (Freidinger et a1. Eur. Pat. No. 0 434 364 A2) (388 mg, 1 mmol) was alkylated as described in Example 14A to provide the product as a colourless solid after chromatography (eluant EtOAc) (460 mg, 930).
R~ (EtOAc) 0.22 NMR (CDC13) b 8.62 (2H, d, J = 7.5 Hz) , ?.55 (3H, m) , 7.4 - 7.1 (BH, m), 6.80 (1H, d, J = 8.5 Hz), 5.42 (1H, d, J = 8.5 Hz), 5.12 (2H, s), 4.72 (2H, m), 2.85 (1H, m) , 1.9 - 1.4 (8H, m) .
15B N-((3RS)-1- clopentylcarbonylmethyl-2,3-dihydro-2 a~o_5-- (4-yyr~dYl? °1H-1, 4-benzodiazepin-3- 1~) -N' - C3 methylphenyl) urea. (Scheme 1 stez~ (ii)) The benzodiazepine of Example 15A (375 mg, 0.724 mmol) was converted to the urea as described in Example 14B.
Tie product was chromatographed (eluant CHC13/MeOH/AcOH
200:2:1 v/v/v) to give a white solid (59 mg, 16%).
Rf (EtOAc) 0.30 NMR (CDC13} b 8.62 (2H, d, J = 7.5 7.7 - 7.0 11H, Hz) , m) , 6. B (1H, m) , .62 (1H, d, 8. 5 Hz) , 4 . 85 5 J =

(1H, d, J = 16 HZ}, 4.60 (1H, d, = 16 Hz), 2.80 J

(1H, m), 2.15 (3H, s), 1.8 - 1.4 (8H, m).

M.S. (FAB, +ve ion) m/e 496.2 (M+H}

N~((3RS)-7.-Cvclopentvlcarbonylmethvl-2 3-dihydro-2-oxo-5-phenyl-1H-1, 4-benzodiaze~in-3-~N' - (3-carboxy~henyl) SIJ~~TtTUTE SHEE'i' WO 93/1fr999 PCT/C~B93/004U4 ' 39 ,:w urea. Compound 11 16A (3RS) -3-a~-Nitroben~loxycarbonvlamino-1-cyclo~entylcarbonylmethyl-2.3-dihydro-2-oxo-5-phenyl-1H-1,'4-benzodiazepin-2-one. (Scheme 3, step (i)) The benzodiazepine of Example 4B (2.04 g, 4.1.3 mmol) was hydrogenated over 5% palladium-on-carbon catalyst (1.2 g) as described in Example LC. The amine was taken up in dry THF' (15 ml) and triethylamine (0.626 ml, 4.5 mmol) and the solution cooled to O°C. The stirred mixture was treated with p-nitrophenyl chloroformate (0.91. g, 4.5 mmol) and stirred at room temperature for 1 hr, then evaporated and flash chromatographed (eluant EtOAc/Hexane 40:60 v/v) to provide the product as a yellow solid (675 mg, 32 d ) .
Rf (EtOAc/Hexane, 60:40 v/v) 0.52 NNiR ( CDC13 ) b 8 . 2 ( 2H, d, J - 8 Hz ) , 7 . 6 - 7 . 0 (22H, m), 5.42 (1H, d, 8.5 Hz), 4.82 (1H, d, J = 16.5 Hz), 4.62 (1H, d, J = 16.5 Hz), 2.9? (1H; m), 1.9 - 1.4 (8H, m).
16B N-((3RS)-1-cyclot~entylcarbonylmeth~l-2,3-dihydro-2-oxo-5-nhenvl-1H-1.4-benzodiazepin-3-yl~,-N'-(3-carboxyphenyl) urea. (Scheme 3. step (ii)) To a stirred solution of the benzodiazepine of Example 16A (175 mg, 0.333 mmol) in DMF (5 ml) was added m-aminobenzoic acid (72 mg, 0.52 mmol) and triethylamine (125 ~.l). The mixture was stirred at 45°C for 18 hrs, cooled and diluted with EtOAc. The mixture was washed with 0.3 M HC1 and brine, then filtered (Whatman~ 1 PS
phase separator) and evaporated. The residue was flash chromatographed (eluant EtOAc/Hexane/acetie acid 60:40:2 v/v/v) to provide the title compound as a colourless solid (232 mg, 760).

2~.~a~~~i~ ~ ~ .
!A'O 93/ 16999 PCd'/G X93/00404 Rf (EtOAc/Hexane/acetic acid 60:40:2 v/v/v) 0.25 NMR (CDC13) b 8.41 (1H, s), 8.37 (1H, d, J = 7.5 Hz}, 8.16 (1H, d, J = 7.5 Hz), 7.82 (1H, s) , 7.7 - 7.2 (12H, m) , 5.65 (1H, d, J
- 8.5 HZ), 5.81 (1H, d, J = 15 Hz), 4.66 (1H, d, J = 15 Hz) , 2.95 (1H, m) , 1.95 - 1.5 (8H, m) .
M . S . ( FAB , +ve i on ) m/ a 419 ( M+Na - HZNC6H~ COaH ) N-~ (3R) -1-CSrcIopentylcarbonylmethy_1-2 3-dihydro-2-oxo-5-phenvl-1H-1,4-benzodiaze~,in-3-yl~-N'-(3-methylghenyl) urea . Compound 12 The benzodiazepine of Example 4B (1.13 g, 2.3 mmol) was hydrogenated as described in Example 4C and the amine chromatographed (eluant CHC13/MeOH/AcOH 25:2:1) to provido a yellow ~il, This was taken up in acetonitrile and (S)-mandelic acid (335 mg, 2.20 mmol) added to the stirred solution, followed 30 min later by 3,5-dichlorosal.icylaldehy~e (10 mg). After stirring overnight the resultant precipitate was collected by suction filtration and washed with cold acetonitrile, to give a white solid (680 mg, 59%).
The solid (460 mg, 0.897 mmol) was partitioned between CHCl~ and 0.5 M NaOH. The organic portion was washed with brine, filtered (Whatman° 1 PS phase separator) and evaporated . The residue was taken up in CHZC12 ( 5 m1 ) and treated with m-tolyl isoc~anate (110 ~.1, 0.852 mmol) at room temperature for 2 hr. The mixture was evaporated and chromatographed (eluant EtOAc/Hexane 40:60 v/v} to provide a colourless solid (320 mg, 760).
Rf (EtOAc/Hexane 40:60 v/v) 0. 16 Ccxlp = +100.4° (CHCI~, C = 0.96) NMR and M.S. identical to Example 4C.
~UBcaTITUTE ~NEET

''3 i_ f ~ ~ P
c~ l~ .
W~ 93/16999 PCT/G893/00404 (N-((3S)-1-Cyclo~entylcarbonylmethyl-2,3-dihydro-2-oxo-5 phenyl-1H-1,4-benzodiazepin-3-vl)-N'-(3-inethylphenyl~
urea. Compound 13 The benzodiazepine of Example 4B (1.98 g, 4 mmol) was hydrogenated as described in Example 4C and the amine chromatographed (Eluant CHC13/MeOH/AcOH 25:2:1) to provide a yellow oil (1.15 g, 79%) . This was taken up in acetonitrile and (S)-mandelic acid (290 mg, 1.91 mmol) added and the mixture stirred at room temperature overnight. The resultant precipitate was collected by filtration (300 mg, 19%) and the filtrate evaporated and partitioned between CHCl3 and 0.25 M NaOH. The organic portion was washed with brine, filtered (v~lhatman° 1 PS , phase separator) and evaporated. The residue was taken up in acetonitrile and (Ft) -mandelic acid (420 mg, 2 . 77 moral) added and the mixture stirred at O°C for 20 min, then 3,5-dichlorosalicylaldehyde (5 mg) added and stirring continued at room temperature overnight. The resulting white precipitate was collected by filtration and washed with cold acetonitrile (800 mg, 560).
The solid (780 mg, 1:52 mmol) was partitioned between CHC13 and 0.25 M NaOH and the organic portion washed with brine, filtered (Whatman° 1 PS phase separator) and evaporated: The residue was taken up in CHZCla (10 ml) and treated with m-tolyl isocyanate (220 dal, 1.70 mmol) 3 0 at room temperature f or 1 hr . The mixture was evaporated and chromatogaphed (eluant EtOAc/Hexane 40:60 v/v) to provide a colourless solid (650 mg, 87%).
Rg (EtOAc/Hexane 40:60 v/v) 0.16 [cx] D = -96 . 0° (CHC13, c = 1.58) NMR and M.S. identical to Example 4C
~all~~1'ITIJT~ SHEEP

WO 93/1b999 PCT/G893/00404 N- ( f 3R) -1- ( (2R) -2-C'~c.lot~entyl-2-hydroxyeth~rl,Z-2, 3 dihvdro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3 methylphenyl) urea. Compound 20 and EXAMPLE 20 y N-((3RD-1-(,X25)-2-Cyclopentyl-2-h~rdrox,yethY,l,Z-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3 yl)-N'-(3-methylphenyl ) urea . Compound 21.
The benzodiazepine of Example 17 (335 mg, 0.677 mmol) was treated with sodium borohydride in ethanol as descrihed in Examples 12 and l3. The residue was chromatographed to afford the two title compounds (eluant EtOAc/Hexane 35:65 v/v).
Less polar product . 105 mg 31%
More polar product . 145 mg 43%
Identical to Examples l2 and 13 by T.L.C., NMR and M.S.

N-((3RS~,-1-Cyclo~entylcarbonylmethy_1-~,3-dihydro-2-oxo-5-,~3~t~yrid~yl~-1H-1 , 4-benzodiazepin-3-yl~ -N' - (3-3 0 methyl~henyl ) urea : Compound 9 21A 2-Nitro-a-(3-pyridyl)benzvl alcohol 3-Bromopyridine (7.90 g, 50 mmol) was taken up in dry THF
(50 ml) and treated dropwise with n-butyl lithium (1.6 M
solution, 32 ml, 51.2 mmol) at -100°C (internal temp.) and the mixture stirred for 15 min at -100°C. 2-Sl~~~"f ITLIT'E SHEET

~~ ~ ~~(~i~
F.d.r.Nz t s l~
W(7 93!16999 PCT/GB93100404 Nitrobenzaldehyde (8.25 g, 54.6 mmol) was added dropwise in a solution of THF (20 ml) and the mixture allowed to warm to O°C over 40 min. The mixture was quenched with water (5 ml) and then evaporated and partitioned between EtOAc and 5% ~CHC03. The organic portion was washed with brine, and filtered (Whatman° 1 PS phase separator) and evaporated. The residue was chromatographed (EtOAc/
Hexane, 95:5 v/v) to provide a yellow solid (5.72 g, 50%) .
Rf (EtoAc3 o.3a NMR (CDC13) b 8.38 (1H, d, J = 7 .5 Hz) ; 8.26 (lH,m) ;
7.96 (2H, m); 7.70 (2H, m): 7.45 (1H, m); ?.22 (IH, m); 6.45 (1H, s).
"3C NMR (CDC13) b 148.0, 147.9, 147.6, 138.5, 138.3, I35:2, 133.6, 128.9, 128.5, 124.5, 123.5, 68.6.
21a 3-(2-Nitrobenzoyl~ nyridine Oxalyl chloride (2.3 ml, 25.8 mmol) was taken up in CHZClz (40 m1) and txeated dropwise with dimethyl sulphoxide (3.67 ml, 51.75 mmol) at -60°C over 10 min. A solution of the alcohol of Example 21A (5.22 g, 22.7 mmol) was added in CH2C12 (5 ml), followed by triethylamine (15.8 ,,.
113.3 mmol). The mixture was stirred at -60°C far 5 min and then at room temperature for 12 hr. The mixture was diluted with EtOAc and washed with 5% KHCb3 and brine, filtered (Whatman° 1 PS phase separator) and evaporated.
The residue was chromatographed (EtOAc/Hexane, 90: 10 v/v) to provide a yellow solid (3:25 g; 63%).
Rf ( EtOAc ) 0 . 3 8 NMR (CDC13),8 8.90 (1H, d, J = 1.5 Hz); 8.82 (1H, m);
8.31 (1H, d, J = 8 Hz); 8.18 (1H, dd, Jl = BHz, J~
- 1.5 Hz); 7.80 (2H, m); 7.50 (2H, m).
~, Wt3 93/16999 PCTlG~93/OO~d04 i3C NMR (CDC13) b 192.0, 153.9, 150.3, 146.3, 136.0, 134.9, 134.4, 131.4, 131.0, 128.5, 124.6, 123.6.
21 C 3 - ( 2 -Aminobenzo~rl ) p~rridine The ketone of Example 21B (1.83 g, 8.06 mmol) was taken up in ethanol/water (1:1, v/v, 10 ml) and treated with iron powder (2.78 g, 48 mmol) . The mixture was heated under reflex and then conc. HC1 (0.17 ml) added in ethanol/water (1:1, v/v, 2 ml). Heating was maintained for a further 1 hr, then the mixture cooled and filtered and evaporated. The residue was partitioned between 0.5 M NaOH and CHCl3 and the organic potion washed with brine, filtered (Whatman~ 1 PS phase separator) and chromatographed (EtOAc/Hexane, 65:35 v/v) to provide a yellow solid (700 mg, 44~).
Rf (EtOAc} 0.45 NMR (CDC13) b 8.72 (1H, d, J = 1.5 Hz); 8.60 (1H, d, J = 7Hz) ; 7. 80 (1H, m) ; 7.20 (3H, m) ; 6 > 60 (1H, d, J = 8 Hz); 6.48 (1H, t, J = 8 Hz); 6.12 (2H, br.s} .
iaC NMR (CDC1~) b 196.3, 151.3, 149.'6, 149.5, 136.4, 135:7, 134.5, 133.5, 123.0, 1.17.2, 115.6, 115.4.
21D (3RS)-3-Benzyloxycarbonylamino-2.3-dihydro-5-(3-py_rzdyl)-1H-1,.4-benzodiazepin-2-one The title compound was prepared from the amine of Example ~21C (?00 mg, 3.57 mmol), using the method of Freidinger .
et al. CEur. Pat. No. 0 434 364 A2), as a white solid (142 mg, 10%).
R~ (EtOAc) 0.2 NMR (CDC13) b 20.12 (1H, S}; 8.6 (2H, m); 7.83 (1H, a~~~s~~~~U~~ a.~~~~~

l~IYO 93/ I b999 PC 1'/G 893/00404 d, J = 7 Hz); 7.4 - 7.0 (5H, m); 6.76 (1H, d, J
- 8 Hz); 5.25 (1H, d, J = 8 Hz); 5.08 (2H, s).
21E (3RS~,-3-Benzyloxycarbonylamino-1-5 c~clonentylcarbonylmethyl-2.3-dihydro-5-t3-~vridyl)-1H-1,4-benzodiazepin-2-one: (Scheme 1~ step (i)) The benzodiazepine of Example 21D (142 mg, 0.35 mmol) was alkylated with the bromomethyl ketone of Example 4A (90 10 mg, 0.49 mmol) using the method described in Example 1B.
The title compound was obtained as a white solid after chromatography (Ei=OAc/Hexane, 95:5 v/v) (164 mg, 96%)'.
Rg (EtOAc) 0.28 15 NMR (CDC13) S 8.68 (1H, S); 8.58 (1H, d, J = 1.5 Hz);
7.98 (1H, d, J = 8 Hz); 7.88 (1H, s); 7.45 (1H, m) ; 7 . 3 - 7 .1 ( 3H, m) ; 6 . 62 ( 1H, d, J = 8 Hz ) ;
5.37 (lH, d, J = 8 Hz); 5.06 (2H, s); 4.63 (2H, s) ; 2.80 (1H, m) ; 1.8 - 1.4 (8H, m) .
20 ,,,:. ;,.,:
21F N- ( (3RS) -1-Cvclor~entylcarbonylmeth,girl-2,3-dihydro-2-oxo-S-(3-pyridyl)-IH-1,4-benzodiazepin-3-vl))-N'-(3-2S methyl,phenyl) urea. Scheme 1, step ~iiL
The benzodiazepine of Example 22E f160 mg, 0.32 mmol) was taken up in CHZC12 (2 ml) at -70aC and treated dropvaise with stirring with boron tribromide (1.0 M in CH2C12, 2.0 30 ml) . The mixture was allowed to warm to room temperature over 1 hour and stirring continued for a further 3 hrs.
The solution was then quenched with water and then partitioned between EtOAc and 1M NaOH. The organic portion was washed with brine, filtered (Whatman° 1 PS
35 phase separator) and evaporated. The residue was taken up ixa CH2Clz (3 ml ) and treated with m-tolyl isocyanate f 45 ~.1, 0.35 mmol) at room temperature for lhr. The mixture '~~' ~~S~~~UTE SH~~

~~.~;~~J
i~0 93/16999 PCT/GB93/004U4 was evaporated and chramatographed (EtOAc/Hexane, 90: 1 0, v/v) to provide the title compound as a white solid (?0 mg, 44%).
S Rf (EtOAc) 0.28 NMR (CI~C13) b 8.88 (1H, s) ; 8. 80 (1H, d, J = 1.5 Hz) ;
8.30 (1H, d, J - 8 Hz) ; ?.?C - ?.20 (lOH, m) ;
6.96 (IH, m) ; 5.80 (1H, d, J = 8 Hz) ; 5. 01 (1H, d, J = 14 Hz); 4.80 (1H, d, J = 14 Hz); 3.02 (1H, m); 2.41 (3H, s); 2.0 - 1.65 (8H, m).
M.S. (FAB) (M+Hl' - 496.3 E~.A.MPZ~E 2 2 N- ( (3RS) -1-Cyclopent_ylcarb_onvlmethyl-2. 3-dihydro-2-oxo-S
(2-t~yridyl ) -1H-1 , 4-benzodiazepin-3-Y1) -N' - (3 carbox~hen~",rl ~ urea . Compound 34 22A N-t(3RS)-1-Cyclopentylcarbonylmeth~rl-2,3-dihydro 2-oxo-5- 2- rid 1 -1H-1 4-benzodiaze in-3- 1 -N' 3 metho carbon 1 hen l urea. Scheme 1 ste ii The benzodiazepine of Example 14A (180 mg, (0.363 mmol) was taken up in dichloromethane (3 ml) and cooled to -70°C under nitrogen. Boron tribromide (2.2 ml of 1 M
solution in CHzCl2) was added dropwise and the mixture stirred over l hr during which the cold bath expired, and thin fns a further 2 hrs at room temperature. The mixture was quenched with iced water and then diluted with ethylacetate and washed with 1M NaOH. The organic portion was washed with brine, filtered (Whatman° 1 PS
phase separator) and evaporated to leave a brown oil.
Methyl(3-amino)benzoate (151 mg, 1 mmol) in CH2C12 (2 ml) at -20°C under NZ was treated with triphosgene (110 mg, 0,37 mmol) .and pyridine (81 ~1 mmol). The mixture was stirred at -20°C for 30 min then a further portion of pyridine ( 81 ~.1, 1 mmol ) added, f of lowed by the amine ~~J~ST~TUTE SH~~'T

~~.~~sF~
W~J 93/16999 PCi'/GB93/004t34 from above. The mixture was stirred at room temperature 1 hr, then evaporated and partitioned between EtOAc and S% KHC03. The organic portion was washed with 20 o citric acid and brine, filtered (whatman° Z PS phase separator) and evaporated and the residue chromatographed (eluant EtOAc) to provide an off-white solid (95 mg, 490).
Rf EtOAc 0.28.
NMR (CDC13) b 8. 60 (d, 1H, J = 2 Hz) ; 7.10 -- 8.10 (M, 20 13H) ; 5.65 (d, 1H, J = 8 Hz) ; 4.62 (m, 2H) ; 3 . 8 (s, 3H); 2.95 (m, 1H): 1.4 - 1.95 (m, 8H) 22B N- ( (3RS) -1-Cyclopent lcarbony_lmethy_1-2. 3-di~dro-2-' oxo-5-(2-p~rridyl)-1H-2,4-benzodiazepin-3-vl)-N'-(3-carbo~henyl ) urea .
The benzodiazepine of Example 22A (95 mg, 0.176 mmol) was taken up 3.n dioxan water (1:1, v/v, 2 ml) and treated with LiOH-H20 (12 mg, 1.S eq) at room temperature for 16 hrs. The mixture was evaporated and partitioned between CHCl3 and 10% citric acid. The organic portion was wa~he3 with brine, filtered (Whatman° 1 PS phase separator) and evaporated. The residue was chromatographed (eluant CHC13/MeOH/AcOH, 100:2:1 v/v/v) 2S to provide a white solid which was freeze dried from dioxan/water to provide the title compound (34 mg, 37%).
I~7MR (CDCl~) b 8 . 62 (d, 1H, J = 2 Hz) ; 7 .1 - 8 . ~ (m, 13H) ; 5 . "70 (d, 1H, J = 8 I-Iz) ; 4 . 58 (m, 2H) ; 3 . 0 (m, 1H) ; 1.4 - 2.0 (m, 8H) .
M.s. (+ve FAS> (M+H)+ - ~a6.~.

N-((3R)-1-Cyclopentylcarbonylmethyl-2,3-dih~rdro-2-oxo-5-hen 1-1H-1 4-benzidiaze in-3- 1 -N'- 3-carbox hen 1 urea . Compound 33 S~~STITtITE SHEET

~~~~~~f~i 'W~ 93/ H 6999 ~ fCT/G B93/00404 The benzodiazepine of, Example 4B was hydrogenated and resolved as described in Example 17. The resultant (S)-mandelate salt (430 mg, 0.838 mmol) was partitioned between CHC13 and 0.25Nd NaOH and the organic portion washed with brine filtered (Whatman~ 1 PS phase separator) and evaporated to give the free amine as a colourless oil.
Methy2 m-aminobenzoate (315 mg, 2.1 mmol) was taken up in 1 O CH2C12 ( 3 ml ) and pyridine ( 7.70 gel , 2 .1 mmol ) and cooled to -60°C under nitrogen. Triphosgene (207 mg, 0.7 mmol) was added and the mixture stirred over 25 min whilst the temperature rose to -20°C. Further pyridine (170 ~l; ~.2 mmol) was added and stirring continued for 10 min at -2 0 ° C and then the amine f rom above added in CH2C12 ( 1 ml ) and stirring continued at room temperature for 2 hrs.
The mixture was then diluted with EtOAc and washed with 1 M HC1 and brine, filtered (WhatmanQ PS paper) and chromatographed (eluant EtOAc/Hexane, 40:60 vjv) to provide the intermediate ester as a colourless solid (375 mg, 83%) .
a The ester was taken up in dioxan/water (1: 1, v/v, 5 ml) and treated with LiOH.H20 (42 mg, 1.4 eq) at room temperature for l6 hrs. The mixture was evaporated and partitioned between EtOAc and 1M HCl. The organic portion was washed with brine, filtered (Whatman~ 1 PS
paper) and evaporated. The residue was chromatographed (eluant EtOAc/Hexane/AcOH, 60/40/2, v/v/v) to provide the title compound as a colourless solid (300 mg, 75%).
Rg (EtOAc/Hexane/Acetic acid, 60:40:2 v/v/v) 0.24.
[cr]n=' +68.4 (EtOAc, c = 0.92).
'H NMk and M.S. identical to Example 16.
Examgles 24 and 25 ~i~~~~~~
W~ 93/16999 PCT/GB93/00404 N~ (3R) -1- ( (2RS) -2-Cyclopentyl-2-hydroxyethyl) -2 , 3-dih~rdro-2-oxo-5-phenyl-1H-1.4-benzadiazepin-3-yl)-N'-(3-carbox~henyl ) urea . Compound 3 5 and N- ( (3R,~- 1- L 2R) -2-C~,rclopentyl-2-h~rdroxyethyl~ -2. 3-dihydro-2-oxo-5-phenyl-IH- 1~4-benzodiazepin-3-yl) -N' - (3-carboxyphenyl ) urea . Compound 3 6 The benzodiazepine of Example 23 (z20 mg, 0.229 mmol) was tal~en up in ethanol at O°C and treated with sodium borohydride (16 mg, 0.4 mmol) for 15 min, then the mixture was allowed to stir at room temperature for a further 2 hrs, then evaporated and the residue chromatographed (eluant EtCAc/Hexane/Acetic acid, 60/40/2, v/v/v) to provide two products:
Ex. 24 - a 1: l mixture of faster and slower isomers (33 mg) Ex. 25 = the pure slower isomer (46 mg) t.l.c. (EtOAc/Hexane/Aeebic acid 60/40/2, v/v/v) R~ faster isomer = 0.24 Rf slower isomer = 0.20 M.S. (M+H)+ - 527 identical for both Examples.
Example 26 N-_~(3R)-1-tart-Butylcarbonvlmethyl-2,3-dihydro-2-oxo-5 phenyl-1H-~ . 4-benzodiazepin-3-yl) -N' - ~3-meth,~rl~henvlZ
urea. Compound 38 ,the benzodiazepine of Example 2B was hydrogenated and the resultant amine resolved into its (R)-isomer (S) mandelate salt as described in Example 1'T. A portion of the salt (x.50 mg, 0.299 mmol) was, partitioned between CHCl~ and 0.25 M NaOH. The organic portion was washed SUSST!'TUTE SHS~' ~~.~'~~~~:3~3 l~J~ 93116999 PCftGB93t00404 with brine, filtered (Whatman° 1 PS paper) and evaporated. The residue was taken up in CHZCIz and m-tolyl isocyanate (42 ~cl, 0.33 mmol) added. The mixture was stirred at room temperature for 1 hr, then evaporated S and chromatographed (eluantvEtOAc/hexane, 40/60, v/v) to provide a white solid which was freeze dried from acetonitrile/water (125 mg, 8?P).
Data identical to Example 2C.
Example 27 N-((3RS)-1-tent-ButylcarbonylmethYl-2 3-dihydro-2-oxo-S
~2-pyrady~l-1H-1 4-benzodiaze~pin-3-,yl) -N' - (3 me~ thylphenyl) urea. Compound 39 27A (3RS)-3-Benzyloxvcarbonv~..amino-1-tert-but lcarbon lmeth 1-2 3-dih dro-2-oxo-5- 2- rid 1 -1H-1~4-benzodiazegin-2-one (Scheme 1 step (ii)) (3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepix~.-2-one (R. M. Freidinger et al. Eur.
Pat. No. 0 434 364 A2) (2.02 g, 5 mmol) was alkylated with 1-bramopinacolpne (1.08 g, 6 mmol) as described in Example 14A, to provide a white solid after chromatography (eluant EtOAc/hexane, 80:20 v/v) (2.16 g, 86%).
~7B N-((3RS)- 1-tert-Butylcarbonylmethyl-2 3-dihvdro-2-oxo-5-(2-nyridvl)-1H-1 4-banzodiazepin-3-yl)-N'-(3-methylnhenyl ) urea Scheme 1 step iii ~",L
A portion of the benzodiazepine from Example 2?A (502 mg, 1 mmol ) was taken up in CHZC12 ( 2 ml ) at -?0 ° C and treated dropwise with BBr3 (6.5 ml, 1.0 M solution in CHZC12) and ~UBS1'ITUTE SHEET

2~~~~~~
WHO 93/16999 PCT/GB93/0040d the mixture stirred for 3 hrs, during which time the cold bath expired. The mixture was quenched with water, then partitioned between EtOAc and 1M NaOH. The organic portion was washed with brine, filtered (Whatman° 1 FS
paper) and evaporated. The residue was taken up in CHzCl2 (3 ml) and treated with m-tolyl isoyanate (I35 ~.1, 1.05 mmol) at room temperature for 1 hr. The mixture was evaporated and chromatographed (EtOAc/Hexane 75:25 v/v) and the resultant white solid recrystallised from acetonitrile (180 mg, 380).
Rg (EtOAc/Hexane, 60:40 v/v) 0.28.
' 1H NMR (CDC13) b 8.78 (d, 1H, J = 2 Hz); 8.27 (d, 1H, J
- 7 Hz); 7:95 fm. 1H); 7.65-6.9 (m, 11H); 5.83(d, ZS 1H, J = B Hz); 5.10 (d, 1H, J = 16 Hz); 4.70 (d, 1H, J I6 Hz); 2.42 (s, 3H); 1.40 (s, 9H).
M.S. (FAB) (M~H)~ 484.4 Exam le 28 N-((3RS~,-1-tert-Eutylcarbonylmethyl-2,3-dih~rdro-2-oxo-5-~phe ~l-1H-1,4-benzodiazepin-3-yl~-N'-(3-carboxyphenyl) urea. Compound 40 The benzodiazepine of Example 2B was hydrogenated as .
described in Example 1C and the resultant amine (600 rng, 1 . 72 mmol taken up in dry THF ( 8 ml ) and Et3N ( 26 0 ~,1, I:9 mmol). A solution of p-nitrophenyl chloroformate (0.38 g, 1.9 mmol) in THF (3 ml) was added dropwise and the mixture stirred at room temperature for 1 hr, evaporated and chromatographed (eluant EtOAc/hexane, 40:60, v/v) to give a white solid (670 mg). This solid was taken up in DMF (10 ml) and treated with m-amino benzoic acid (245 mg, 1.75 mmol) at 45°C for 18 hrs. The mixture was evaporated and chromatographed (eluant EtOAc/hexane/acetic acid, 60:40:2, v/v/v) and the praduct recrystallised from acetonitrile to provide the title ~U~STfTUTE SHEET

W~ 93/16999 PCT/GB93/04404 compound (328 mg, 38%).
1H NMR (CDC13).~ 7.8 - 7.0 (14H, m); 6.80 (1H, d, J
- 7 Hz); 5.6 (IH, d, J -- 8 Hz); 4.9 (1H, d, J = 18 Hz); 4.8 (1H, d, J = 18 Hz); 1.40 (9H, s) .
M.S. (FAB) (M+H)' - 513.4 Example 29 N-((3RS)-1-Cyclopentylcarbonylmethyl-2 3-dihydro-2-axo-5-hen 1-1H-1 4-benzodiaze in-3- 1 -N'- 6-meth 1-2- id 1 urea. Compound 27 This was prepared following the method of Example 1C
using the benzodia~epine of Example 4B (165 mg, 0.33 mmol), 5o palladium-pn-carbon (80 mg) and the isocyanate prepared below:
Ta a stirred solution of 2-amino-6-picoline (108 mg, 1 mrnol ) in CHxCl2 ( 10 ml ) ~, t -2 0 ° C was added triphosgene (dip tng, 0.37 mmol) and pyridine (79 mg, 1 mmol). The mixture was stirred for 30 min while warming to room temperature. Pyridine (79 mg, 1 mmol) was added and the reaction was heated to raflux for 30 min. The resulting solution of isocyanate was cooled to O°C and used directly. .
The crude product was purified by f lash chromatography on silica gel (Eluant EtOAc: 40-60 pet ether 80-20 v/v) to give the title compound as a white solid (45 mg, 28%, 96%
pure by HPLC) , R~ (EtOAc: 4d-60 pet ether 20:80) 0.20.
NMR (CDC13) b 10.8 (1H, broads); 7.70 - 6.80 (13H, m); 5.?0 (1H, d, J = 8 Hz); 4.82 (1H, d, J =
17 Hz) ; 4.75 (IH, d, J .- 17 Hz) ; 2.95 (1H, ~~~S~f~~~~ 3HE~

WO 93/16999 PCTfGB93100404 . , . 53 , ..
quintet, J - 7 Hz); 2.60 (3H, s); 1.95 - 1.75 (4H, m) ; 1.70 - 1.45 (4H, m) .
M.S. (FAB, +ve ion) m/e 496.0 (M+H).
Example 30 N-((3RS)-1-Cyclopentvlcarbonylmethyl-2 3-dihydro-2-oxo-5-phenvl-1H-1,4-benzodiazepin-3-vl)-Nr-(3epyridyl) urea Compound 26 This was prepared follawing the method of Example 1C
using the benzodiazepine of Example 4B (270 mg, 0.55 mmol) , 5 o palladium-on-carbon (100 mg) and the isocyanate prepared below:
To a stirred solution of nicotinic acid (1?2 mg, 1.4 mmol) and diisapropylethylamine (250 ~.1, 1.4 mmol) in THF
(15 ml) at O°C was added isobutyl chlaroformate (182 ~zl, 1.4 mmol). The mixture was stirred at O°C for 30 min, then a solution of sodium azide (97 mg, 1.5 mmol) in H~0 (1 ml) was added and the mixture was starred for 2 hours while warming to room temperature. The mixture was evaporated in vacua and the residue taken up in cold EtOAc, washed with cold saturated KHCO3 and cold brine, filtered (Whatman° 1 PS phase separator) and concentrated ;gin vacuo. The residue was heated in THF (5 ml) at 60°C
for 5 min to give the isocyanate and used directly.
The crude product was purified by flash chromatography on silica gel (Eluant CHC13: MeOH: AcOH 100:2:1 v/v) to give the title compound as a crystalline solid (34 mg, 130 >
99% pure by HPLC).
Rf (CHC13: MeOH: AcOH, 100:2:1) 0.10.
NMR (CDC13) 8.70 - 7.20 (16H, m); 5.50 (1H, d, J ~ 8 Hz); 4.75 (1H, d, J - l8Hz); 4.67 (1H, d, J
- 18 Hz); 3.70 (1H, m), 1.90 - 1.20 (8H, m).
MS (FAB, +ve ion) z/m 482.0 (M+H) ~~.~~~J
WO 93/16999 PC1'lGB93/00404 Example 31 N-((3RS)-1-Cyclo~entylcarbonylmeth~l-2,3-dihydro-2-oxo-5-phenyl-1H-1.4-benzodiazepin-3-~l,)_-N'-(3-carboxymethylphenyl) urea. Compound 24 31A Mteth~l 3-amino phenvl acetate To a solution of 3-aminophenylacetic acid (3.02 g, 20 mmol) and methanr~l (s0 ml) was added acetyl chloride (2 ml, 28 mmol). The reactian was heated to reflux for six hours. After allowing reaction to cool to room temperature the solvent was evaporated in vacua. The resultant product was ta)Cen up in CHC13 and washed with saturated KHC03 and brine; filtered (Whatman° 1 PS phase separator) , and concentrated in vacuo to afford the title acetate as a brown m~bile oil (3.0 g, 9~.%) .
NMR (CDC13) $ 7.35 - 6.90 (4H, m); 4.?5 (2H, s); 3.80 (3H, s) ; 3.65 (2H, s) .
3~.B N- ( (3RSZ- 1.-Cyclot~~ntylcarbonvlmethyl-2 3-dihydro-2-oxo--5- phenyl-2H-1.-. 4 -benzodiazepin-3 -vl ) -N° - ( 3 -methoxycarbony_lmethylphenyl) urea. (Scheme 1 step (ii) This was prepared following the method of Example 1C
using the benzodiazepine of Example 4B (165 mg, 0.33 mmol), 5n palladium-om-carbon (80 mg) and the isocyanate prepared from ,the amine of Example 31A following the method of Example 29:
The crude product was purified by f lash chromatography on silica gel (eluant EtOAc: hexane fr 60:40 vjv) to afford the methyl ester as a white solid (180 mg, 97 %).
Rf (EtOAc: hexane fr 60:40) 0.23.
~v~s-re~r~~E s~E~r ,,~~ a W~ 93/ 16999 '~ ~ % ~ r .,. '1 ii P~T/G B93/00404 31C N-((3RS)-1-cyclopent~lcarbonylmethyl-2,3-dih~dro-2-oxo-S-r~henyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxymethylphenyl) urea 5 To a solution of the benzodiazepine of Example 31B (18C
mg, 0.32 mural) in dioxan (10 ml) was added a salution of Li,OH . H20 ( 27 mg, 0 . 64 mmol ) in H20 ( 6 ml ) . The mixture was stirred for I8 hours, then dilute aq. HCl (10 ml) was added. The mixture was extracted with EtOAc twice, 10 and the combined organic layers were washed with water and brine, filtered (WhatmanQ 1 PS phase separator) and concentrated an vacuo. The crude product was purified by flash chromatography on silica gel (eluant EtOAc: hexane fr: AcOH ?0:30:2 v/v/v) to give the title compound as a 15 white solid (105 mg, 610, > 98% pure by HPLC).
Rf (EtOAc: hexane fr: AcOH, 70:30:2) 0.20 .
NMR (CDCl3) b 8. 00 (1H, s) ; 7.65 - 6.90 (15H, m) 5.65 (1H, d, J - 8 Hz); 4.71 (2H, s). 3.50 20 (2H, s) : 1.95 - 1.50 (9H, m) .
M.S. (FAR, +ve ion) m/e 539.1 (M+H).
Example 32 25 N-(t3RS)-1-C~rclohexvlmethy~carbonylmethvl-2.3-dihvdro-2-oxo-5--t~henyl-7.H-1.4-benzodiaze~zn-3-~1) -N' - 3-methy_lphenyl) urea Compound 29 32A Bromomethyl evclohexylmeth~l ketone (Scheme 2 30 steps (i) - (iii)) This was prepared following the method of Example 3A, The intermediate diazoketone was prepared from cyclohexylacetic acid (4.27 g, 30 mmol) , thionyl chloride 35 (8.7 mls, 120 mmol) and CH2Na (generated from Diazald°
14.3, 66 mmol) and purified by flash chromatography on silica gel (eluant EtOAc: hexane fr 15:85 v/v). The SU~S'~i'~UTE SHEET

~~.'?
WO 93/i6999 P~ f/GB93/00404 diazoketone was subsequently treated with a saturated solution of HBr in EtOAc. Flash chromatography on silica gel (eluant EtOAc : hexane fr 5 : 95 v/v) afforded the title compound as a pale brown mobile oil (2.8 g, 430).
, ., NMR (CDC13) 1 b 3 . 99 (2H, s) ; 2 . 70 (2H, d, J = 8 Hz) ;
2.00 (1H, m); 1.85 - 1.10 (IOH, m).
32B (3RS)-3-Benzyloxycarbonylamino-1-cyclohex~ 1~ methylcarbonylmeth~rl-2, 3-dihydro-5-,phenyl-1H-1,4-benzodiazepin-2-one (Scheme 1, step (i)) This was prepared following the method of Example 1B, ' using the Bock benzodiazepine (250 mg, 0.62 mmol), sodium hydride (26 mg of an 80o dispersion in oil, 0.87 mmol) and the bromomethylketone of Example 32A (219 mg, 1 mmol). The crude product was purified by flash chromatography on silica gel eluant (EtOAc: hexane fr 35:65 v/v) iro afford the title compound as a colourless crystalline solid (315 mg, 970).
Rf (EtOAc: hexane fr, 40:60) 0:25.
NMR (CDC13) b 7.50 - 7.00 (14H, m); 6.60 (1H, d, J =
8 Hz); 5.40 (1H, d, J = 8 Hz); 5.10 (2H, s); 4.78 (1H, d, J = 17 Hz); 4.67 (1H, d, J = 17 Hz); 2.35 ' (2H, m); 1.85 (1H, m), 1.65 - 0.90 (lOH, m).
32C N-((3RS)-1-Cyclohexylmethylcarbonylmeth~rl-2,3 dihydro-2-oxo-5-phenyl-~.H-1,4-benzodiazepin-3-yl~-N'-~3 3 0 methyl~phenyl ) urea : ( Scheme 1, step ( ii;~") This was prepared following the method of Example 1C
using the benzodiazepine of Example 32B (315 mg, 0.60 mmol), 5o palladium-on-carbon (250 mg) and m-tolyl isocyanate (91 ml, 0.71 mmol). The crude product was purified by flash chromatography (eluant EtOAc: hexane fr 40:60 v/v) to give the title compound which was ~IJ~STt'CUTE SHEET

~~~ ).~~ii bV~ 93!16999 PCt'/GB93/00404 crystallised from acetonitrile to give a white solid (51 mg, 160, > 98% pure by HPLC).
Rf (EtOAc: hexane fr, 40:60) 0.20.
NMR (CDC13) 8 7.80 - 6.90 (15H, m) ; 5.?0 (1H, d, J
- 8 Hz) ; 4 .74 (IH, d, J = lBHz) ; 4.67 (1H, d, J - 18 Hz) ; 2.45 - 2.20 (SH, m) ; 1.95 - 0.90 (1~.H, m) .
M.S. (FAB +ve ion) m/e 523.1 (M+H).

N-L(3RS)-1-Cyclouent~lr m~tbylcarbonylmethyl-2.3-dihvdro-2 ' ox_o-5-t~henyl-1H-1.4-benzodiaz~in-3-yl) -N' - (3 1S methylphenyl"~ urea. Compound 30 33A Bromome~h~rl cyclopentylmeth~rl _ketone (Scheme 2 steps (i)~(iii) ).
20 This was prepared following the method of Example 3A.
The intermediate diazoketone was prepared from cyclopentylacetic acid E3.85 g; 30 mmol), thionyl chloride (8.7 mls, 120 mmol) and CHzN2 (generated from Diazald °, 14.3 g, 66 mmol) and purified by flash 25 chromatography on silica gel (eluant EtOAc: 40-60 pet ether 15:85 v/v): The diazoketone was subsequently trea'ced with a saturated solution of HBr in EtOAc . Flash chromatogaphy on silica gel (eluant EtOAc: 40-60 pet ether 5:95 v/v) afforded the title ke~one as a mobile oil 30 (2.1 g, 34%) .
NMR (CDC1~) b 3.99 (2H, s); 2.80 (2H, d, J = 8 Hz);
2.35 (1H, m); 1.95 - 1.30 (8H, m).
35 33B (3RS) -3-Benz,~rloxvcarboz~ylamino-1-cyclotaentylmethvlcarbonylmethyl - 2 . 3 - di ~dro- 5--t~henyl -1H-1 4-benzodiazepin-2-one- Scheme 1 step (i)) .,, __ ::. . . . .. _ .. ..

lr ~ v ~~ ~l WO 93/ ! 6999 PCTlG~93/0040~6 This was prepared following the method of Example 1B, using the Bock benzadiazepine (250 mg, 0.62 mmol), sodium hydride (26 mg of an 80o dispersion in oil, 0.8?
mmol) and the bromomethyl ketone of Example 33A (205 mg, ~. mmol). The crude product was purified by flash chromatogaphy on silica gel (eluant EtOAc: hexane fr 35:65 v/v) to afford the title compound as a colourless crystalline solid (300 mg, 95%).
R~ (EtOAc: hexane Fr 4~D:60) 0.25.
NMR (CDC13) b 7. 70 - 6 .75 (15H, m) ; 5.50 (1H, d, J =
8 Hz); 5.20 (2H, s); 4.74 (1H, d, J - 18 Hz);
4.67.(1H, d, J = 18 Hz); 2.50 (2H, m); 2.25 (1H, m); 1.85-1.15 (BH, m).
33C N-((3RS)-1-Cyclopen~lmethvlcarbonvlmethvl-2.3-dihvdro-2-o~eo-5-t~henyl-1H-1 4-benzodiazepira-3-girl) -N' - (3- , methylphenyl ) urea . ( Scheme 1, ste~r~ ( i i ) ) This was prepared following the method of Example 1C
using the benzodiazepine of Example 33B (300 mg, 0.59 mmol), 5% palladium-on-carbon (250 mg) and m-tolyl isocyanate (9~. ~1, 0.71 mmol). The crude product was purified by flash chromatography on silica gel (eluant-EtOAc: hexane fr 40:60 v/v) to give the title compound which was crystallised from acetonitrile to give a white solid (171 mg, S7o; > 99o pure by HPLC).
Rf (EtOAc: hexane fr 40:60) 0.20.
NMR (CDC13) 8 7.85 - 6.98 (15H, m); 5.85 (1H, broad s); 4.80 (2H, s); 2.55 (2H,m); 2.45 (3H, s);
2.43 - 2.30 (1H, m) ; 1..90 - 1.20 (8H, m) .
N1.S. (FAB, +ve ion) m/e 509.1 (M+H).

~ .n ~'.~.N'.~ ~.~~
!~V(> 93/16999 FCT/GB93/004~D4 I~- ( ( 3RS ) -1- ( 1-Methyl cyclohex~rl ) carbonylmethvl ) -2 3 -dihydro-2-oxo-5-phenyl-lI3-1,4-benzodiazewin-3-y_l)-N'-(3-methylghenyl urea . Compound 31 34A Bromamethyl (1-methvlcyclohexyl) ketone. (Scheme 2 steDS ~l~ - (iii) ) This was prepared using the method of Example 3A. The intermediate diazoketone was prepared from 1-methyl_1_ cyclohexanecarboxylic acad (4.27g, 30 mmol), thionyl chloride (8.7 m1, 120 mmol) and CH2N~ (generated from Diazald o 14.3 g, 66 mmol). Without purification the diazoketone was subsequently treated with a saturated solution of HBr in EtOAc. Flash chromatography (eluant EtOAc: hexane fr 5:95 v/v) afforded the ketone as a mobile oil (1.90 g, 29%).
NNIR (CDC13) b 4.25 (2H, s) ; 2.05 (2H, m) ; 1 .70 - 1.40 ,., (8H; m) ; I.25 (3H, s) .
34B (3RS) -3-Benz~loxycarbonwlamino--1- ( (1 methylcyclohexyl)carbonvlmethyl)-2 3-dihydro-5-phenyl 1,4-benzodiazepin-2-one (Scheme 1 step (i)) This was prepared following the method of Example IB, using the Bock benzodiazepine (250 rng, 0.62 moral), sodium hydride (26 mg of an 80% dispersion in oil, 0.87 mmol) and the bromomethylketone of Example 34A (219 mg, l mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc: hexane fr 35:65 vjv) to afford the title compound as a colourless crystalline ~salid (270 mg, 86%).
R~ (EtOAc: hexane fr 40:60) 0.24.

Ed ~ hJ
Wfl 93/16999 P~.'T/~893/004a4 NMR (CDCl~) b 7.70 - 7.10 (14H, m) ; 6.80 (1H, d, J =
8 Hz); 5.55 (1H, d, J = 8 Hz); 5.30 (2H, s); 5.10 (1H, d, J = 17 Hz); 4.75 (1H, d, J = 17 Hz); 2.10 (2H, m); 1.70 - 1.40 (10H, m); 1.30 (3H, s).
34C N- ( (3RS) -1- ( (1-methylcvclohex~rl) carbonylmethyl) -2,3-dihydro-2-oxo-5=phenyl-IH-1 4-benzodiazepin-3--yl)-N°-~3-methylphenyl) urea. (Scheme 1 step (ii)) 10 This was prepared using the method of Example 1C using the benzodiazepine of Example 34B (270 mg, 0.52 mmol), 5%
palladium-on-carbon (150 mg) and m-tolyl isocyanate (84 ~.1, 0.66 mmol) : Tie crude product was purified by flash chromatogaphy on silica gel (eluant EtOAc: hexane fr 15 40:60 v/v) to give the title compound which was w crystallised from acetonitrile to give a crystalline solid (98 mg, 360 >99o pure, by HPLC).
Rf (EtOAc: hexane fr 40:60) 0.20.
20 NMR (CDCI3) b 7.?0 - 6.90 (15H, m); 5.80 (1H, d, J =
$ HZ) ; 4.90 (7:H, d, J' = 17 Hz) ; 4 .75 (1H, d, J = i 17 Hz) ; 2:3f? (3H, s) ; 2.00 (2H, m) ; 1.60 - 1.35 (IOH, m) ; 1.20 (3H, s) .
M.S. EFAB +ve ion) m/e 523.3 (M+H).

N-((3RS)-1-Cvclo~entvlcarbonylmethvl-2 3-dihvdro-2-oxo-5 ~~-enyl-1H-1.4-benzodiazepin-3-vl)-N'-(3 30 carboxamidophenyl) urea. Compound 37 This was prepared following the method of Example 16B
using the benzodiazepine of Example 16A (225 mg, 0.43 mmol) and 3-aminobenzamide (87 mg, 0.64 mmol). The crude 35 product was purified by flash chromatography on silica gel (eluant EtOAc) to provide the title compound as a crystalline solid (30 mg, 130, > 99% by HPLC).
SUBSTITUTE 56~~~' Wt? 93/16999 PCflG893100404 Rf (EtOAc) 0.20 NMR (CDC13) b 8.95 (1H, s) ; 8.27 (1H, d, J = 8 Hz) ;
8.2~ (1H, d, J = 8 Hz); 7.65-7.20 (15H, m); 5.55 (1H, d, J - 8 Hz); 4.65 (2H, s); 2.~0 (1H, quintet, J = 8 Hz); 1.85 - x.50 (8H, m).
M.S. (FAB +ve ion) m/e 524 (M+H).
EXAMIaLE 3 6 N- 3RS -1-tert-Am lcarbon lmeth 1-2 3-dih dro-2-oxo-5-hen 1-7.H-1 4-benzodiaze in-3- 1 -N'- 3-meth 1 hen 1 urea. Comgound 41 36A 1-Bromo-3 3-dimethylpentan-2-one (Scheme 2 steps (i) - yiii)) This was prepared following the method of Example 3A.
The intermediate diazoketone was prepared from 2,2 dimethylbutyric acid (5.8 g, 50 mmol), thionyl chloride (14.6 ml, 200 mmol) and CH~Nz (generated from Diazald a ' 21.5 g, 100 mmol) and purified by flash chromatography on silica gel (eluant EtOAc: hexane fr 20:80 v/v). The diazoketone was subsequently treated with a saturated solution of HBr in EtOAc. Flash chromatography an silica gel. (Eluant EtOAc: hexane fr 15:85 v/v) afforded the title ketone as a pale brown oil (1.50 ~, 160).
NMR (CDC~3) 8 4.25 (2H, s) ; I.70 (1H, q, J = 8 Hz) ;
x..30 (6H, s) ; 0.97 (3H, t, J = 8 Hz) .
36B N- 3RS -1-tert-Am lcarbon lmeth 1-3-bent lox -carbonylamino-2,3-dihvdro-5-phenyl-3.H-1 4-benzodiazepin=
2-one. LScheme 1, step (i)) Th3.s was prepared following the method of Example 1B, using the Bock benzodiazepine (500 mg, 1.25 mmol), sodium hydride (54 mg of an 80% dispersion in oil, x..75 ~IJ~~T'I'~'t~'~E SHE~'f Wt~ 93/16999 PCT/GB93l00404 mmol) and the bromomethyl ketone of Example 36A (300 mg, 1.5 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc: hexane fr 35:65 v/v) to afford the title compound as a colourless crystalline solid (565 mg, 910).
Rf (EtOAc: hexane fr 40:60) 0.20 NMR (CDC13) b 7.90 - 7.30 (14H, m); 6.9 0 (1H, d, J =

8 Hz); 5.80 (1H, (2H, s); 5.1.0 d, J = 8 Hz);
5.40 (1H, d, J = 18 Hz); 4.75 (1H, d, 1~ Hz); 1.90 J =

(2H, m) ; 1.40 (6H, s) ; 1.00 (3H, J = 8 Hz) .
t, 36C N- ( (3RS) -1-tent-Amylcarbonylmethyl-2J , 3-dihyrdro-2-oxo-5-phenyl-1H-1, 4-benzodiazetain-3-yl)-N'-(3-meth ylphenyl) urea. (Scheme 1 steps ii)) This was prepared following the method of Example 1C
using the benzodiazepine of Example 36B (240 mg, 0.46 .
mmol), 5% palladium-on-carbon (250 mg) and m-tolyl isocyanate (76 ~.1, 0.6 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAchexane fr 40:60 v/v) to give the title campound y which was crystallised from acetonitrile to give a white solid (98 mg, 430, >99o by HPLC) .
Rf (EtOAc: hexane fr 40:60) 0.20.
NMR (CDC13) b 7.50 - 6 . 80 (15H, m) ; 5 > 65 (1H, d, J =
$ Hz); 4.70 (1H, d, J = 18 Hz); 4.65 (1H, d, J =
18 Hz); 2>20 (3H, s); 1.50 (2H, q, J - 8 Hz);
1.00 (6H, s); 0.70 (3H, t, J = 8 Hz).
M.S. (FAH +ve ion) m/e 497.2 (M+H).

N-((3RS)-1-tart-Amvlcarbon~lmethyl-2.3-dih~rdro-2-oxo-5-phenyl-1H-1.4-benzodiazepin--3-yl)-N'-(3-carboxyp~enyl~
urea. Compound 42 SHE

tfe t=.~ x v li 37A (3RS) -3-r~-Nitrobenzyloxycarbon~tlamino 1 tert amylcarbonylmethyl-2 3-dihydro-2-oxo-5-phenyl 1H 1 4 benzodiazepin-2-one (Scheme step (i) ) ~ This was prepared following the method of Example 16A
using the benzodiazepine of Example 36B (325 mg, 0.68 mmol). 5% palladium-on-carbon (250 mg) and p-nitrophenyl chloroformate (150 mg, 0.75 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc: hexane fr 35:65 v/v) to provide the product as a yellow solid (135 mg, 38%).
Rf (EtOAc: hexane fr 40:60) 0.28.
NPR (CDCl3) b 8.10 (2H, d, J = 8 Hz) ; 7.50 - 7. 00 (12H, m); 5:40 (1H, d, J=8 Hz); 4.85 (lH, d, J = 17 Hz): 4.60 (1H, d, J = 17 Hz); 1.55 (2H, q, J = 8 Hz) ; 3:.10 (6H, s) : 0.75 (3H, t, J = 8 HzJ.
37B N- 3RS - ~-tern-Am lcarbon lmeth 1-2 3-dih dro-2-Qxo-S-x~henyl-1H-1 4-benzodiazegin-3 yl) N' 3 (carboxyphen~-~.~ urea (Scheme 3 step (ii) ) This was prepared following the method of Example 16B
~zsirag the benzodiazepine of Example 37A, (135 mg, 0.26 'mmol) and m-aminobenzoic acid (54 mg, 0.39 mmol). The crude product was purified by flash chromatography on silica gel (eluan~ EtOAc: hexane fr: AcOH 60:40:2) to give the title compound which was crystallised from acetonitrile to give a colourless solid (30 mg, 22a, >
97% pure by HPhC).
Rf (EtOAc: hexane fr: AcOH 60:40:2) 0.20.
NMR (CDC13) S 8 .10 - 6 . 80 (16H, m) ; 5. SO (1H, d, J =
S Hz); 4.80 (1H, d, J = 18 Hz); 4.65 (1H, d, J'=
18 Hz); 1.40 (2H, q, J - 8 Hz); 1.00 (6H, s);
0.70 (3H, t, J = 8 Hz).

~i~~~
l~Ca 93/ i 6999 PCT/GB93/00404 .. 6 4 M.S. (FAB +ve ion) m/e 527.1 (M+H).

N-((3RS)-1-tent-Butylcarbon~lmethyl-2.3-dihydra-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-vl)-N'-(3-dimethyl-aminophenvl) urea. Compound 43 This was prepared following the method of Example 27B
using the benzodiazepine of Example 2?A (185 mg, 0.38 mmol } , BBr3 ( 2 . 5 ml , 1. 0 M sol . in CH2C12 ) , and the isocyanate prepared as below:
' To a solution of 3-dimethylaminobenzoic acid (165 mg, 1 mmol) in toluene (5 ml) was added diphenylphosphoryl azide (275 mg, 1 mmol) and Et3N (101 mg, 1 mmol) . The mixture'was st~.rred at room temperature fox 2 hrs, then heated at reflus~ for 3 hrs. The solution of the above free amine in toluene (5 ml) was added to the cooled mixture and stirred at room temperature overnight, then evaporated, taken up in EtOAc, washed with 5% KHC03, H20 and brine, filtered (Whatman° 1 PS phase separator} and evaporated, and chromatographed (eluant EtOAc) to provide a colourless solid (38 mg, 200, 91o pure by HPLC).
Rf (EtOAc) 0.15.
NMR (CDC13) b 8.78 (d, 1H, J = 2 Hz); 8.27 (d, 1H, J
- 8 Hz); 7.~5 (m, 1H}: 7.65 - 6.6 (m, 11H); 5.83 (d, 1H, J = 8 Hz); 5. OS (d, 1H, J = 16 Hz); 4.60 (d, 1H, ~=16 Hz}; 3.00 (s, 6H); 1.40 (s, 9H).
M.S: (FAB) (M+H)' EX1~MPLE 3 9 N-((3RS)-1-tent-Butylcarbon~rlmethyl-2,3-dihydro-2-oxo-5-(2-gyridyl) -1H-1. 4-benzodiazepin-3- r~l) -N' - (3-~J t t 17 WO 93/16999 P(.°T/G89310~3404 carbox~henyl) urea. Compound 44 39A mono-Methyl isophthalate 5 Dimethyl isophthalate (2.28 g, 11.7 mmol) was taken up in dioxan (25 ml) and treated with a solution of LiOH.H20 (510 mg, 12.1 mmol) in water (15 ml) as described in Example 31B. The pxoduct was purified by chromatography (eluant EtOAc: hexane fr:AcOH 50:50:2 v/~r/v) to pro~cride 10 the title compound (1.1 g, 48%).
NMR (CDC13) $ 8.45 (s, 1H) ; 8.10 (2H, m) i 7.45 (1H, m) ; 3.80 (3H, s) .
15 39B_ N-((3RS)-1-tern-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-,~2-pyridyl~-1.H-114-benzodiazepin-3-yl)-N'-(3- .
methoxycarbony~hen3rl~ urea. (Scheme 1. stew lii) ) This was prepared following the method of Example 27B
20 using the benzodiazepine of Example 27A (185 mg, 0.38 mmol ) , BBr~ ( 2 . 5 ml , 1. 0 M sol . in CH2Clz ) .and the isocyanate prepared using the acid of Example 39A (250 mg; 1.4 mmol) with following the method of Example 38.
The product was purified by chromatography (eluant EtOAc) 25 to provade the title compound (110 mg, 56%).
NMR (CDC13) $ 8.30 (1H, d, J - 2 Hz); ?.95 - ?.00 (13H, m): 5.60 (1H, d, J - 8 Hz); 4.80 (1H, d, J

- 16 Hz); 4.50 (1H, d; J = 16 Hz); 3.70 (3H, s);
30 1.20 (9H, S) .
SUBSTITUTE SHEET

~3'p 93/15999 PG'1'/GB93/00404 39C ((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1 4-benzodiazenin-3-yl)-N'-(3-carboxvohenyl) urea This was prepared following the method of Example 31B, using the benzodiazepine of Example 39B (110 mg, 0.21 mmol ) and Li.OH . HZO ( 17 mg, 0 . 42 mmol ) . The crude product was purified by flash chromatography (eluant CHC13: MeOH:
AcOH 75:2:1 v/v/v) to provide the title compound which was freeze-dried from MeCN/H20 to give the product as a white solid (20 mg, 190, >98% pure by HPLC).
Rf (EtOAc:AcOH 100:2) 0.12.
NI~IR (CI7CL3) b 8.50 (1H, d, J = 2 Hz) ; 8.10 - 7.35 (13H, m); 5.65 (1H, s); 5.15 (1H,' d, J = 18 Hz); 4.90 (1H, d, J = 18 Hz); 1.35 (9H, s).
M.S. (FAB) (M+H)+

N~3RS -1-C~rclopentylcarbonylmethyl-2 3-dihydro-2-oxo-S-phen~.lilH-1 4-benzodiazepin-3=yl) -N' tdrme~thylaminophenyl) urea. Compound 45 This was prepared following the method of Example 1C
using the benzodiazepine of Example 4B (400 mg, (0.8 mmol) , 5% palladium-on-carbon (400 mg) and the isoeyanate (3 mmol) prepared as in Example 38. The crude product was purified by flash chromatography on silica gel (eluant EtOAc: hexane fr 60:40 v/v) to give the title compound which was crystallised from aceton5.trile to afford a white solid (84 mg, 25% >99% pure by HPLC).
Rf (EtOAc:hexane fr 60:40 v/v) 0.20.
NMR (CI7C13) b 7.60 - 6.50 (15H, m) ; 5.65 (1H, d, J =
8 Hz), 4.65 (s, 2H), 2.8 (s, 6H); 1.90 - 1.40 1'CTlG~93/~0404 WO 93116999 ~ ~ ~' '~ '~ :~' '~

( 9H, m) .
M.S. (FAB, +ve ion) m/e 524.5 (M+H) N- ( 3RS) -1-tart-Butylcarbon~lmethyl-2, 3-dihydro-2-oxo-5-phenyl-1H-1.4-benzodiazepin-3-yl)-N'-(3-dimethyl-aminophenyl ) urea . Comt~ound 4 6 20 This was prepared following the method of Example 1C
using the benzodiazepine of Example 2B (380 mg, 0.8 mmol) , 5% palladium--on-carbon (300 mg) and the isocyanate (3 mmol) prepared as in Example 38.
15 The crude product was purified by flash chromatography on ' silica gel (eluant EtOAc:hexane fr 55:45 v/v) and crystallised from acetonitrile to give the title compound as a white powder (127 mg, 31 0, >99% pure by Hk~LC).
20 Rf (EtOAc:hexane fr 60:40) 0.23.
NMR (CDC13) b 7.60 - 6.9 (15H, m}; 5.60 (1H, d, J = 8 Hz); 4.78 (1H, d, J - 18 Hz); 4.68 (1H, d, J =
18 Hz} ; 2.80 (6H, s) ; 1.20 (9H, s) .
M.S. (FAB, -rve ion) m/e 512.5 (M+H).

N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihvdro-2-oxo-5 30 -pk~enyl-1H-1. 4-benzodiazepin-3-vl) -N' - (3-methoxy~ahen~l) urea . Compound 4 7 This was prepared following the method of Example 1C
using the benzodiazepine of Example 4B (400mg, 0.8 mmol) , 35 5% palladium-on-carbon (300 mg) and 3-methoxyphenyl isocyanate (136 ul, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (eluant ~~~~T~'~~T~ SH~~

,:.,<,-.:_.....,.,_. .....,'..:, ~.:..~'.;.-.~... .. .
.,..s _ 4 .
s,.::

7:.,...
:>~.
7.
A .
.,:7. ;
,.v4 ~ ~. '. S 7 . .. . ... . . . , n... ,., . , fa..... 7 >. . . ..
~! 4t..i. . 2. F 4..:~ i. ;.. .. , ~...n..v.: A .,.,. ._,.... . . .....r .. .t. ,~". .. . . .. . , , 17 :n ....
,.n..~ .,n.... ..n v. . ... ..
W~ 93/16999 PCTl~B93f00404 EtOAc: hexane fr 50:50 v/v) to give the title compound which was crystallised from acetonitrile to give a white powder (265 mg, 650, >99o pure by HPLC).
Rf (EtOAc: hexane fr 50:50) 0.20.
NMR (CDC13) b 7.66 - 6.80 (15H, m); 5.75 (IH, d, J =
8 Hz) ; 4.85 (2H, d, J = 8 Hz) ; 3.90 (3H, s) ;
3.00 (IH, m); 1.95 - 1.40 (8H, m).
M.S. (FAB, +ve ion) m/e N-((3RS)-1-tent-Bu~lcarbonylmethyl-2.3-dihydro-2-oxo-5 phenyl-1H-1, 4-benzodiazepin-3-yl) -Iv' - (3-methoxvt~henyl) I5 urea. Compound 48 This was prepared following the method of Example 1C
using the benzodiazepine of Example 2B (385mg, 0.8 mmol), 50 palladium-on-carbon (300 mg) and 3-methoxyphenyl 2 0 isocyanate ( 13 6 ~Z1, 1. 04 mmol ) . The crude product was purified by flash chromatography on silica gel (eluant EtOAc: hexane fr 45:55 v/v) a:nd crystallised from acetanitrile to provide the title compound as a white powder (249 mg, 630; >99o pure by HPLC).
Rf (EtOAc: hexane fr 50:50) 0.23.
NMR (CDC13) b 7.60 - 6.50 (15H, m); 5.85 (IH, d, J =
g Hz); 4.92 (IH, d, J - I8 Hz); 4.82 (1H, d~ J = 18 Hz); 3.90 (3H, s); I.30 (9H, s).
M:S. (FAB, -we ion) m/e EXAM~~LE 44 N-((3RS)-I-Cyclo~enty_lcarbonylmethvl-2,3-dihvdro-2-oxo-5-phenyl-IH-1.4-benzodiazepin-3-yl)-N'-(3-nitrotahen~rl) ~LJ~~TITUTE ~HEE'~' W~ 93!16999 PCT/GB93/004ti4 urea. Compound 49 This was prepared following the method of Example 1C
using the benzodiazepine of Example 4B (400mg, 0.8 mmol), 5o palladium-on-carbon (300 mg) and 3-nitrophenyl isocyanate (171 mg, 1.04 mmol) . The crude product was purified by flash chromatography on silica gel (eluant EtOAc: hexane fr 45:55 v/v) and crystallised from acetonitrile to give the title compound as a pale yellow solid (291 mg, 69%, >99% pure by HPLC).
Rf (EtOAc: hexane fr 50:50) 0.22.
NMR (CDC13) b 8.00 - 7.10 (15H, m); 5.65 (1H, d, J
- 8 Hz); 4.74 (1H, d, J - 17 Hz); 4.67 (1H, d, J = 17 Hz); 2.95 (1H, m); 1.90 - 1.30 (8H, m) .
M.S.

N- (3RS)-1-tert-Butvlcarbony!methyl-2,3-dihydro-2-oxo-5-hen 1-1H-1 4-benzodiazez~in-3- 1 -N'- 3-nitro hen 1 urea. Compound 50 This was prepared following the method of Example 1C
using the benzodiazepine of Example 2B (385mg, 0.8 mmol), 5% palladium-on-carbon (300 mg) and 3-nitrophenyl isocyanate (171 mg; 1.04mmol). The crude product was purified by flash chromatography an silica gel (EtOAc:
hexane Fr 45:55 v/v) and crystallised from acetonitrile to provide the title compound as a pale yellow solid (283 mg, 69a >99o pure by HPLC).
Rf (EtOAc: hexane fr 50:50) 0.24.
NMR (CDC13) 8 8.10 - 6.90 (15H, m); 5.65 (1H, d, J =
8 Hz); 4.85 (2H, s); 1.25 (9H, S).
M.S.
SUSSTiTUTE SHEET

WO 93/H6999 ~ i'CTl~B93/00404 N- (,-( 3RS ) -? - ( ( 1-methvlcvclopentyl ) carbonylmethyl ) - 2 , 3 -5 dihydro-2-oxo-5-phenyl-1H-1.4-benzodiazepin-3-yl)-N'-(3-methylohen"yl) urea. Compound 32 46A 1-Methylc~rcl~,Fentane carboxylic acid 10 Cyclohexene (25 ml, 0.246 mol) was treated with conc.
sulphuric acid (200 ml) and formic acid (a8.9 ml, 0.5 mol) at 5°C for two hours. The mixture was poured onto ice and extracted twice with EtOAc. The organic extracts were washed wa.th brine, then extracted with 2M KOH. The ~5 basic extract was acidified with 2M HC1 and extracted with. CHC13, filtered (Whatman° 1 PS phase separator) and evaporated. The resultant brown oil was purified by bulb-to-bulb distillation (125°C/oil pump) to give the title compound as a colourless oil (860 mg, 2%).
46B Bromomet~l ~-met~lcyclo~entyl ketone Scheme 2, steps ti) - (ii:i) ) Thzs Haas prepared following the method of Example 3A. The 25 intermediate diazoketone was prepared from the acid of Example 46A (860 mg, 6.7 mmol) , thionyl chloride (2m1, 30 mmol) and CH~N2 (generated from Diazald° 4.3 g, 20 mmol) .
The di~zoketor~e uias subsequently treated with a saturated solution of HBr in EtOAc. Flash chromatography on silica 30 gel (eluant EtOAc: hexane fr 7:93 v/v) afforded the title compound (270 mg, 20%).
NMR (CDC13) cS 4.20 (2H, s) ; 2.15 - 1.45 (8H, m) ; 1.35 (3H, s) .
a~~STI'~U°~E SI~E~ i' .5. ~,, ~J :~ rj i3 ~CT/GB93/0~0404 ~'~'O 93/16999 46C (3RS)-3-Benzyloxycarbonylamino-1-(1-methylcyclopentyl)carbonylmethyl-2,3-dihydro-5-phenyl-1H-1,4-b~nzod~azenin-2-one (Scheme 1, step (i)) This was prepared following the method of Example 1B, using the Bock benzodiaZepine (202 mg, 0.5 mmol), sodium hydride (21 mg, of an 80% dispersion in oil, 0.70 mmol) and the bromomethyl ketone of Example 46B (133 mg, 0.65 mmol). The crude product was purified by flash chromatogaphy on silica gel (eluant EtOAc:hexane fr 40:60 v/v) to afford the title compound as a eolourless crystalline solid (290 mg, 74%).
Rf (EtOAc: hexane fr 40:60) 0.24.
NMR (CDC13) 8 7.55 - 7.05 (14H, m): 6.55 (1H, d, J -8 Hz) ; 5.35 (1H, d, J - 8 Hz) ; 5. 05 (2H, s) ;
4.77 (IH, d, J = l7Hz) ; 4.66 (1H, d, J = l7Hz) ;
2.10 - 1.40 (8H, m); 1.20 (3H, s).
46D N- ( f3RS) -1- ( (1-Methylcyclogentvl) carbonvlmethyl) -2_3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3~y1)-N'-(3-methylphenyl) urea (Scheme 1, step (ii)) This was prepared following the method of Example 1C
using the benzodiazepine of Example 46C (190 mg, 0.37 mmol), 5o palladium-on-carbon (150 mg) and m-tolyl isocyanate (65 ~cl, 0.50 mmol). The crude product was purified by flash chromatography (eluant EtOAc:hexane fr 40:60 v/v) to give the title compound which was lyophilised from MeCN/H20 to give the product as a white solid (102 mg, 54%, >97o pure by HPLC).
Rf (EtOAc:hexane fr 40:60) 0.20.
NMR (CDC13) b 7.70 - 6.90 (15H, m); 5.70 (1H, d, J =
8 Hz); 4.88 (1H, d, J = 17 Hz); 4.82 (1H, d, J =
17 Hz) ; 2.30 (3H, s) ; 2.10 - 1.40 (8H, m) ; 1.25 SIISSTITtJTE S~IEET

r, ~. n p.
J ~ f.~
W~ 93/36999 P~'/GB93/00404 (3H, s) .
M.S. (FAB +ve ion) m/e 509.3 [M+Hl N- ( (3RS) -1- tent-Butylcarbonylmet~h~l-2 ~ 3-dihydro-2-oxo-5-~henvl-1H-1.4-benzodi;~a~zepin-3-yl) -N' - (3-formylaminophenyl) urea. Compound 51 47A 3-Formylaminobenzoic acid Acetic anhydride (50 ml) was added to 98 o formic acid (85 ml). The mixture was stirred at room temperature far 30 wins, then 3-aminobenzoic acid (10 g, 73 mmol) was added and the mixture was stirred for one hour at room temperature. Water (850 ml) was added and the mixture was stirred ovenight at room temperature. The resultant white precipitate was collected (10.66 g, 88A).
NMR (CDC13) b 8.90 - 7.50 (7H, m) .
47B N-((3RS)-1-tent-Butylcarbon~lmethyl-2 3-dih~dro-2-oxo-5-phenyl-1H-1,4-benzodiazapin-3 yl)-N'-(3-formylaminophenyl) urea (Scheme I step (ii)) The benzodiazepine of Example 2B was hydrogenated as described in Example lC and the resultant amine (250 mg, 0.71 mmol) in toluene (2 ml) was treated with the isocyanate prepared using the acid of Example 47A (410 mg, 2.5 mmol) following the method of Example 38. The product was purified by chromatography twice (eluant EtOAc and CHCI3:MeOH':AcOH 80:20:1 v/v/v) and crystallised from acetonitrile to give a colourless solid (75 mg, 21p, >97o pure by HPLC).
'H NMR (CDC13) b 8.90 - 8.10 (3H, m) ; 7.75 - 7.10 (14~I, m); 6.70 (1/2H, d, J=lBHz); 5.75 (1H, m); 4.90 (1H, m);
1.30 (9H, 3s) .
~IJ~ST~TU'f E SH~E°~

,:;e:, <:. .,;; .... . ~ .. : - - ~ :.. . :, . . . . .. . . .
)~ ~~~1 t~
CVO 93116999 PC 1'1GB93I00404 M.S. [M+H]' - 512.2.
Example 48 N- ( t3R) -1- ( (2R) -2-Hydroxy-3 3-dimethylbutyl) -2~3-dih~ dt ro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl~ urea Comgound 52 The benzodiazepine urea of Example 26 (180 mg, 0.373 mmol) was taken up in a mixture of methanol and dichloromethane (5 mI, 1/1, v/v) and CeC13.7H20 (255 mg, 0 . 416 mmol ) was added and the mixture stirred to dissolve alt solids and then cooled to -78°C. Sodium borohydride (20 mg, 0.529 mmol) was added and the mixture stirred at -78°C for 10 min then at -10°C for lh, warming to room temp over 2 hours. The mixture was partitioned between r CHC13 and brine and the organic portion dried and evaporated. The residue was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 40:60 v/v) to provide a colourless solid (105 mg, 58%, >98o pure by HPLC).
Rf (EtOAc: 60- 80 pet. ether 40:60) 0.31 2S ~H NMR (CDGl3) 8 ?.8 - 6.9 (15H, m) . 5.6 (1H, d, J
BHz); 4.35 (1H, m); 3.6 (2H, m): 2.2 (3H; sl ; 0.85 (9H, s) .
M.S. (FAB, +ve ion) m/e = 485.3 [M+H]
Example 49 N-((3RS)-l~Cyclooentvlcarbonylmethvl-2 3-dihydro-2-oxo-5--phenvl-1H-1.4-benzodiazepin-3-yl)-N'-(3-cyano~henyl) urea . Compound 22 This was prepared following the method of Example 1C
using the benzodiazepine of Example 4B (300 mg, 0.6 ~UBST1TUTE SHEET

T r 415 r r, S 2 S Gi;. ~4V .L;.::. 5 ~'Y F m .P
.. ~.~...,. . .~rW ,. , , ,. ,.,.,F..,>. ..'°S. ....
2.I~: ~~~~ .
~O 93!16999 PCT/GB93/00404 mmol), 5% palladium-on-carbon (150 mg) and the isocyanate prepared from 3-cyanobenzoic acid (295 mg, 2 mmol) following the method of Example 30. The crude product was purified by flash chromatography on silica gel (eluant CHCI3:AcOH 100:2 v/v) to give the title compound which was lyophilised from MeCN/H20 to afford a white crystalline solid (30 mg, l0%, >97% pure by HPLC).
NMR (CDC13) b 8 .20-8 . 05 (4H, m) ; 7 . 70-7.10(llH,m);5.50(IH,d,J=8Hz);4.75 (1H, d, J .-- l7Hz); 4.66 (1H, d, J = l7Hz); 1.75 - 1.35 ( 9H, m) .
M.S. (FAB): (M+H)' - 506.1 ;, ~~". v:'':..
Exam le 50 N- ( (3RS) -1-te.rt-Butylcarbony!methyl-2t3-dihydro-2-oxo-5 phenyl-1H-1.4-benzodiazeoin-3 yl)-N'-(3-cyanophen~rl) urea. Compound 23 . ~ -., .,..: ,;..
This was prepared following the method of Example 1C
using the benzodiazepine of Example 2B (290 mg, 0.6 mmol) , 5 o palladium--on-carbon (150 mg) and the isocyanate prepared from 3-cyanobenzoic acid (29S mg, 2 mmol) following the method of Example 30. The crude product was purified by flash chromatography on silica gel (elcaant CHCI3:AcOH, 100:2 v/v) to afford the title compound which was lyophilised from MeCN/H20 (36 mg, 120, >96% pure by HPLC).
NMR (CDC13) b 8.20 - 8.05 (4H, m); 7,70 - 7.10 (11H, m); 5.50 (1H, d, J - 8Hz); 4.90 (1H, d, J -l7Hz) ; 4.70 (1H, d, J = l7Hz) ; 1.15 (9H, s) .
M.S. (FAB) : CM+H]' - 494.2 r.~ ~?
WO 93/16999 PCTlGB93/00404 Example 51 N-((3RS)-1-(1-Adamantvl)carbonvlmethyl-2,3-dihydro-2-oxo 5 5 -phenyl -1H-1, 4 -benzodiazepin-3 -yl ) -N' - ( 3 -meth~rlphen~rl ) urea . Compound. 25 51A 1-Adamantyl bromometh~rl ketone (Scheme 2~ steps (ii) - ,~iiiL
This was prepared following the method of Example 3A.
The intermediate diazoketone was prepared from 1-adamantane carboxylic acid chloride (2.98 g, 15 mmol) and CHxN2 (generated from Diazald° 8.7 g, 40 mmol) and subsequently treated with a saturated solution of HBr in EtOAc. Flash chrom~tngraphy on silica gel (eluant EtOAc:hexane fr 8:92) afforded the title compound as a pale brown mobile oil (2.30 g, 600).
NMR (CDC13) S 4.20 (2H, s) ; 2.15 - 1.75 (15H, m) .
51B (3RS)-1-(1-Adamantvl)carbonylmethyl-3-benzvloxvcarbonvla~nino-2,3-dihvdro-5-~henvl-1H-1.4-benzodiazepin-2-one -(Scheme 1, step (i)) This vaas prepared following the method of Example 1B, using the Bock benzodiazepine (202 mg, 0.5 mmol), sodium hydride (21 mg of an 80% dispersion in oil, 0.70 mmol) and the bromamethylketone of Example 51A (167 mg, 0.65 mmol). The crude product was purified by flash chromatography (eluant EtOAc:hexane fr 40:60 v/v) to afford the title compound as a colourless cx-ystalline solid (130 mg, 460).
NMR (CDC13) b 7.75 - 7.15 (l4H,m) ; 6.80 (1H, d, J =
8Hz) ; 5.55 (1H, d, J = 8Hz) ; 5.25 (2H, s) ; 5.07 (1H, d, J = l7Hz); 4.76 (1H, d, J = l7Hz); 2.15 -~~G~~~~~
PCTf C B93l00404 ~ ~ ~~'~'~~9 1.80 (15H, m) .
51C N-((3RS)-1-(1-Adamantyl)carbonylmethyl-2,3-dihydro-2-oxo-5=phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methvlnhenvl) urea (Scheme 1, step (ii)) This was prepared following the method of Example 1C
using the benzodiazepine of Example 51B (130 mg, 0.23 mmol), 5% palladium-on-carbon (100 mg) and m-tolylisocyanate (45 ~.1, 0.35 mmol). The crude product was purified by flash chromatography (eluant EtOAc:hexane fr 35:65 v/v) to give the title compound which was lyophilised from MeCN/HZO to give a white solid (5? mg. 44 0, >96% pure by HPLC) . , NMR (CDC13) b 7.75 - 7.10 (14H, m); 6.82 (lH,d,J =
SHz); 5.75 (lH,d,J = 8Hz); 4.~0 (lH,d,J = l7Hz);
4.80 (lH,d,J ~ l7Hz); 2.30 (3H, s); 2.10 - 1.60 (15H, m).
i~I.S. (FAB +ve ion) m/e 561.3 [M+H]

N- ( (3RS) -1- (3-Cyclohexyl-3-methyl-2-oxobut~l~-2 , 3 dihydro-2-oxo-5-phenyl-IH-1,4-benzodiazepin-3=y11-N'-f3 methy~henyl) urea. Compound 28 52A Methyl-2-methyl-2=phenylnro~anoate To a solution of methyl phenylacetate (10.5 g, 70 mmol) in THF (125 ml) at 0°C was added sodium hydride (2.25 g, 80% dispersion in oil, 75 mmol). The mixture was stirred for 30 wins at 0°C, then iodomethane (4.4 mls, 70 mmol) was added and the mixture was stirred for a further 30 mins at 0°C. Further sodium hydride (2.25 g, 80%
dispersion in oil 75 mmol) was added and the mixture was stirred for 30 mins at 0°C, then iodomethane (8.8 mls, 140, mmol) was added and the mixture was left for 48 ~lI~STI i IJT~ ~H~E'T

~ ;~ r ~~Y~~~t~ii hours at room temp. The reaction was quenched with H20 and the mixture was concentrated to remove the THF. The residue was taken up in EtOAc and washed with 5% KHC03, 0.3 M KHSOS and brine, filtered (Whatman° 1 PS phase separator) and evaporated to give the title compound as an oil (3.20 g, 260) .
NMR (CDC13) b ?.50 - ?.25 (5H, m) ~ 3.60 (3H, s) ; 1.55 (6H, s) .
52B 2-Methyl--2 phen~rlpropanoic acid A solution of the methyl ester of Example 52A (3.20 g, 18 mmol) in dioxan (25 ml) was treated with Li0H.H20 (1.50 g, 36 mmol) in water (15 m1) as described in Example 31B, to give the title compound as a colourless oil (1.85 g, 630) (CDC13) b 7.50 - ?.25 (6H, m); 1.55 (6H, s).
52C 2-Cvclohexul-2-methylpropanoic acid A solution of the acid of Example 52B (1.85 g, 11.3 mmol) in MeOH (100 mL) was degassed for 10 mires using nitrogen.
So Rhodium-on-carbon (2 g) was added and the mixture was degassed for a further 10 mans, then hydrogenated at room temperature/ 6 0 p . s . i . ( Parr ) f or 4 days . The mixture was filtered through celite and the filtrate was evaporated to give the title compound as a colourless oil (1.70 g, 88%) .
I~1MMR (CDC13) b 1-90 - 1.00 (11H, m) j 1.20 (6H, s) .
52D 1-Bromo-3-cyclohexyl-3-meth°~lbutan-2-one (Scheme 2, step (i) - (iii This was prepared following the method of Example 3A.
The intermediate diazoketone was prepared using the acid ~U~3S'fiTU'fE SHEET

W~ 93/16999 P~.T/~B93100404 78 , of Example 52C (170 g, 10 mmol), thionyl chloride (2 ml, 30 r~,mol) . and CHZNZ (generated from Diazald~ 8.7 g, 40 mmol) and subsequently treated with a saturated solution of HBr in EtOAc. Flash chromatography on silica gel (eluant EtOAc: hexane fr 5:95 vjv) gave title the compound as a pale brown mobile oil (280 mg,ll%).
NMR (CDC13) S 4.30 (2H, S) ; 2.90 - 1.10 (11H, m) ; 1.20 (6H, s) .
52E (3RS)-3-Benz~loxycarbon~lamino-1-(3-~rclohexyl - 3-methyl-2-oxobut~rl)-2,3-dihvdro-5-phenyl-1H-1,4 benzodiazepin-2.~one ( Schemed , step ( i ) ~
Th~.s was prepared following the method of Example 1B
using the Bock benzodiazepine (202 mg, 0.5 mmol), sodium hydride (21 mg of an 80o dispersion in oil, 0.70 mmol) and the bromomethylketone of Example 52D (160 mg, 0.65 mmol). The crude product was purified by f~.ash chromatography (eluant EtOAc:hexane A 35:65 vjv) to afford the title compound as a colourless crystalline solid (70 mg, 25e)~
,;;.' NI''IR (CDCl3) b 7:55 - 7.05 (l4H,m) ; 655 (1H, d, J -gHz) ; 5.30 (1H, d, J - 8Hz) ; 5.02 (2H, s) ; 4 . 78 (1H, d, J = l7Hz); 4.58 (1H, d, J = l7Hz)~ 1.70 0.90 (11H, m);' 1.00 (6H, s).
52F N-,~(3RS) - 1- (3'-Cyclohexyl-3-methyl-2-oxolaut~tl) -2 , 3 dih dro-2--oxa-5- hen l-1H-1 4-benzodiaze in-3- 1 -N'-~3 methy_l~ahen~l urea (Scheme lj step ~ii~~
This was prepared following the method of Example 1C
using the benzodiazepine of Example 52E (70 mg, 0.13 mmol), 5p palladium-on-carbon (50 mg) and m-tolylisocyanate (20 ~cl, 0.16 mmol). The crude product was purified by flash chromatography (eluant EtOAc:
hexane fr 40:60 vjv) to give the title compound which was SUBSTITUTE SHES'i' ~'~D 93/16999 PCTlGB93100404 lyophilised from MeCN/H20 to give the product as a white solid (35 mg, 50%, >95% pure by HPLC).
NMR (CDC13) 8 7.?0 - 6.95 (14H, m) ; 6.60 (1H, m} ; 5.?5 (~.H, d, J - 8Hz) ; 4 .90 (1H, d, J = L'7Hz) ; 4.83 (1H, d, J - l7Hz); 2.35 (3H, s); 1.90 - 0.95 (11H, m); 1.10 (6H, s).
M.S. [M+H]' - 551.3.
Example 53 N- f'~3RS) -1- (1-Meth~lc r~clopro)~vl) carbonylmethyl-2~3-dihydro-2-oxo-5-lahenyl-1H-~., 4-benzodiazepin-3-~1) -N' - (3-ms~th,~rl_phenyl ) urea . Compound 54 53A Bromomethyl 1-methylcy_cloprogyl ketone To a stirred solution of methyl 1-methylcyclopropyl ketone (5 g, 50.9 mmol) in MeOH (30 ml) at O°C was added bromine (2.6 m1, 5l mmol) dropwise. The mixture was stirred at O°C for 2 hours. Water (15 ml) was added and the mixture was stirred at room temp overnight. Further water (45 ml) was added and the product was extracted into Et20. The organic extract was washed with 10% K2C03, HZO and brine, dried over CaCl2 for 30 mina, filtered (Whatman~ 1 PS phase separator) and concentrated in vacuo to afford the title compound as a clear mobile oil (8.2 g; 91%) .
NMR (CDC13) b 3:95 (2H, s); 1.40 (3H, s}; 1.3p (2H, t, J = 7Hz); d.80 (2H; t, J = 7Hz).
53B (3RS)-3-Benzvloxycarbonylamino-1-(1-methylcyclopropvl)carbonvlmethyl-2,3-dih~rdro-1H-1,4-benzodiazepin-2-one (Scheme 1~' step (5.) ) This was prepared following the method of Example 1B, ~~~~5 TlTUTE SHEET

iVO 93/ 16999 V PCT/GB93/00404 using the Hock benzodiazepine (202 mg, 0.5 mmol), sodium hydride (21 mg of an 80o dispersion in oil, 0.?0 mmol) and the bromomethyl ketone of Example 53A (133 mg, 0.75 mmol). The crude product was purified by flash 5 chromatography on silica gel (eluant EtOAc:hexane fr 40:60 v/v) to afford the title compound as a colourless crystalline solid (190 mg, ?90).
NMR (CDC13) b 7.55 - 7.10 (14H, m); 6.65 (1H, d, J
10 8Hz) ; 5.40 (1H, d, J - 8Hz) ; 5.10 (2H, s) ;
4.77 (1H, d, J = 17HZ) ; 4.55 (1H, d, J = l7Hz) ;
1.40 (3H, s, ) ; 1.25 (2H, t, J = 7Hz) ; 0. 75 (2H, t, J = 7Hz ) .
15 53C IvT-((3RS)-1-fl-Methylcyclopropyl)carbonvlmethyl-2.3-dihydro-2-oxo-5~ahenyl-1H-1,4-benzodiazepin-3-girl)-N'-3-meth;~lphen~l ) urea Scheme 1, step tii ) ) This was prepared following the method of Example 1C
20 using the benzodiazepine of Example 53B (190 mg, 0.4 mt,ial) , 5% palladium-on-carbon (200 mg) and m tolylisocyanate (65 ~cl, 0.5 mmol) . The crude product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 45:55 v/v) to give the title compound 25 which was lyophilised from MeCN/H20 to give a white solid (150 mg, 780, >98% pure by HPLC).
Rg (EtOAc:hexane fr 40:60) 0.16.
~R (CDC13) b 7.70 - 7.10 (l4H;m) ; 6. 85 (1H, d, J =
30 8Hz); 5.75 (1H, d, J - 8Hz); 4.82(1H, d, J -l7Hz) ; 4.75 (1H, d, 'J = ~.?HZ) ; : .35 (3H, s) ; 1.45 (3H, S) ; 1.30 (2H, t, J = ?Hz) ; 0. 90 (2H, t, J =
7Hz ) .
M.S. (FAB, -eve ion) m/e 481.2 [M+H].

21~~~~~~t WO 93116999 PC'1'/GB93/00404 Examvle 54 N-~( 3RS Ll-tart-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5 (2-chlorophenyl-1H-1, 4-benzodiaze~in-3-yl) -N' - (3 meth~rlphenyl) urea. Compound 55 54A 3RS)-3-Benzyloxycarbonylamino-1-tert-butylcarbon~rlmethyl-7-chloro-5- (2-chlorophen~rl) -IH-1 , 4 benzodiazepin-2-one (Scheme 1. step (1)) This was prepaxed following the method of Example 1B, using (3RS)-3-benzyloxy-carbonylamino-7-chloro-5-(2-chlarophenyl)-1Fi-1,~-benzodiazepin-2-one (241 mg, 0.51 1S mmol, prepared in analogy to the Bock benzodiazepine), sodium hydride, (22 mg of an 80% dispersion in oil, 0.72 mmol), and 1-bromopinacolone (179 mg, 1 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 30:70 v/v) to afford the title compound (145 mg, 52%).
NMR (CDCI~) b ?:80 - 7.30 (12H, m): 6.80 (1H, d, J =
8Hz); 5.60 (1H, d, J - 8Hz); 5.30(2H, s);
5.25 (1H, d; J = l7Hz) ; 4.60 (~.H, d, J = l7Hz) ;
1.35 (9H, S) .
548 N-((3RS)-~-text-Butylcarbonylmethyl-2,3-dihydro-2-oxo-S- (2-chloraphen~l~,-1H-1,4-benz.odiazex~in-3-yl-N' - (3-m~th,~r2phen~rl ) urea ( Scheme 1, step ( ii ) ) Thas was prepared following the method cf Example 1C
using the benzodiazepine of Example 54A (145 mg, 0.26 mmol), 5o palladium-on-carbon (120 mg) and m-tolyl isocyanate (40 ~cl, 0.32 mmol) . The crude product was purified by chromatography (eluant EtOAc:hexane fr 40:60 v/v) to provide the title compound which was lyophilised from MeC:N/H20 to give the product as a white solid (45 SIJBSTI i USE SNEER' U t .~... . ..~:.. ' ,,;~,: ;~:. ,:,~ .:.~ .;., '.: :v:' . ...' ' ::..'.
,,.;.. ~'!;. ...:.. . ..:'~a . ~..; ::. :.-..~ .~. : - ~ . , ~. 1 ~:. ,l ~l ~ v WC? 93/1999 PC'T/GB93/8(~404 mg, 310) .
NMR (CDC13) b 7.70 - 6.95 (14H, m); 5.80 (1H, d, J =
8 Hz); 5.30 (1H, d, J = 17 Hz); 4.60 (1H, d, J =
17 Hz) ; 2.40 (3H, s) , 1.30 (9H, s) .
M.S. (FAB, +ve ion) m/e 517.2 [M+Hl Note: The 7-chloro substituent is lost during the hydrogenolysis.

N-((3RS~1-Isopro~ylcarbonylmethy_1-2.3-dihydro-2-axo-5-phenyl-1H-1.4-benzodiazepin-3-yl-N'-(3-methylphenyl) urea . Compound 56 55A 1-Bromo-3-meth~rlbutan-2-one (Scheme 2, steps (i) - (~.ii)~
This was prepared following the method of Example 3A.
The intermediate diazoketone was prepared from isobutyric acid 8.82 g (100 mmol), thionyl chloride (30 ml,-400 mmol) and CHaN2 (generated from Diazald~, 43 g, 200 mmol) and subsequently heated with a saturated solution of HBr in EtOAc. Flash chromatography on silica gel (eluant ~5 EtOAc:hexane fr 6:94 v/v) afforded the title compound as mobile oil (300 mg, 1.8n).
NMR (CDC13) b 4.25 (2H, s; 3.00 (1H, heptet, J - 8 Hz); 2.25 (6H, d, J = 8 Hz).
55B (3RS) -3-Benz~rlox~ycarbonylamino-1-iso~ropyl-carban lmeth 1-2 3-dih dro-5- hen 1-1H-2 4-benzodiazex~in-2-one (Scheme 1, seep ti)) This was prepared following the method of Example 1B, using the Bock benzodiazepine (606 mg, 1.5 mmol) , sodium hydride (63 mg of an 80% dispersion in oil, 2.1 mmol) and the bromomethylketone of Example 55A (300 mg, 1.8 mmol).
SU~STI'~"UTE ~~iE~1' ~ ~ ~ ~ ~ tj z < a WO 93116999 Pt.'T/GB93/00404 The crude product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 40:60 v/v) to afford the title compound as a colourless crystalline solid (250 mg, 36%) .
NMR (CDC13) b 7.?0 - ?.20 (14H, m); 6.75 (1H, d, J =
8 Hz); 5.50 (1H, d, J = 8Hz); 5.20 (2H, s); 4.85 (1H, d, J = l7Hz) ; 4.75 (1H, d, J = l7Hz) ; 2.80 (1H, heptet, J = SHz); 1.25 (6H, d, J = 8Hz).
55C N-((3RS)-2-Isopropvlcarbonylmeth'rl-2,3-dihvdro-2-oxo-5-phenyl-1H-la4-benzodiazepin-3-,yl)-N'(3-methvlphen~yrl,~ urea ( Scheme 1, step ( i i~ ) 15, This was prepared following the method of Example 27B
using the benzodiazepine of Example 55B (250, mg, 0.53 mm~l ) , BBr3 ( 3 . 2 ml , I . 0 M sol in CHZC12 ) and m-tolyl isocyanate (40 ~.1, 0.31 mmol). The product was purified by flash chromatography on silica gel (eluant EtOl.~c:hexane fr 55:45 v/v) to provide the title compound which was lyophilised from MeCN/H20 to give the product as a white solid (5l mg, 21%, >98% pure by HPLC).
Rf (EtOAc:hexane ~r 50:50) 0.16.
NMR (CT)C13) b 7.70 - ?.15 (14H~ m) ; 6.85 (1H, d, J =
8Hz); 5.70.(1H, d, J = 8Hz); 4.75 (2H, s); 2.70 (1H, hep~et, J = 8Hz); 2.30 (3H, s); 1.18 (6H, d, J = 8Hz ) . .
M.S. (FAB; +ve ion) m/e 469.3 (M+H]

N-((3R)-1-tart-Butylcarbonvlmethyl-2.3-dih~rdro-2-oxa-5-phenyl-1H-1.4-benzodiazepin-3-yl)-N'-~3-meth,~rlaminonhenyl) urea. Compound 57.
~v~~~~~U~~ ~~~~

2~~~~~~
W~ 93/16999 PCT/GB93/OtD404 56A N-Methyl-3-methoxycarbonylformanilide This was prepared following the method of Example 1B, using 3-carboxyformanilide (2.28 g, 13.8mmo1), sodium hydride (1.05 g of an 80o da.sgersion in oil, 34.5 mmol) and iodometho~ne (2.85 mls, 45 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 60:40 v/v) to afford the title compound as a colourless crystalline solid (2.30 g, 860) .
II~MR (CDCl3) c~ 8.50 (1H, s; 7.90 - 7.40 (4H, m) ; 3.95 (3H, s) ; 3.40 (3H, s) .
56B N-Methyl-3-carboxyformanilide This was prepared following the method of Example 31B, using tine ester of Example 56A (1.90 g, 9.8 mmol) and-LiOH.H20 (840 mg, 20 mmol). The title compound was obtained as a colourless crystalline solid after work up (985 mg, 56p), 56C N-((3R)=1-tent-Butylcarbonylmethyl-2,3-dihydro 2-oxo-5-phenyl-1H-1,4-benzodiaze"pin-3 yl)-N'-~3-f,N
form 1-N-meth lamina hen 1 urea Scheme 1 ste ii ) The resolved aminobenzodiazepine of Example 26 (980 mg, 2.8 mmol) in toluene (ZO ml) was treated with the i~ocyanate prepared from the acid of Example 56B (985 mg, 5.5 mmol) following the method of Example 38. The product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 75:25 v/v) to provide the title compound (960 mg, 65%).
NMR (CDC13) b 8.45 (1H, s) ; 7.65 - 7.05 (14H, m) ; 6.70 (1H, d, J = 8 Hz); 5.70 (1H, d, J = 8 Hz); 4.98 ~~~a~~~~u~~ iH~~~

~~.~~~~~>
W~ 93/16999 PC'i'/GB93/04404 (1H, d, J = 17 Hz); 4.75 (1H, d, J = I7 Hz); 3.20 (3H, s); I.30 (9H, s).
56D N- ( (3R) -1-tart-Eut~rlcarbor_ylmeth~l-2, 3-dihydro-2 5 oxo-5-pher~rl-IH-I, 4-benzodiaze~in-3-yl) -N' - (3 methylaminophenyl ) urea The benzodiazepine of Example 56C (960 mg, 1.8 mmol) was taken up in acetone (15 ml) and treated with 4N HC1 (9 10 ml). The mixture was stirred at room temp for 3 days, then evaporated, taken up in CH2C12, washed with 5% KHCO3, filtered (T~lhatman° 1 PS phase separator) and evaporated.
The residue was purified by flash chromatography on silica gel (eluant CHCI3:MeOH:AcOH 120:2:1 v/v/v) to give 15 the title compound which was crystallised from MeCN/Et20 to give a white solid (400 mg, 45%, >99% pure by HPLC).
NMR (CDC13) b 7.70 - 7.20 (13H, m) ; 6.75 (1H, s) ; 6.65 (1H, d, J - 8Hz): 6.30 (1H, d, J - 8Hz); 5.75 20 (1H, d, J - 8Hz); 4.85 C2H, s); 2.80 (3H, s);
1.20 (9H, s).
M.S. (FAE +ve ion) rc~/e 498.3 [M+H~

~1- 3RS --1-tern-Bud. lcarbon lmeth l-2 3-dih dro-2-oxo-5 2-x~yridyl~-1H-1,4-benzodiazepin-3-y1) -N° - (3 meth~minophenyl) urea. Compound 58 30 57A N- ( L3RS~ -I- tart-Eut~,rlcarbon~rlmethyl-2 , 3-dih~rdxo ~, 2-oxo-5- (2~,pyridyl~-1H-1.4-benzodiazel~in-3--yl) -N' - (3-~N-, f orm~tl --N-methyl amino) phen~rl ) urea ( Scheme 3 , step ( ii ) This was prepared following the method of Example 27B
35 using the benzodiazepine of Example 27A (340 mg, 0.7 mmol ) , HBr~ ( 4 . 4 ml , 1. 0 M sol in CH~C12 ) and the isocyanate prepared using the acid of Example 56B (420 SIJ~STITIJTE S~EE°f :. . ..,e :~.. . r. .,~... !_.;. ..:'' ' ~~~ .v:'. .. ,::.,. ~ .::-. ,.~:;:~ .
. ~.v ", ~w~ .... . ..
..y,.,Sj' . ~.:::.. '~,., .~ ,., . .',:.,~. . ~., v... .;, . _..,., .,;,:, ,....:... ..,.. ..~;. ~ .;:..,.~ ~.. ~.~~,. y , ~._,:.'.. ,.....:..~: .
...,,,:.~... , ..~,.:v.._ ~ ..
...... ,,s.,. ,...~.s- .;...,,.,. ,n.,r.......". . .. .. . :.. ..~.:.
,.~.,,:r,.,,.,t ...... . . . , ;.. . . ,.. .. r.... . , .. .
~~~,~.'~3ju WO 93!16999 PCT/GB93/00404 mg, 2.3 mmol) following the method of Example 38. The product was purified by flash chromatography on silica gel (eluant EtOAc) to provide the title compound (185 mg, SOo) .
NMR (CDC13) c5 8.2:5 (1H, d, J - 8Hz) ; 8. 00 (1H, s) ;
7.80 - 6.80 (12H, m); 6.~0 (1H, d, J = 8Hz); 5.35 (1H, d, J - 8Hz) ; 4 .62 (1H, d, J - l7Hz) ; ~ .30 (1H, d, J = l7Hz); 2.90 (3H, s); 0.90 (9H, s).
57B N- l (3RS,~ - 1-tart-Hutylcarbon>rlmethyl-2, 3-dihydro-2-oxo-5- 2- rid 1 -1H-1 4-benzodiaze in-N'-3- 1 -3-meth~rlaminonhenyl) urea This was prepared following the method of Example 56D, using the benzodiazepine of Example 57A (185 mg, 0.35 mmol), acetone (5 m1) and 4N HC1 (3 ml). The crude product was purified by flash chromatogaphy on silica gel (eluan~ CHCI3:Me0~T:AcOH 120:2:1 v/v/v) to provide the title compound which was lyophilised from MeCN/Ha0 to g~:ve the product as a white solid (67 mg, 38%, >95a pure by HPLC ) .
NMR (CDCl,) b 8:30 (1H, d, J = SHz); 7.95 (1H, d, J =
8 Hz) ; 7.60 (1H, t, J = 7Hz) ; 7.35 (1H, t, J
7Hz); 7.20 - 6.85 (8H, m); 6.50 (1H, d, J = 8Hz);
6:30 (~H, d, J.= 8Hz): 6.10 (1H, d, J - 8Hz);
5.40 (1H, d, J = 8Hz) ; 4.75 (IH, d, J - l7Hz) ;
~.~0 (1H, d, J = l7Hz) ; 2:60 (3H, s) ; 0,95 (9H, s) .
M.S. (FAB +ve ion) m/e 499.3 [M+H) N- 3R -1-tart-But !carbon !meth 1-2 3-dih dro-2-oxo-5-phenvl-1H-1,4-benzodiaze~in-3-y1) -N' - (3- (N-ethyl-N-methylamino)phenyl) urea. Compound 59 'f ~ ~
~.L~ ~~~s;
WO 93/16999 PCT/GB93f00404 58A Met~l-3-(N-ethyl-N-meth~lamino)benzoate This was prepared following the method of Example 56D
using the methyl ester of Example 56A (2.35 g, 12.2 mmol), acetone (100 ml) and 4N HCl f60 ml). The resultant amine was taken up in MeOH:AcOH (99:1, 70 ml) at O°C. Acetaldehyde (1.0 ml, 18 mmol) and NaBH3CN (1.13 g, 18 mmol) were added. The mixture was stirred at O°C
for 2 hours, then evaporated, taken up in EtOAc, washed with 5o KHC03, brine, filtered (Whatman° 1 PS phase separator) and evaporated. The residue was purified by flash chramatography on silica gel (eluant EtOAc:hexane fr 15:85 v/v) to give the title compound (2.15 g, 91%).
NMR (CDC13) a 7.40 - 7.25 (3H, m); 6.90 (1H, m); 3.90 (3H, s) ; 3 .45 (2H, quartet, J = 7Hz) ; 2.95 (3H, s) ; 1. a5 (3H, t, J = 7Hz) . ...
58B 3-(N-Eth~rl-N-methylamino)benzoic acid This was prepar~:d following the method of Example 318, using the ester of Example 58A (2.15 g, 11.1 mmol) and LiOH.H20 (920 mg, 22 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr:Ac~H 35:65:2) to give the title compound, .
(1:9!? g; 95n) .
58C N- 3R -1-tart-But lcarbon lmeth l-2 3-dih dro-2-oxo-5- hen 1-1H-1 4-benzodiaze in-3- 1 -N'- 3- N-eth ~.-N-methylaminophenyl) urea (Scheme l~ste~,a) (ii)~
The resolved aminobenzodiazepine of Example 26 (245 mg, .7 mmol) in toluene (5 m1) was treated with the isocyanate prepared using the acid of Example 58B (250 mg, 1.4 mmol) following the method of Example 38. The product was purified by flash chromatography on silica gel Eeluant EtOAc:hexane fr 45:55 v/v) to give the title SU~3STiTUTE SHEET

.,:..: ., :.,;,. ,.. . .: . ... ;.::. :::. ..,. : ,. , . ..;:... .. . . . ; .
.,: ;.:-. .. .
2~.~~'~~~
WO 93116999 PCT/G893/004i)4 compound which was crystallised from acetonitrile to give the product as a white solid (237 mg, 64 0, >99 o by HPLC) .
NMR (CDC13) ~ 7.70 - 7.05 (13H, m); 6.58 (1H, d, J =
8Hz); 6.50 (1H, d, J - 8Hz); 5.$0 (1H, d, J -8Hz) ; 4.90 (1H, d, J = l7Hz) ; 4.83 (1H, d, J -l7Hz) ; 3.40 (2H, quartet, J = 7Hz) ; 2.95 (3H. s) ;
1.25 (9H, s) ; 1.15 (3H, t, J = 7Hz) .
M.S. (FAB, +ve ion) m/e 526.3 [M+H]

N ((3R) 1 tert-Butylcarbonylmethyl-2 3-dihvdro-2-oxo-5 ~henvl 1H 1L4-benzodiazepin-3-yl)-N'-(3 diethylamino~henyl) urea Compound 60 59A ' 3-Ethoxvcarbonvl-N-ethylformanilid~
This was prepared following the method of Example 1B, using 3-carboxyformanilide (5.0 g, 30 mmol), sodium hydride (2.26 g, of an 80o dispersion a.n oil, 75 mmol) I ' and ioc3oethane (5.2 ml, 64 mmol). The product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 50:50 v/v) to provide the title compound (6.00 g, 27.1 mmol).
~v(g, (CDC13) b 8:50 (1H, s); 8.00 - 7.50 (4H, m); 4.50 (2H, q, ~ _ 7I-iz) ; 4.00 (2H, q. J - 7Hz) ; 1.50 (3H, t, J = 7Hz) ; 1.30 (3H; t, J = 7Hz) .
59B Eth~~l 3-diethylaminabenzoate This was prepared using the method of Example 56D using the ethyl ester of Example 59A (3,50 g. 15.8 mmol), acetone (130 ml) and 4 N HC1 (80 m1). The resultant amine was alkylated following the method of Example 58A
using acetaldehyde (1.3 ml, 23.3 mmol) and NaB~I3CN (1.46 ~o~~~~

WO 93/16999 P~,'T/GB93/00404 g, 23.3 mmol). The crude product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 10:90 v/v) to give the title compound (1.90 g, 54a).
NMR (CDC13) b 7.95 - 7.80 (3H, m}; 7.40 (1H, m); 4.90 (2H, q; J - 7Hz); 3.90 (4H, q, J - 7Hz}; 1.95 y (3H, t, J = 7Hz}; 1.75 (6H, t, J = 7Hz).
59C 3-Diethylaminobenzoic acid This was prepared following the method of Example 318, using ester of Example 59B (1.90 g, 8.6 mmol) and LiflH.HaO (720 mg, 17.2 mmol}. The crude product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr:AcOH 30:?0:2 v/v/v) to give the title compound (1.0 g; 60%).
59D I~1- ( (3R) -1--tart-Butylcarbonylmethyl-2~~ 3-dih~rdro-2 oaco-5-ph_, envy-1H-1 .4-benzodiazepin-3~v1) -N' - (3 diethylami:no~ahenylJ ~~rea (Scheme 1, step (ii)) The resolved aminobenzodiazepine of Example 26 (175 rng, 0.5 mmol) in toluene (5 ml) was treated with the lsocyana~e prepared using the acid of Example 59C (240 25- mg; 1.2 mmol) following the method of Example 38. The product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 45:55 v/v) to give the title compound which was crystallised from MeCN to give the product as a white solid (147 mg; 550, X99% pure by 3 0 HPLC ) .
NMR (CDC13) b 7:70 - (13H, m); 6.60 (1H, d, J =
7.05 ' gHz); 6.50 (1H, d, - 8Hz}; 5.80 (1H, d, J -J

8Hz ) ; 4 . 90 ( 1H, d, = l7Hz ) ; 4 . 76 ( 1H, d, J
J

35 l7Hz); 3.45 (4H, q, = 7Hz); 1.30 (9H, s); 1.20 J

(6H, t, J = 7Hz}.

M.S. (F.AB, -we son) m/e 540.3 [M+H~

2~~ 3~~
WO 93!16999 PC.'T/G~93/00404 N-((3RS}-1-tert-Butylcarbonylmethvl-2,3-dihydro-2-oxo-5-phenyl-IH-1,4-benzodiazepin-3-yl-N'-(3-5 dimethylaminomethylphenyl} urea. Compound 61 60A 3-Dimethvlaminomethvl benzonitrile To a solution of 3-cyanobenzaldehyde (2.50 g, 29 mmol) in 20 MeOH:AcOH (25 ml, 99:1) was added dimethyl amine (2.5 ml, 50 mmol} at 0°C, followed by NaBH~CN (1.80 g, 29 mmol) .
The mixture was stirred at O°C for 18 hours, then evaporated, taken up in EtOAc, washed with 5o KHCO3, brine filtered (Whatman° 1 PS phase separator) and 25, evaporated. The residue was purified by flash chromatography on silica gel (eluant EtOAc:MeOH 98:2 v/v}
to give the title compound (2.25 g, 38 %).
(CDC13) b 7.75 - 7.60 (4H, m); 3.50 (2H, s); 2.35 20 (6H, s) .
608 Methyl 3-dimethylaminomethylbenzoate 25 A solution of the nitrite of Example 60.?-~, (1.I5 g, 7.2 mmol) in 4M HCl/MeOH (200 ml) was stirred at O°C for 2 hours and at room temperature for 28 hours. H20 (25 ml}
was added and the mixture was stirred for one hour at room temp, then evaporated and azeotroped with toluene, 30 taken up in CHC13, washed with 5o KHC03, filtered (Whatman° 2 PS phase separator} and evaporated to give the title compound (1.20 g, 86%).
NMR (CDC23) 8 8.00 - 7.50 (4H, m}; 4.00 (3H, s); 3.60 35 (2H, s) ; 2.30 (6H, s) .
60C 3-Dirnethylaminomethylbenzoic acid 2:a.~~~, WO 93/16999 ~CT/GB93/00404 This was prepared following the method of Example 31B, using the ester of Example 60B (1.20 g, 6.2 mmol) and LiOH.H20 (540 mg, 13 mmol). The crude product was purified by flash chromatography on silica gel S (eluant:CHCI3:MeOH:AcOH 25:10:1 v/v/v) to give the title compound (750 mg, 68%).
60D N-((3RS)-1-tart-Butvlcarbonylmethyl-2.3-dihydro ' 2-oxo-S-~hen~l~lH-2-, 4-benzodiazepin-3-yl) -N' - (3 dimethy_laminometh~rl~henyl) urea (Scheme 1, step fiii)) The benzodiazepine of Example 2B was hydrogenated as described in Example 1C hnd the resultant amine (192 mg, 0.55 mmol) in toluene (5 ml) was treated with the isocyanate prepared using the acid of Example 60C (250 mg, 1.4 mmol) following the method of Example 38. The praduct was purified by flash chromatogaphy on silica gel (eluant CHCI3:MeOH:AcOH 20:2:1 v/v/v) and crystallised from acetonitrile to give a white solid (SO mg, 17p, >990 pine by HPLC).
NMR (CDC13) b 7.55 6.90 (ISH, m); 5:57 (1H; d, J =
8Hz) ; 4:80 (1H, d, J = l7Hz) ; 4.70 (1H, d, ,~ _ l7Hz); 3:40 (2H, s); 2.25 (6H, s); 1.15 (9H, s).
M. S . (FAB, +ve ion) m/e 526 . 3 [M+H]

~7_ 3RS -2-tart-But lcarbon lmeth 1-2 3-dih dro-2-oxa-5 (2~pyridyl) -1H-1~4-b~nzodiazepin-3 :yl) -N' - (3- LN-ethyl-N
'methylamino)phenyl) urea: Compound 62 The benzodiazepine of Example 27A was deprotected as ~Iascribed in Example 27B and the resultant amine (200 mg, 0.57 mmol) in toluene (5 mls) was treated with the isocyanate prepared using the acid of Example 58B (250 mg, 1.4 mmol) following the method of Example 38. The S~JES'TI'TU'~E SHEE't .. __ _.. ..~ ~. , ~ _ .._ ._. , w..r ..... . :. .,. , , .., ~~.~~ ~!.~~
'WO 93/16999 PCT/GB93/00404 product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 90: 10 v/v) to give the title compound which was lyophilised from MeCN/H20 to give a white solid (125 mg, 420, >95% pure by HPLC).
Rf (EtOAc:hexane fr 90:10) 0.23.
M.S. (FAB, +ve ion) m/e 527.3 (M+H]

N ((3RS) 1 tent-3-Butvlcarbon~rlmethyl-2 3-dihvdro-2-oxo-5 (2 pyridvl)-1H-1 4-benzodiazepin-3-yl)-N'-(3-dimethylaminomethvlphenyl) urea. Compound 63 ~'he benzodiazepine of Example 27A was deprotected as described in Example 27B and the resultant amine (200 mg, ' 0.57 mmol) in toluene (5 ml) was treated with the isocyanate prepared using the acid of Example 60C (250 mg, 1.4 mmol) following the method of Example 38.~~ The product was purified by flash chromatogaphy on silica geh ,. , (eluant CHCI3:Me0H:AcOH 18:4:1 v/v/v) to give the title comppund which was crystallised from EtOAc-hexane fr to give a white solid (76mg, 250, >99% pure by HPLC).
Nil'~IR (CDC13) b 8.50 (1H, d, J = 8Hz) ~ 8.00 - 7.20 (12H, m); 6.80 (1H; d, J = 8Hz)~ 5.60 (1H, d, J = 8Hz)~ ;
4 _ 80 (li-~; d; J = I7Hz) ; 4 .50 (1H, d, J = 1?Hz) ;
3:40 (2H, s): 2.20 (6H, S)~ 1.20 (9H, s).
M.S. (FAB, +ve ion) m/e 527.3 [M+H1 N~ 3RS -1-tent-But lcarbon lmeth 1-2 3-dih dro-2-oxo-5 2- rid 1 -1H-1 4-benzodiaze in-3- 1 -N'- 3 diethylaminophenyl) urea. Compound 63 The benzodiazepine of Example 27A was deprotected as described in Example 27B and the resultant amine (200 mg, ...-. . . . . , . , . ,. .,. . . ..., . ,,. .,.: > ~ ,, .. , . _ >; _ t _ ,.... .,., .
.... . ...:-. ,t,... , .- ..: . .: . . ,. ~- . ; .

7 ;~ a W~ 93/16999 PCTIG893l00404 0.5? mmol) in toluene (5 ml) was treated with the isocyanate prepared using the acid of Example 59C (212 mg, 1.1 mmol) following the method of Example 38. The product was purified by flash chromatogaphy on silica gel (eluant EtOAc:hexane fr 75:25 v/v) to give the title compound which was crystallised from acetonitrile to give a white solid (200 mg, 65%, >99o pure by HPLC).
NMR (CDC13) b 8.60 (1H, d, J = 8Hz); 8.17 (1H, d, J =
8Hz); 7.70 - 6.90 (10H, m); 6.40 (2H, m); 5.75 (H, d, J - 8Hz); 4.90 (iH, d, J - l7Hz); 4.40 (1H, d, J=17HZ); 3.30 (4H, q, J = 7Hz); 1.20 (9H, s); 1.15 (6H, t, J = 8Hz) M.S. (FAB, +ve ion) m/e 541.4 [M+H]
15.

~3R~,- - tart-Butvlcarbon~rlmethyl-2 , 3-dihydro-2-oxo-5 ~hen~l-1H-1~, 4-benzodiazepin-3-yl)N' - (3 dimethylamino.Lhenylj urea. Comt~ound 65 This was prepared from the resolved aminobenzodiazepine ' of Example 26 (1.88 g; 5.4 mmol) following the method of Example 38. The product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 55:45 v/v) and then lyophilised from dioxan-H20 to give the title compound as a white solid (1.72 r, 62%, >980 pure by H:E~LC) .
R~ (EtOAc:Hexane fr 60:40 v/v) 0.21.
M.S. (FAB, +ve ion) m/e 512.3 [M+H]
[rx] D = +97.3° (c = 0.776, CHC13) , ..
W~ 93/1b999 PCTl~B93/OU404 N-((3RS)-1-tert-Butylcarbon~rlmethyl-2,3-dihydro-2-oxo-5 (4-meth~ilphen~rl) -1H-1 4-benzodiazepin-3-yl) -N' - (3 methylphenyl) urea. Compound 66 65A ~3RS)-3-Benzylox carbonylamino-1-tert-butylcarbonylmethyl-2 3-dihydro-S-(4-methvlnhenyl)-1H-1 4-benzodiazepin-2-one (Scheme 1, step (i)) This was prepared from (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(4-methylphenyl)-1H-1,4-benzodiazepine-2-one (200 mg, 0.53 mmol, prepared by analogy to the Bock benzadiazepine) following the method of Example 2B. The 15, product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 35:65 v/v) to give the title compound as a colourless oil (252 mg, 960).
NMR (CDC13) b 7.53 (3H, m); 7.41 - 7.13 (9H, m); 6.68 2 0 ( 1H, d, J = 8fIz ) ~ 5 . 44 ( 1H, d, J = 8Hz ) ~ 5 .18 (2H, s) ~ 5 ~ 00 " (1H, d, J = l7Hz) ; 4 . 67 (1H, d, , J - l7Hz) ~ 2.42 (3H, s) ; 1.28 (9H, s) .
25 65B N-((3RS~ -1-test-Butylcarbonylmethyl-2,3-dihvdro-2'oxd 5 (4-methyl.~henyl)-1H-114-benzodiazepin-3-yl)-N'-~3-methyl~henvl) urea (Scheme 1 step (ii)) This was prepared from the benzodiazepine of Example 65A
30 following the method of Example 148. The product was purified by flash Chromatography on silica gel (eluant EtOAc:hexane fr 37:63 v/v) and lyog~ilised from dioxan H20 to give the title compound as a white solid (118 mg, 470, >98% pure by HPLC).
Rg (ETOAc/Hexane 40:60 v/v) 0.18 ~ (CLC13) b 9.02 - 8.92 (3H, m)~ 8.82 - 8.20 (11H, V1'~ 93/15999 ~ $ ~ a ~ ~ ti PCT/GB93I0~404 m); 7.10 (1H, d, J = 5Hz); 6.32 (1H, d, J = 8Hz};
6.17 (l, d, J = 8Hz); 3.82 (3H, s); 3.72 (3H, s);
2.66 (9H, s} .
M.S. (FAB, +ve ion) m/e = 497.3 [M+H]

N-f~3R)-1-tent-Butylcarbonvlmethvl-2.3-dihydro-2-oxo-5 ~he~l-1H-1~4-benzodiazepin-3-yl)-N'-(3-aminogh~n~rl) 10 urea . Co~ound 67 66A N-(f3R)-1-tart-Butvlcarbonylmeth~l-2.3-dihydro-2-oxo-5-phen~rl-1H-1.4-benzodiazepin3-yl)-N'-(3-25 nitr~hen~tl) urea lScheme 1, step ii) ) ' The resolved aminobenzodiazepine of Example 26 was treated with m-nitrophenyl isocyanate as described in Example 45 to provide a colourless oil (490 mg, 94%).
Data identical to Example 45.
66B N-((3R)-1-teat-Butylcarbonylmethyl-3-dihvdro-2 oxo-5-phenyl-1H-1.4-benzodiazet~in-3-yl)-N'-(3 aminophenyl) urea The benzodiazepine of Example 66A (245 mg, 0.468 mmol) was taken up in 1M ammonium chloride (8 ml) and treated with zinc dust (620 mg) and the mixture stirred rigorously as ethanol (8 ml) was added slowly to the mixture. After 1/2 hour the mixture was filtered and evaporated. The residue was purified by flash chromatogaphy on silica gel ( eluant EtOAc : hexane f r 8 0 : 2 0 v/v) and lyophilised from MeCN-H20 to give the title compound as a white solid (115 mg, 670, >98% pure by HPLC ) .
SUB~'TITUTE E~IEE°~' ::,..
., .t ::., , in:.,.:
..'i ...
jY
...1..
p-..
n ,.
., ... . . . , , r . . ~ . , I
".. ..,.r.. ,. " :'.. sa :.. ". ., .... .._ ... . .. ,. .. ,. ,. . ... " ..._ . .. ..~ ..... ...~ ... ... ... .. . , ... , .. . ,.... .

.~ ~~i ~
WO 93!16999 PCTlGB93t00404 RE (EtOAc = 0.64.
1H NMR (CDC13) S 7.8 - 7.0 (11H, m) ; 6. 9 (1H, t, J
- 8.5Hz); 6.75 (m, 2H); 6.35 (1H, d, J
8.5Hz) ; 5.7 (1H, d, J = 8.5Hz) ; 4.95 (2H, s); 3.75 (2H, br.s.); 1.21 (9H, s).
[a] D = +25° (c = 0 . 993 , MeOH) M.S. (FAB, +ve ion) '"/e = 484.3 [M+H]

N ((3RS,L 1 tart-Butylcarbonylmethyl-7-chloro-2 3-dihvdro-1 2 oxo phenyl-1H-1 4-benzodiazeroin-3-vl)-N'-(3-methyl~ahenyl) urea. Compound 74 67A (3RS)-3-Benzyloxycarbonvlamino-1--tart butylcarbonylmethyl-7-chloro-2,3-dihydro-5-phenyl-1H-1,4 benzodiaze~in-2-one (Scheme 1 step !i)) This was prepared from (3RS)-3-benzyloxycarbonylamino-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (640 mg, 1.46 mmol, prepared by analogy with the Bock benzodiazepine), sodium hydride (62 mg of an 80%
dispersion in oil, 2.04 mmol) and 1-bromopinacolone (537 mg, 3 mmol) following the method of Example 1B. The crude product was purffied by flash chromatography on silica gel (eluant EtOAc:hexane fr 30:70 v/v) to afford the title compound (700 mg, 930).
NMR (CDC13) b 7.70 - 7.30 (13H, m); 6.8 (1H, d, J -8Hz); 5.60 (1H, d, J = 8Hz); 5.30(2H, s); 5.05 (1H, d, J = l7Hz) ; 4 . 80 (1H, d, J = l7Hz) ; 1.35 (9H, s) .

!r VN~ 93/16999 ~ ~ ~ ~ ~ ~ l~ PCT/GB93/00404 67B N-((3RS)-1-text-Butylcarbonylmethyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazenin-3-~1)-N'-(3-methylphenyl L urea ( Scheme 1, step ( i i ) ) This was prepared following the method of Example 27B
using the benzadiazepine of Example 67A (270 mg, 0.52 mmol) , BBr3 (3.4 ml, 1.0 M sol in CHZC12) and m-talyl isocyanate (90 ~cl, 0.66 mmol). The product was purified by chromatography (eluant EtOAc:hexane fr 40:60 v/v) to provide the title compaux~d which was freeze dried from MeCN/H20 to give the product as a white solid (83 mg, 31%, >99% by HPLC).
7.5 NMR (CDC13) b 7.70 - 6.95 (14H, m); 5.80 (1H, d, J = 8Hz); 4.90 f2H, s}; 2.40 (3H, s); 2.25 (9H, s) .
M.S. (FAB; +ve ion) m/e 57.2 [M+H]
2 0 EXAMPLaE 6 8 N-((3RS)-1-tert-Bu~lcarbonvlmethyl-7-chloro-2,3-dihydro-2-oxo-5-x7henyl-1H-1, 4-benzodi.azepin-3-yl) -N' - (3-di.meth~,rlaminophenyl, urea . Compound 75 This was prepared following the method of Example 27B ..
using the benzodiazepine of Example 67A (430 mg, 0.83 mmol } r BBr3 ( S . O ml , 1. 0 M sol in CH2C12 ) and the isacyanate prepared using 3-dimethylaminobenzoic acid -30 (400 mg, 2.4 mmol} following the method of Example 38.
The product 'was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 45: SS v/v} to provide the title compound which was lyophilised from MeCN/H20 to give a white solid (100 mg, 220, >98m pure by HPLC).

NNIR (CDC13} 8 7.60 - 6.90 (12H, m) ; 6.SO (ZH, d, J =
8Hz} ; 6.40 (1H, d, J - 8Hz) ; 5.60 (~.H, d, J -,..r, .
-, T

,. _'.'.'. .. '..'f ._ '~'4 ,....~.~.,. . ..",...,: ,.. .. ' =..:. ',~:. .. ~
,.'.: , .: , ,w . .,. ' ~ '~'. . .. . ..,. .,::.: ~. ~. . . ....
e~ ~ ~ V

8Hz) ; 4.?5 (2H, s) ; 2.90 (6H, s) ; 2.10 (3H, s) ;
1.15 (9H, s) .
M.S. (FAB, +ve ion) m/e 546.3 [M+H]

N- ( (3RS) -1-tart-Butylcarbonylmeth~l) -7-chloro-2~3-dih~dro-2-oxo-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-3-yl ) -N' - (3 -methylPhenyl ) urea . Compound 76 This was prepared following the method of Example 27B
using the benzodiazepine of Example 54A (1.70 mg, 0.31 mmol ) , BBr~ ( 2 mi , 1. 0 M sol in CH2C12 ) and m-tolyl isocyanate (60 ~.1, 0.4 mmol). The product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 35:65 v/v) to provide the title compound which was lyophilised from MeCN/H20 to give a white solid (39 mg, 5 1 %, >99o pure by HPLC).
Rø (EtOAc:hexane fr 40:60) 0.25.
M.S. (FAB, +ve ion) m/e 551.2 [M+H) N-((3RS)-1-tart-Butylcarbonylmethyl-2,3-dihydro-8-methyl-2-oxo-5-t~henyl-1H-1,4-benzodiazepin-3-yl) -N' - (3-methvlphenvl) urea. Compound 77 70A (3RS)-3-Benzyloxycarbonylamina-tart-1-butvlcarbonvlamino-2,3-dihvdro-8-methyl-5-~henvl-1H-1,4-benzodiazepin-2-one (Scheme 1, step (i)) This was prepared from (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-8-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (240 mg, 0.64 mmol, prepared by analogy to the Bock benzodiazepine) following the method of Example 2B. The product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 30:70 v/v) to give the title ~~?~~~~~~s W~ 93/16999 P~'1'/~893/44444 compound as a colourless oil (289 mg, 910).
Rf (EtOAc:hexane fr 30:70 v/v)0.17.

NMR (CDC13) ~ 7.67(2H, m); 7.4 (9H, m); 7.25 (1H, d, J - 8Hz) ; 6.96 70 (1H, d, = 9Hz) (1H, J ;
S) ;
6.

5.47 (1H, d, = 9Hz); 5.19 (2H, s); 4.98 (1H, J d, J=lBHz) ; 4.70(1H, d, J lBHz) ; 2.46 (3H, - s) ;

1.30 (9H, s) .

70B N-(~3RS)-1-tert-Butylcarbonvlmeth~rl-2.3-dihvdro-8-meth~"1-2-oxo-5 =phen~~l-1H-1, 4-benzodiaze"pin-3-y1) -N° - (3-methvlphenyl) urea (Scheme 1, step (iii ~
This was prepared from the benzodiazepine of Example 70A
(289 mg, 0.58 mmol) following the method of Example 148. The product was purified by flash chromatography on silica gel (eluant EtOAc:hexane fr 37:63 v/v) and lyophilised from dioxan-H20 to give the title compound as a white solid (106 mg, 3?~, >98fl pure by HPLC).
2a Rg (EtOAc:hexane fr 4C:60 V/V) 0.18.
NMR (CDC13) 6 7.67 (2H, m) ; 7.46 (2H, m) ; 7.26 -- 6 .79 (9H, m); 5:68 (1H, d, J = 7Hz); 4.93 (1H, d, J =
llHz); 4.?5 (1H, d, J = llHz); 2.45 (3H, s); 2.33 (3H, s) ; 1.27 (9H, s) .
M.S. (FAB, +ve ion) m/e = 497.2 jM+H) ~:.
Compounds 53, 68-73, 78 and 79 are obtainable by methods analogous to those described in the above Examples.
The compounds of the present invention are potent and selective antagonists at the CCK-B receptor and inhibit gastric acid secretion stimulated by pentagastrin. The methods of measuring these activities are described below:
ill~a'~'I i U'i'E S~E~'i' Measurement of binding affinity for CCK-B receptors About 100 SD rats were decapitated without anaesthesia, the whole brain was immediately excised from each of the rats and homogenized in 10-fold volume of 0.32 M aqueous solution of sucrose by the use of a Teflon TM-coated homogenizer, the homogenate thus obtained was centrifuged for ten minutes at 900 g by the use of a cooled centrifuge, and the supernatant was further centrifuged for 15 minutes at 11500 g. The precipitate thus obtained was dispersed in 50 mM Tris-HCl buffer (pH 7.4) containing 0.08% Triton TM X-100, this suspension was allowed to stand for 30 minutes and again centrifuged for minutes at 11500 g, the precipitate thus obtained was 15 washed twice with 5 mM Tris-HCl buffer and twice with 50 mM Tris-HCl buffer in that order with centrifugal separation, the washed precipitate was suspended in 50 mM
Tris-HCl buffer, and the suspension thus obtained was stored at -80°C until the membrane preparation was required.
The membrane preparations were warmed to room temperature, diluted with 10 mM HEPES buffer (containing 130 mM NaCl, 5 mM MgCl 2, 1 mM EGTA and 0.25 mg/ml bacitracin; pH 6.5) and incubated at 25°C for 120 minutes in the presence of [ 125I)BH-CCK-8 and the test compound, then separated by suction filtration. Non-specific binding was determined in the presence of 1 ~M CCK-8. The amount of labelled ligand bound to the receptor was measured by the use of a ~-counter; IC So values were determined, being that concentration of test compound required to inhibit specific binding by 50%.
Measurement of binding affinity for CCK-A receptors The pancreas of an SD rat was homogenized in a 20-fold volume of 50 mM Tris-HCl buffer (pH 7.7) by the use of a PolytroneTM-type homogenizer, the homogenate was twice centrifuged for 10 minutes at 50000 g by the use of an ultra-centrifuge, the precipitate thus obtained was suspended in a 40-fold volume of 50 mM Tris-HC1 buffer (containing 0.2& BSA, 5 mM MgCl 2, 0.1 mg/ml bacitracin.
and 5 mM DTT; pH 7.7), and the suspension was stored at -80°C until the membrane preparations were required.
The membrane preparations were then warmed to room temperature, diluted 1:10 with the buffer and incubated at 37°C for 30 minutes in the presence of [ 3H]L-364,718 and the test compound then separated by suction filtration. Non-specific binding was determined in the presence of 1 M L-364,718. The amount of labelled ligand bound to the receptor was measured by the use of a liquid scintillation counter; ICSO values were determined, being that concentration of test compound required to inhibit specific binding by 50%.
A high affinity for the CCK-A receptor in a gastrin/CCK-B
antagonist is thought to be undesirable as it may lead to side-effects such as cholestasis and gall stone formation during therapy. Therefore it is preferable for the therapeutic agent to be selective for the CCK-B receptor.
This selectivity is expressed by the ratio IC So (CCK-A)/ICso (CCK-B); the higher the value of this ratio the better is the selectivity.
The table below summarizes CCK-B and CCK-A binding data for examples of preferred compounds, as well as the A/B
ratio. Many compounds display a marked increase in CCK-B
receptor binding affinity when compared to the compound of Example 281 of U.S. Patent No. 4,820,834 (also known as L-365,260). Several compounds also show much greater selectivity for the CCK-B receptor over the CCK-A
receptor than that reported for the compound of Example 281 of U.S. Patent No.4,820,834.

2~~~~~
WO 93/15999 ~Cf/GB93/OO~dO~t Recegtor ICso(nM) binding affinity COMPOUND CCK-B CCK-A AIB Ratio Compound Example 281 of of US Patent 29 12,000 410 No. 4,820,834 Example 4 0.23 440 1,900 Example 9 7.3 >10,000 >1,400 Example 12 1.4 >10,000 >7,100 Example 13 0.11 >10,000 >91,000 Example 14 0.12 2,600 22,000 Example 17 0.07 2,500 36,000 Example 19 0.92 1,00 1,.200 Example 22 3.5 >10,000 >2,900 Example 23 0.08 870 11,000 Example 24 0.97 >10,000 >10,000 Example 25 . 0.65 >10,000 >15,000 .

Example 31 0.53 3,400 '6,400 Example 32 0.28 480 1,700 Example 34 0.38 >10,000 >26,000 Example 35 1.2 1,900 1,700 Example 36 0.57 720 1,300 Example 37 1.1 5,600 5,100 Example 39 0 .10 240 2, 400 Example 41 6.2 6,700 1,100 Example 42 0.07 360 5,100 Example 4~ 0.17 1,600 9,400 Example 45 0.16 590 3,700 Example 56 0.11 I20 1,100 Example 66 0.5 950 1,900 Measurement of inhibition of pentaaastrin-stimulated gastric acid rat secretion in ~. caranula was inserted into the trachea of a rat anaesthetised with urethane (intraperitoneally ~ i.~ x~ e. t, WO 93/16~~9 P~1'/GB93/004a~8 administered, 1.25 g/Kg), its abdominal wall was incised to expose the gastric and duodenal portions, and a polyethylene cannula was set in the anterior stomach after ligation of the cardia. The duodenum was then subjected to slight section, a polyethylene cannula was inserted from the incised portion toward the stomach, and the pylorus was li~ated to fiat the cannula.
Physiological saline (with pH adjusted to 7.0) was perfused from the anterior stomach toward the pylorus at a rate of 3 ml/min, and the gastric-acid secretion was measured by continuous titration of the perfusate by the use of a pH-scat (A't~T-201; product of Toa Electronics, Ltd.). The continuous titration was carried out by using 25 mM NaOH solution until the pH reached 7.0, and the result was expressed as the amount of gastric acid secreted for every ~.0 minutes (,uEq/10 min. ) . Pentagastrin was intravenously administered at a rate of 15 ~g/Kg/hr.
The secretion of gastric acid increased upon administration of pentagastrin, reaching the maximum ,.
level after 60 minutes and stably maintaining this level after that. A best drug was then intravenously administered, and the secretion of gastric acid was measured; EDSO values were determined, being the amount of the drug required to reduce the amount of secreted g~stic acid down to 500 of the maximum level.
Representative EDSO values are shown below.
~U~~Tr~~~~ ~~E

~~ 3~'~3 !i~~ 93/16999 PCI'lGB93/004tDA

ED50 (umolkg~
X50 (I~~g) Cflxnpound of Ex~nnplc 281. of Z3S Patent 110. 4,820,834 . 4.2 Compound of Example ~ ~ 0.OI6 Compound of Ex~pIe 3 0.018 Compound of Exa~gh 7 0.047 Measurement of inhibition of pentaqastrin-stimulated .
gastric acid secretion in dog Assays were performed using male beagle dogs (°! - 12 kg) two months after surgical preparation of Heidenhain 'pouches follo~ring the conventional procedure. Each dog was used only once per week.
The animals were deprived of food with free access to water for 18 hr prior to the experiment . The gastric juice was collected from the gastric canula by gravity drainage every l5 min, and acid output was determined by automatic titration with 0.05 N NaOH to pH 7.0 (Comtite-70 Hiranuma, Tokyo, Japan). Drugs were administered ' orally 3 hr after the start of the pentagastrin (8 ~.g/kg/hr) infusion. The effect of each drug was calculated as the percentage inhibitcian of stimulated :acid output. The table below shows the maximum inhibition observed for representative Examples. Each result is a mean for 3 - 5 animals.
SI~SSfisTiJTE SH~~i'.

W'D 93/1b999 ~ ~ c',~.~ .~; ~~ ~ ii PCT/G~93/04~44 Inhibition (dose) compound ef Exarraplo 2~ 1 of LTS Patcr~t No. 4.~?.t;D,~34 i~'~v (1~ ~cmolJkg) Co~pound of Exaznplc 26 530 (3 ~CCno~c~) Coaapound of Example 27 Cx6~b (3 'rmolJk~) ~ompour~d of Ex~mplo 3~ I00~ (3 ~mollqt$) compound of Examph 64 100 (3 ~.mol/k~) 1~
. The experiments described above demonstrate that the compounds of the present invention are potent selective gastrin/CCK-B antagonists and inhibit the stimulation of gastric acid release due to pentagastrin. They are therefore useful in the treatment of disease states in which gastrin or CCK-E receptor is implicated as a mediating factor. Euch disease states would include disorders of the gastro-intestinal system, for example gastric and duodenal ulcers, gastritis, reflux esophagitis, Zollinger-Ellison syndrome, gastrin-sensitive pancreas, and gastrin-sensitive tumors.
I?isorders of the central nervous system such as anxiety and psychoses would also be amenable to treatment with the compounds of this invention. The compounds can also be used in the control of appetite and pain.
The compounds of this invention and salts thereof can be administered orally including sublingual administration) or parenterally in the form of tablets, powders, capsules, pills, liquids, injections, suppositories, ointments and adhesive plasters.
The carrier and excipient for pharmaceutical manufacturing can be a solid or liquid, non-toxic medicinal substance, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and other ~U~ST'ITIJT~ SH~~'f ~~.~~~.j~v W~ 93/6999 PCT/GB93/00404 commonly employed materials. .
Examples of formulations using the compounds of this invention are described below.
Examples of tablet preparation Composition 20 mg=Tablet 40 mg-Tablet ~:ompound o ~x~plc 4 20 ing 40 nxg Lactose 73.4. 80 Coy Starch 18 20 HydroxygropyicclluTose 4 5 CarboxymctbyIcclIulose Ca 4 4.2 11~g Stearate 0.6 0.$

Total 120 mg 150 mg Prex~aration of 20 mg-tablets Compound of Example 4 (100 g), lactose (367 g) and corn starch (90 g) were homogeneously mixed together by the use of a flow granulating coater (product of (Ohgawara 5e'isakusho), .100 aqueous solution of hydroxypropylcellulose (200 g) was sprayed into the mixture, and granulation was then performed. After drying, the granules were filtered through a 20-mesh sieve, 20 g of carboxymethylcellulose Ca and 3 g of magnesium stearate were then added, and the mixture, was treated in a rotary tablet machine equipped with a pestle of 7 mm x g.4 R (product of Hata Tekkosho), thus producing tablets each weighing 120 mg ~5 Pre~,aration of 40 mgt-tablets Compound of Example 4 (140 g), lactose (2~0 g) and corn starch (70 g) were homogeneously mixed together by the ~U~~TITUT~ SHED' Yd~ 93f 16999 ~ ~ ~ ~$ ~ :~ t~ PCTfGB93f004a4 ,. 1 use of a flow granulating coater (product of Ohgawara Seisakusho), 10% aqueous solution of hydroxypropylcellulose (175 g) was sprayed into the mixture, and granulation was then performed. After drying, the granules were filtered through a 20-mesh sieve, 14.7 g of carboxymethylcellulose Ca and 2.8 g of magnesium stearate were then added, and the mixture was treated in a rotary tablet machine equipped with a pestle of 7.5 mm x 9R (product of Hata Tekkosho) , thus producing tablets each weighing 150 mg.
The clinical dosage of the compounds of this invention will be determined by the physician taking into account the precise illness, and the body weight, age, sex, medical history and other factors of the, patient to be treated. In general the dosage when administered orally will be between 1 and 1000 mg/day in either a single dose or sub-divided into smaller multiple doses.
SI~~S°~'f~'I~TE iH~~'~

Claims (20)

CLAIMS:

1. ~A benzodiazepine of formula I, or a pharmaceutically acceptable salt thereof:
wherein (a R1 is -CH2CHOH(CH2)a R4 or a ketone group -CH2CO(CH2)a R5 in which a is 0 or 1 and R4 and R5 are selected from alkyl groups of up to 8 carbon atoms; C3 to C8 cycloalkyl groups; C3 to C8 cycloalkyl groups substituted with one or more alkyl groups of up to 8 carbon atoms; adamantyl and saturated heterocyclic groups of formulae II and III:
in which R6 is one of H, C1-C3 alkyl, and C1-C3 acyl and b is 1 or 2;
(b) R2 and R3 are independently selected from unsubstituted or substituted phenyl and pyridyl, the substituents being selected from halogen atoms and hydroxy, amino, nitro, carboxylic acid, carboxamido, cyano groups, alkyl, alkoxy, alkylamino and dialkylamino groups, wherein the or each alkyl group is of up to 8 carbon atoms;
(c) W and X are selected independently from halogen and hydrogen atoms and alkyl and alkoxy groups of up to 8 carbon atoms.

2. ~A compound according to claim 1 wherein R4 is selected from the group consisting of C4-C7 linear alkyl;
C4-C7 branched alkyl; C3 to C8 cycloalkyl; cycloalkyl substituted with one or more alkyl groups and contains from 3 to 8 carbon atoms; formula II; and formula III:

in which R6 is one of H, C1-C3 alkyl, and -CO-alkyl, wherein the alkyl of -CO-alkyl is C1-C3; and b is 1 or 2;
and R5 is one of C1-C3 alkyl and as defined for R4.

3. ~A compound according to claim 1 or 2 wherein at least one of R2 and R3 is selected from the group consisting of unsubstituted phenyl, substituted phenyl, unsubstituted pyridyl, and substituted pyridyl.

4. ~A compound according to claim 3 wherein at least one of R2 and R3 is selected from the group consisting of unsubstituted phenyl, monosubstituted phenyl, disubstituted phenyl, unsubstituted 2-pyridyl, monosubstituted 2-pyridyl, disubstituted 2-pyridyl, unsubstituted 3-pyridyl, monosubstituted 3-pyridyl, disubstituted 3-pyridyl, unsubstituted 4-pyridyl, monosubstituted 4-pyridyl, and disubstituted 4-pyridyl.

5. ~A compound according to any one of claims 1 to 4 wherein R1 is - CH2CO(CH2)a R5, wherein R1 is -CH2CO(CH2)a R5, R2 is selected from the group consisting of unsubstituted phenyl; phenyl having a meta substituent selected from the group consisting of F, Cl, Br, OH, OCH3, NH2, NMe2, NO2, Me, (CH2)c -CO2H, CN, NHMe, NMeEt, NEt2, CH2NMe2, and NHCHO; 2-, 3 - or 4-pyridyl; and 2-, 3- or 4-pyridyl with a substituent selected from F, Cl, CH3 and CO2H; and R3 is phenyl or 2-, 3- or 4-pyridyl.

6. A compound according to any one of claims 1 to 4 wherein R1 is -CH2CHOH(CH2)a R4 and R2 and R3 are as defined in claim 5.

7. A compound according to any one of claims 1 to 6 wherein the absolute configuration at the 3-position of the benzodiazepine ring is R (as shown in IV) ~

8. A compound according to any one of claims 1 to 7 wherein W and X are H.

9. At least one compound selected from the following compounds according to claim 1 and pharmaceutically acceptable salts thereof:

1. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

2. N-((3RS)-1-Diethylmethylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

3. N-((3RS)-1-Cyclobutylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

4. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

5. N-((3RS)-1-Cyclohexylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

6. N-((3RS)-1-Cycloheptylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

7. N-((3RS)-Cycloheptylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-chlorophenyl) urea;

8. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzdiazepin-3-yl)N'-(3-methylphenyl) urea;

9. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-(3-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

10. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-(4-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

11. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea;

12. N-((3R)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

13. N-((3S)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

14. N-((3RS)-2,3-Dihydo-2-oxo-5-phenyl-1-((2R)-2-pyrrolidylcarbonylmethyl)-1H-1,4-benzodiazepin-3-yl) -N'- (3-methylphenyl) urea;

15. N-((3RS)-2,3-Dihydro-2-oxo-5-phenyl-1-((2S)-2-pyrrolidylcarbonylmethyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

16. N-((3RS}-1-((2R)-1-Acetyl-2-pyrrolidylcarbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

17. N-((3RS)-1-((2S)-1-Acetyl-2-pyrrolidylcarbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

18. N-((3RS)-1-((2RS)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

19. N-((3RS)-1-((2SR)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

20. N-((3R)-1-((2R)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

21. N-((3R)-1-((2S)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

22. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-cyanophenyl) urea;

23. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-cyanophenyl) urea;

24. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin 3-yl)-N'-(3-carboxymethylphenyl) urea;

25. N-((3RS)-1-(1-Adamantyl)carbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

26. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-pyridyl) urea;

27. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(6-methyl-2-pyridyl) urea;

28. N-((3RS)-1-(3-Cyclohexyl-3-methyl-2-oxobutyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

29. N-((3RS)-1-Cyclohexylmethylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

30. N-((3RS)-1-Cyclopentylmethylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

31. N-((3RS)-1-((1-Methylcyclohexyl)carbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

32. N-((3RS)-1-((1-Methylcyclopentyl)carbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

33. N-((3R)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea;

34. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea ;

35. N-((3R)-1-((2RS)-2-Cyclopentyl-2-hydroxyethyl)-2 3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea;

36. N-((3R)-1-((2R)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea;

37. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxamidophenyl) urea;

38. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

39. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

40. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea;

41. N-((3RS)-1-tert-Amylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

42. N-((3RS)-1-tert-Amylcarbonylmethyl-2,3-dihydro-2-oxo-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea;

43. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea;

44. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-carboxyphenyl) urea;

45. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea;

46. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea;

47. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl) urea;

48. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methoxyphenyl) urea;

49. N-((3RS)-1-Cyclopentylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-nitrophenyl) urea;

50. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-nitrophenyl) urea;

51. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-formylaminophenyl) urea;

52. N-((3R)-1-((2R)-2-Hydroxy-3,3-dimethylbutyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

53. N-((3R)-1-((2S)-2-Hydroxy-3.3-dimethylbutyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

54. N-((3RS)-1-(1 -Methylcyclopropyl)carbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea 55. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

56. N-((3RS)-1-Isopropylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

57. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylaminophenyl) urea;

58. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylaminophenyl) urea;

59. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-(N-ethyl-N-methylamino)phenyl) urea;

60. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-diethylaminophenyl) urea;

61. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminomethylphenyl) urea;

62. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(N-ethyl-N-methylamino)phenyl) urea;

63. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminomethylphenyl) urea;

64. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-y1)-N'-(3-diethylaminophenyl) urea;

65. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea;

66. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(4-methylphenyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

67. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-aminophenyl) urea;
68. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

69. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-aminophenyl) urea;

70. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylaminophenyl) urea;

71. N-((3R)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea;

72. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-aminophenyl) urea;

73. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylaminophenyl) urea;

74. N-((3RS)-1-tert-Butylcarbonylmethyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

75. N-((3RS)-1-tert-Butylcarbonylmethyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl) urea;

benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

77. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-8-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) urea;

78. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-(N-ethyl-N-methylaminophenyl) urea; and 79. N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-diethylaminophenyl) urea.

10. A medicinal composition comprising a compound according to any one of claims 1 to 9 and at least one of a carrier and an excipient.

11. A medicinal composition according to claim 10 wherein the composition is a gastrin or CCK-B receptor antagonist.

12. A medicinal composition according to claim 11 wherein the composition is for the treatment of diseases induced by the failure of a physiological function controlled by gastrin.

13. A medicinal composition according to claim 12 wherein the physiological function is selected from the group consisting of gastric and duodenal ulcers, gastritis, reflux esophagitis, gastric and colon cancers, and Zollinger-Ellison syndrome.

14. A medicinal composition according to claim 11 or 12 wherein the composition is for the treatment of diseases induced by the failure of physiological function controlled by the central CCK-B receptor.

15. A medicinal composition according to claim 11 or 12 wherein the composition is for the reduction of anxiety or for the appetite regulation.

16. A process for the production of benzodiazepine of general formula I, or pharmaceutically active salt thereof, as defined in claim 1, wherein R1 is -CH2CO (CH2) a R5, the process comprising the reaction of 3-aminobenzodiazepine V with organic isocyanate R2-NCO:

17. A process for the production of benzodiazepine of general formula I, or pharmaceutically acceptable salt thereof, as defined in claim 1, wherein R1 is -CH2CO (CH2) a R5. the process comprising the reaction of 3-p-nitrophenyloxycarbonylamino benzodiazepine VI with amine R2 -NH2 =

18. A process for the production of a benzodiazepene of general formula I or pharmaceutically active salt thereof, as defined in claim 1, wherein R1 is -CH2CHOH(CH2)a R4, the process comprising reaction of the benzodiazepene of formula I wherein R1 is CHI2CO (CH2) a R5 with a reducing agent.

19. Use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for the prevention or treatment of disease induced by failure of physiological function controlled by gastrin or central CCK-B receptor.

20. Use of a compound according to any one of claims 1 to 9 for the prevention or treatment of disease induced by failure of physiological function controlled by gastrin or central. CCK-B receptor.