Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazephines as cholecystokinin-B receptor antagonists

3596

J . Med. Chem. 2000, 43, 3596-3613

Articles

Syn th esis a n d SAR of New 5-P h en yl-3-u r eid o-1,5-ben zod ia zep in es a s

Ch olecystok in in -B Recep tor An ta gon ists

Antonella Ursini,* Anna M. Capelli, Robin A. E. Carr,^†Paolo Cassara`,^‡Mauro Corsi, Ornella Curcuruto,

Giovanni Curotto, Michele Dal Cin, Silvia Davalli, Daniele Donati, Aldo Feriani, Harry Finch,^†Gabriella Finizia,

Giovanni Gaviraghi, Marc Marien,^#Giorgio Pentassuglia, Stefano Polinelli, Emiliangelo Ratti, Aldo Reggiani,

Giorgio Tarzia,^§Giovanna Tedesco, Maria E. Tranquillini, David G. Trist, and Frank T. M. Van Amsterdam

Glaxo Wellcome Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy, and Glaxo Wellcome Medicines Research

Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

Received May 5, 2000

A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as

cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies

revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition

of substituents at the urea side chain provided in some cases more potent compounds. Moreover

the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the

racemic ureas resulted in our lead compound GV150013.

In tr od u ction

Cholecystokinin (CCK) is a gastrointestinal peptide

hormone of 33 amino acids that was originally isolated

from porcine gut.¹It is also found in high concentrations

in the brain, mainly as the C-terminal octapeptide,^2,3

usually sulfated on tyrosine 7 (CCK-8S). CCK exhibits

many of the characteristics of a neurotransmitter: it is

synthesized in neurons, it is stored in synaptic vesicles,

it is metabolized in the brain, it is released upon

depolarization, and it has specific binding sites associ-

ated with nerve terminals containing CCK.⁴Thus, CCK

can be considered to belong to a class of peptides that

act both as gut hormones and as central neurotrans-

mitters. CCK interacts with at least two types of

receptors.⁵These subtypes have been designated CCK-A

and CCK-B. The former is located predominantly in the

periphery, and the latter is found in high abundance in

the brain. The gastrin receptor of the stomach shares

similarities with the CCK-B receptor but can be phar-

macologically distinguished from it.^6,7The classification

of CCK receptors into two subtypes is supported by the

use of nonpeptidic, selective competitive antagonists,

like L-364,718 ((S)-devazepide)^8,9and the peptoid

F igu r e 1. Chemical structure of 3-(arylaminocarbonyl)amino-

PD-134308¹⁰(CI-988) for CCK-A and CCK-B receptors,

or 3-(aryloxycarbonyl)amino-2,4-dioxo-5-phenyl-2,3,4,5-tet-

rahydro-1H-1,5-benzodiazepine (I), devazepide (II), and PD-

134308 (III).

respectively (Figure 1). The regional distribution of the

two receptors in the brain together with studies with

selective agonists and antagonists in different animal

models have suggested possible therapeutic targets for

drugs acting through CCK receptors. These include

cognitive processes, emotional states such as anxiety¹⁰

and panic, motivation such as drug-seeking behavior,

nociception,¹¹and sleep disorders.¹²CCK-B antagonists

have been developed from numerous structural classes.¹³

One of the most throughly investigated is the benzodi-

azepine family, represented by the potent and selective

L-365,260.

As part of our research for new anxiolytic compounds

acting as potent and selective CCK-B antagonists and

devoid of side effects which are typical of marketed

* To whom correspondence should be addressed. Tel: 39-045-

9218896. Fax: 39-045-9218117. E-mail: au4438@glaxowellcome.co.uk.

^†Glaxo Wellcome Medicines Research Centre, U.K.

^‡Present address: Pro. Bio. Sint. Srl gruppo Archimica, Via

Valverde 20, 2221100 Varese, Italy.

#

Present address: Centre de Recherche Pierre Fabre, Castres,

France.

^§Present address: Istituto di Chimica Farmaceutica, Universita′

di Urbino, Piazza Risorgimento 1, 61029 Urbino (PS), Italy.

Published on Web 09/19/2000

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3597

Sch em e 1^a

a

t

Reagents and conditions: (i) ref 18; (ii) NaH, RX, DMF, rt, 20 h; (iii) BuOK, ArSO₂N₂, THF, -78-0 °C, 24 h; (iv) H₂/Pd, C, CaCO₃,

AcOEt, EtOH, 1 atm, rt, 4 h.

Sch em e 2^a

drugs, we investigated a novel class of 1,5-benzodiaze-

pine-2,4-diones, which was considered an attractive

template in view of combining the high flexibility in the

substitution pattern and the potentially straightforward

synthesis and high-yielding processes to be applied for

their preparation.

Ch em istr y

Initially, compounds bearing an aryl substituent at

the N-5 position and either 3-(arylaminocarbonyl)amino

or 3-(aryloxycarbonyl)amino at the C-3 position (Figure

1, structure I, X ) NH) were prepared, and the nature

of the substituent at N-1 position was particularly

explored.^14,15The synthesis of both classes of compounds

has been accomplished according to the same procedure,

and here we report detailed results only on ureido

derivatives (Figure 1, X ) NH). The structures of

3-ureido-1,5-benzodiazepines which comprise this report

are presented in Table 1. The compounds collated in

Table 1 were prepared according to the general pro-

cesses outlined in Schemes 1-3, the key precursor of

the ureidic bond being the free amine 5 depicted in

Figure 2, which may be easily transformed into the

target compounds I of Figure 1. It is worth noting that

above-mentioned compounds have a stereogenic center

at C-3, and its resolution may be crucial in view of the

pharmacological profile of the pure enantiomers (see

below). Since the reaction outlined in Scheme 3 is

unlikely to cause racemization at C-3, it is clear that it

would be possible to obtain the enantiomerically pure

ureas after separation of the corresponding amines 5,

thus highlighting the strategic importance of such a key

intermediate. The synthesis of the key intermediate 5

follows procedures disclosed in earlier reports.^14-16

Representative reaction conditions are provided in the

Experimental Section describing the preparation of

compounds represented in Schemes 1-3.

For the synthesis of compounds 13, 14, 24, 25, 31,

32, 47 and 54-63, pure enantiomers of the required

intermediate reported in Figure 2 were obtained in

chirally homogeneous form according to the procedure

summarized in Scheme 4.

a

Reagents and conditions: (i) RBr, NaH (method A) or RCHO,

NaCNBH₃(method B₁) or R₂CO, toluene, molecular sieves, 120

°C, 6 h then NaBH₄, EtOH, rt, 30 min (method B₂); (ii) PhNH-

CH(COCl)₂, THF, 50 °C, 3 h; (iii) Zn/AcOH, rt, 6 h or H₂, Pd/C,

HCl, AcOEt, H₂O, atm, rt, 4 h.

Two main synthetic approaches were used for the

preparation of free amines 5. A first procedure (Scheme

1) considered as a common intermediate the 2,4-dioxo-

5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (2),

obtained using known procedure from commercially

available phenylenediamine 1.¹⁷Alkylation at the N-1

position of the benzodiazepine nucleus using either an

alkyl bromide or an alkyl mesylate gave compounds 3

3598 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20

Ursini et al.

Sch em e 3^a

a

Reagents and conditions: (i) COCl₂in toluene solution, CH₂Cl₂, rt, 4 h; (ii) ArNH₂, CH₂Cl₂, CH₃CN, rt, 7 h; (iii) ArNCO, CH₂Cl₂, rt,

1 h; (iv) PhOCOCl, Py, CH₂Cl₂, rt, 30 min; (v) ArNH₂, DMF, 160 °C, 2 h.

reduction of the nitro group.¹⁶The resulting amines

were alkylated generally by using an alkyl bromide in

the presence of sodium hydride to obtain the intermedi-

ates 7. When bulky groups had to be introduced, the

intermediate 7 was conveniently obtained by reductive

amination of either aldehydes or ketones (7m ,p ). The

F igu r e 2. 3-Amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-

condensation of 7 with phenylhydrazonomalonyl dichlo-

1,5-benzodiazepine.

ride¹⁸followed by reduction with zinc and acetic acid

led to the 3-amino-substituted benzodiazepines 5.

in moderate to high yield, depending on the steric

hindrance of the alkyl group. Subsequently an azido

The final ureido derivatives I listed in Table 1 were

made available by well-known methods, outlined in

group was introduced at the C-3 position generally using

Scheme 3. The reaction with aryl isocyanate is obviously

2,4,6-triisopropylbenzenesulfonyl azide in the presence

of a base (e.g. potassium tert-butoxide). The azido group

in compounds 4 was then hydrogenated to the corre-

sponding amines of general formula 5 by using pal-

ladium on calcium carbonate as catalyst.

The alkylation of the intermediate 2 represents the

the most convenient, but the other routes involving

either the synthesis of 3-isocyanobenzodiazepines 9 by

reaction with phosgene or the synthesis of carbamate

10 by reaction with phenyl chloroformate¹⁹have proven

useful particularly when the required substituted aryl

isocyanates were not commercially available. Although

modulation of the binding affinity was achieved by

introducing appropriate substituents at the aromatic

rings, the most remarkable increase in affinity and

CCK-B receptor selectivity was found with the resolu-

tion of the stereogenic center at C-3 of the benzodiaze-

pine ring.

limiting step of the above-mentioned route, and yields

may be very low according to the steric hindrance of the

alkylating agent. Moreover, the synthesis of benzodi-

azepines substituted either at the N-5 phenyl (e.g. 15,

19, 21) or at the fused aromatic ring¹⁶generally required

a noncommercially available substituted phenylenedi-

amine as starting materials. Therefore, an alternative

route was set up as reported in Scheme 2. The starting

phenylenediamines 1 and 6 were generally prepared by

reaction of 2-fluoronitrobenzene or substituted 2-fluo-

ronitrobenzene with either aniline or 2-fluoroaniline in

the presence of potassium fluoride and subsequent

As far as the resolution into enantiomers is concerned,

preparative HPLC performed on final ureas was ini-

tially used, but it had to be limited to small-scale

preparations. Therefore, a more general and effective

chemical method was sought, and attention was focused

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3599

Sch em e 4^a

a

Reagents and conditions: (i) (1R)-(-)-10-camphorsulfonic acid, EtOAc; (ii) 5% NH₄OH, CHCl₃. Experimental procedures described in

ref 14.

on the enantiomeric separation of the corresponding

well as rat pancreatic membranes (CCK-A receptors)

and are listed in Table 2.

amine precursors, particularly taking into account that

their transformation to the target ureas generally

involves nonracemizing conditions. Several known reso-

lution methods could in theory be applied to our class.

Among them, the most common is the formation and

preferential crystallization of diastereomeric salts with

chiral acids (e.g. camphorsulfonic acid, Scheme 4).²⁰The

use of covalent diastereomeric derivatives (e.g. amides)

is generally precluded by the strong conditions required

for their cleavage to obtain the resolved amines, but

recently the resolution of 3-amino-1,4-benzodiazepines

was achieved by means of the preparation and separa-

tion of diastereomeric phenylalanyl amides^21-23or car-

bamates.²⁴This procedure, which is based upon the

reaction of the racemic amine with N-Boc-protected

phenylalanine, followed by separation of the two dia-

stereomeric amides and subsequent Edman degrada-

tion, was also applied to our series, and the desired

enantiomers were obtained with excellent enantiomeric

excess. However, the total yield of the process was quite

low due to a difficult chromatographic separation of the

two diastereomers and the low conversion during the

Edman degradation step. Therefore, we developed a new

method based on the resolution of phenylglycine deriva-

tives.^25,26Accordingly, the racemic amine is reacted with

a chiral auxiliary, namely the tosyl derivative of (S)-

(+)-methyl mandelate, followed by the chromatographic

separation of the two diastereomers formed and the

subsequent hydrogenation of the separated compounds

to give the free amines with good enantiomeric excess.

As anticipated, the enantiomerically pure amines 5 were

converted into the target ureas without observing any

racemization. As far as the absolute configuration of

these compounds is concerned, X-ray analysis of single

crystals of the 4-bromophenyl compound 56 was per-

formed and coupled to CD measurements of both enan-

tiomers among a series of derivatives; as a result, the

(R)-configuration for the (+)-enantiomer was unambigu-

ously confirmed.

Furthermore, for a selected group of compounds,

species selectivity was determined for CCK-B receptors

using membranes from guinea-pig and rat as well as

HeLa transfected human cortical CCK-B receptors. The

results for the best compound GV150013 (24) and

reference antagonists are discussed in the next section

and summarized in Table 3. The more interesting

compounds were also evaluated in vivo to establish their

anxiolytic activity.²⁹Finally, some compounds have been

evaluated in comparison with diazepam for potential

side effects such as tolerance and withdrawal.

Resu lts a n d Discu ssion

Considering the general formula I of Figure 1 a high

flexibility toward the substitution pattern is evident. At

first, we carried out a wide exploration to understand

which kind of substitution would be more critical to our

objective. After an initial evaluation, we restricted our

interest in compounds bearing both an aryl substituent

at the N-5 position and an alkyl chain at the N-1

position, and two main subclasses of derivatives were

selected, that is C-3 ureas and C-3 carbamates. Here

the discussion is dedicated to the former, while carbam-

ates have been discussed in detail elsewhere.^30,31In view

of optimizing the in vitro profile of a first set of

derivatives, we focused our attention on the nature of

the substituent at the N-1 position and a quantitative

structure-activity (QSAR) study was performed on a

series of 21 N-1 alkyl derivatives. A model was derived

using PLS analysis implemented in program GOLPE.³²

After variable selection, a 4-component model was

obtained that explains 84% of the activity variance. The

model was transformed into a pseudo-MLR (multiple

linear regression) equation where a single pseudo-

coefficient multiplies each independent variable. These

coefficients express the effect of each single X-parameter

on the dependent variable and can be useful to interpret

the whole model:

pK_i(B) ) 0.49p_i- 0.13p_i²- 0.44MR -

0.20MR²+ 0.39Sb - 0.67D₁+ 7.15

Biology

All the compounds synthesized were tested in vitro

according to slighty modified methods to determine their

affinity for CCK-A and CCK-B^27,28receptor subtypes.

The affinity and B/A selectivity of 1,5-benzodiazepines

with different substitutions have been determined by

radioligand binding studies using cerebral cortex mem-

branes from guinea-pig and rat (CCK-B receptors) as

LV ) 4, R²) 0.84, s ) 0.21, n ) 21

All the parameters in the equation are referred to the

substituents at N-1: pK_i(B) is the affinity for the CCK-B

receptor subtype; p_iis the calculated lipophilicity;³³MR

3600 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20

Ta ble 1. 1-Alkyl-5-aryl-3-ureido-1,5-benzodiazepine-2,4-dione

Ursini et al.

compd

R₁

R₂

R₃

stereo

synth method (Scheme 3)

11

12

13

14

15

16

17

18

19

20

21

22

23

butyl

H

F

H

F

rac

+

iii

iii, v

iii

ii

3-methylbut-1-yl

-

3-methylbut-1-yl

rac

+

1,3-dimethylbut-1-yl

2,3-dimethylbut-1-yl

3,3-dimethylbut-1-yl

1-cyclopentylprop-2-yl

2-cyclopentylethyl

2-phenylethyl

H

F

H

F

adamant-1-ylmethyl

2-(adamant-1-yl)ethyl

adamant-2-yl

24 (GV150013)

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

-

rac

+

bicyclo[2.2.1]-2-heptyl

adamant-2-ylmethyl

3-methylbut-1-yl

3-N,N-dimethylamino

3-methylthio

3-N,N-dimethylamino

3-methylthio

3-cyano

3-(tetrazol-5-yl)

3-[2-(2,2-dimethylethyl)tetrazol-5-yl]

3-trifluoromethoxy

3-methylthio

3-N,N-dimethylamino

3-(tetrazol-5-yl)

3-methylbut-1-yl

F

3-methylbut-1-yl

F

-

3-methylbut-1-yl

F

rac

+

3,3-dimethylbut-1-yl

2-cyclopentylprop-2-yl

2-cyclopentylethyl

adamant-1-ylmethyl

adamant-1-ylethyl

adamant-2-yl

H

F

v

ii

F

v

H

F

ii

3-N,N-dimethylamino

4-N,N-dimethylamino

3-methylthio

ii

F

ii

F

ii

3-(tetrazol-5-yl)

F

ii

3-hydroxy

H

iii

v

3-methyl

rac

+

3-nitro

3-bromo

3-ethoxycarbonyl

3-carboxy

3-N,N-dimethylamino

3-hydroxymethyl

3-(morpholin-4-yl)methyl

4-bromo

+

3-bromo

+

4-(3-ethoxycarbonylpropyl)oxy

4-(3-carboxypropyl)oxy

4-hydroxy

+

3-(2-(morpholin-4-yl)ethoxy)carbonyl

3-amino

+

(1,2-dihydroxypropyl)amino

3-acetamido

+

rac

3-formylamino

3-N,N-dimethylamino

3-methylthiophenyl

3-N,N-dimethylamino

3-(tetrazol-5-yl)

v

ii

iii

adamant-2-yl

bicyclo[2.2.1]-2-heptyl

adamant-2-ylmethyl

3-N,N-dimethylamino

3-chloro

3-N,N-dimethylamino

is the calculated molar refractivity;³⁴Sb is Austel’s

parameter;³⁵and D₁is a dummy variable that accounts

for the presence (D ) 1) or absence (D ) 0) of branching

on the first carbon atom of the substituent. The analysis

of the PLS model reveals that the lipophilicity and the

steric hindrance of the substituent are critical param-

eters in view of optimizing the affinity for the CCK-B

receptor subtype with respect to the substitution at

position N-1.

On the basis of the previous analysis, and with the

aim of defining a better compromise for both the affinity

and the selectivity with respect to the substituent at

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3601

Ta ble 2. pK_iValues^afor 1-Alkyl-5-aryl-3-ureido-1,5-benzodiazepine-2,4-diones in CCK-B and CCK-A Binding Assays

compd

R₁

R₂

R₃stereo CCK-A pK_i^bCCK-B pK_i^b

B/A^c

89

209

457

44

25

55

110

166

74

22

138

32

309

1738

6

19

162

48

501

933

39

11

12

13

14

15

16

17

18

19

20

21

22

23

butyl

H

F

rac

+

6.26

6.49

5.34

6.74

6.71

6.94

6.91

6.95

7.15

7.11

7.00

6.57

6.15

5.79

6.32

6.66

6.60

7.08

6.90

6.70

7.14

7.44

7.65

8.13

7.01

7.64

7.31

6.95

7.93

7.71

7.33

7.32

6.18

7.65

6.92

5.80

6.60

6.52

6.72

6.09

6.20

6.35

5.67

4.70

5.46

5.81

8.21

8.81

8.00

8.38

8.11

8.68

8.95

9.17

9.02

8.45

9.14

8.08

8.64

9.03

7.08

7.47

7.94

8.81

8.71

9.60

9.68

8.73

9.48

9.52

9.31

9.19

9.54

8.61

8.54

9.14

9.22

8.82

9.17

8.33

9.12

9.65

9.24

8.81

8.72

8.42

8.53

9.01

8.95

9.75

8.52

8.85

9.08

8.28

8.42

9.18

9.25

9.53

9.17

8.90

8.88

9.02

7.88

7.22

8.63

8.68

8.99

8.76

8.9

3-methylbut-1-yl

-

3-methylbut-1-yl

rac

+

1,3-dimethylbut-1-yl

2,3-dimethylbut-1-yl

3,3-dimethylbut-1-yl

1-cyclopentyl-prop-2-yl

2-cyclopentylethyl

2-phenylethyl

H

F

H

F

H

F

adamant-1-ylmethyl

24 (GV150013) adamant-1-ylmethy

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

adamant-1-ylmethy

2-(adamant-1-yl)ethyl

adamant-2-yl

-

rac

+

bicyclo[2.2.1]-hept-2-yl

adamant-2-ylmethyl

3-methylbut-1-yl

3-N,N-dimethylamino

3-methylthio

3-N,N-dimethylamino

3-methylthio

3-methylbut-1-yl

F

3-methylbut-1-yl

F

-

3-methylbut-1-yl

rac

+

110

74

15

3,3-dimethylbut-1-yl

2-cyclopentylprop-2-yl

2-cyclopentylethyl

adamant-1-ylmethyl

adamant-1ylethyl

H

F

3-cyano

3-(tetrazol-5-yl)

151

70

3-[2-(2,2-dimethylethyl)tetrazol-5-yl]

3-trifluoromethoxy

3-methylthio

3-N,N-dimethylamino

3-(tetrazol-5-yl)

3-N,N-dimethylamino

4-N,N-dimethylamino

3-methylthio

20

38

16

F

32

H

F

31

71

F

141

30

F

3-(tetrazol-5-yl)

F

468

550

162

158

48

3-hydroxy

H

3-methyl

rac

+

3-nitro

3-bromo

3-ethoxycarbonyl

3-carboxy

275

646

398

12023

6607

2455

613

>1905

>2630

30903

603

13804

10965

575

591

1175

22

3-N,N-dimethylamino

3-hydroxymethyl

3-(morpholin-4-yl)methyl

4-bromo

+

3-bromo

+

4-(3-ethoxycarbonylpropyl)oxy

4-(3-carboxypropyl)oxy

4-hydroxy

3-(2-(morpholin-4-yl)ethoxy)carbonyl

3-amino

(1,2-dihydroxy propyl)amino

(1,2-dihydroxypropyl)amino

3-acetamido

+

<5

4.69

+

6.47

5.39

5.13

6.20

5.82

5.95

6.53

6.60

6.85

7.01

7.35

7.32

7.2

+

rac

3-formyl

3-N,N-dimethylamino

3-methylthio

3-N,N-dimethylamino

3-(tetrazol-5-yl)

3-N,N-dimethylamino

3-chloro

3-N,N-dimethylamino

adamant-1ylethyl

adamant-2-yl

bicyclo[2.2.1]-2-heptyl

adamant-2-ylmethyl

4

60

47

40

28

54

a

b

Inhibition of binding of [³H]pCCK-8. Mean value of three experiments. ^cSelectivity factor between CCK-B and CCK-A receptors.

position N-1, a series of compounds bearing different

groups at position N-1, while retaining or not retaining

the substituents at other positions, were synthesized.

Relevant results are reported in Table 2. The introduc-

tion of bulky cyclo-bridged groups such as adamantyl

is well-accepted in terms of receptor affinity, while

important changes in the selectivity were obtained by

varying either the length of the chain linking such a

group to the 1,5-benzodiazepinic nucleus or the position

by which the cyclo-bridged group is linked to the chain.

3602 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20

Ursini et al.

Ta ble 3. pK_iValues^afor GV150013 and Reference Compounds in CCK-B and CCK-A Assays

compd

hCCK-B pK_i( SEM

n

guinea-pig CCK-B pK_i( SEM

n

rat CCK-B pK_i( SEM

n

rat CCK-A pK_i( SEM

n

GV150013 (24)

L-365,260

PD134,308

L-364,718

9.43 ( 0.12

8.80 ( 0.06

9.45 ( 0.06

7.53 ( 0.10

4

3

9.15 ( 0.04

8.53 ( 0.11

8.73 ( 0.06

7.06 ( 0.02

14

4

10

3

8.55 ( 0.05

7.91 ( 0.05

8.03 ( 0.04

6.57 ( 0.10

4

3

4

5.83 ( 0.05

6.48 ( 0.09

6.16 ( 0.06

9.83 ( 0.05

11

3

6

4

a

Values in displacing [³H]CCK-8S from rat pancreatic, guinea-pig, and rat membranes and comparison with human CCK-B receptor

affinities; data are means of n experiments. Experiments were performed on a membrane preparation obtained from a transfected HeLa

cell line.

F igu r e 4. Chemical structure of GV150013

F igu r e 3. Structure and conformation of 56 as determined

by X-ray crystallography.

Thus, for example, the 1-adamantyl derivatives were

more CCK-B-selective than the corresponding 2-ada-

mantyl ones. Although a SAR cannot be established yet

for the whole substitution pattern, some preliminary

comments can be made other than those reported for

the substitution in position N-1: (1) a meta substituent

on the ureidic phenyl (e.g. dimethylamino or methylthio)

may enhance CCK-B receptor affinity (this is however

F igu r e 5. Superimposition of GV182635 (purple) with the

pharmacophore model.

dependent on the substituent at N-1 position); (2)

introduction of an o-fluoro substituent at N-5 phenyl

proved to be beneficial particularly in combination with

a m-dimethylamino substituent at the urea side chain

and a branched alkyl at N-1; (3) substitution with

halogens at the fused aromatic ring was not as efficient

as in other series (e.g. carbamates).^16,30,31

Finally, the separation of the isomers of the most

interesting compounds revealed that for the current

series the (+)-isomers are more CCK-B-selective than

the corresponding (-)-ones, as a result of either reten-

tion or slight increase in CCK-B receptor affinity

associated with a drop of CCK-A potency. This effect

was observed for the N-5 aryl derivatives, and it is

particularly relevant in the case of the 1-adamantyl-

methyl series. As a result of this evaluation, GV150013

(Figure 4) has emerged as a potent and selective CCK-B

antagonist and has progressed into development. Fur-

thermore, the X-ray structure of GV182635, 56, was

aligned to a possible pharmacophore model of eight

potent and selective peptoidic derivatives synthesized

at Parke Davis Lab.¹⁰The pharmacophore model,

developed in house, was identified with the use of the

active analogue approach (AAA)³⁷mode, implemented

within Sybyl,³⁸followed by molecular dynamics simula-

tions (MD) within Discover³⁹(CVFF force field)⁴⁰with

distance restraints taken from the pharmacophore AAA

distance maps.³⁶The superimposition was carried out

by aligning the adamantyl group, the ureidic substitu-

ent, and the phenyl ring of the benzodiazepine deriva-

tive on the corresponding pharmacophore features (the

adamantyl group, the indole, and the phenyl ring) of

the peptoidic derivatives, respectively. As can be seen

in Figure 5, the 1,5-BDZ structure, as exemplified by

56, exhibits a good alignment to the pharmacophore

model, and the seven-membered ring could mimick the

γ-turn at the Trp residue of the peptoidic derivatives.

In Table 3, the binding profile of GV150013 is

reported and compared with values obtained for two

other CCK-B antagonists, PD134,308 and L365,260.

GV150013 shows higher affinity than the reference

compounds in all the three species in wich the binding

for the CCK-B receptor subtypes was assayed, except

in the human recombinant assay, where it demon-

strated the same affinity as PD134,308. Furthermore,

GV150013 shows the higher B/A selectivity in all the

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3603

Ta ble 4. GV150013 in Animal Model of Anxiety

models with an activity in the range 0.3-3 µg/kg,

depending on the species. Moreover, GV150013 is devoid

of any significant side effects and is a compound that

might be useful in the treatment of anxiety, panic, and

sleep disorders.

model

ED₅₀(µg‚kg^-1

)

route

mouse black/white box

rat social interaction^a

marmoset human threat

rat vogel

0.05

po

iv

po

sc

0.03

1.6

0.02

no effect up to µg‚kg^-1

Exp er im en ta l Section

a

Against FG 7142, 10 mg‚kg^-1, ip.

In the preparations and examples, unless otherwise stated:

Melting points (mp) were determined on a Bu¨chi melting point

apparatus and are uncorrected. All temperatures refer to °C.

Infrared spectra were measured on a Bruker IFS 48 (FT)

spectrometer in chloroform-d₁solutions or in Nujol mull.

Proton magnetic resonance (¹H NMR) spectra were recorded

at room temperature either on a Varian Unity 400 operating

at 400 MHz or on a Varian VXRS 5000 operating at 300 MHz.

All spectra are in CDCl₃solution (unless otherwise specified)

and referenced to residual solvent signal. Chemical shifts are

reported in ppm downfield from Me₄Si and are assigned as

singlets (s), doublets (d), doublet of doublets (dd) or multiplets

(m). Column chromatography was carried out over silica gel

60 (Merck AG Darmstadt, Germany). Mass spectra were

recorded on a VG-4 triple quadrupole Fison instrument in FAB

mode. Elemental analyses were performed by our analytical

group on Carlo Erba elemental analyzer. Optical rotations

were determined at 20 °C with a J asco DIP 360 Instrument (l

) 10 cm, cell volume ) 1 mL, λ ) 589 nm). Solutions were

dried over anhydrous sodium sulfate. Methylene chloride was

redistilled over calcium hydride; tetrahydrofuran was redis-

tilled over sodium; ethyl ether was redistilled over sodium;

ethyl acetate was dried over activated molecular sieves. The

following abbreviations are used in the text: EA ) ethyl

acetate, CH ) cyclohexane, P ) petroleum ether 40-60 °C,

THF ) tetrahydrofuran, MC ) methylene chloride, EE ) ethyl

ether, petrol ) petroleum ether, bp 40-60 °C. TLC refers to

thin-layer chromatography on silica plates using Merck silica

gel 60 F-254 glass plates (0.25 mm). All the compounds are

intended as racemic mixtures unless otherwise indicated.

species. Interestingly, both GV150013 and the reference

CCK-B antagonists compounds exhibited their highest

affinity against the human receptor and their lowest in

the rat assay. The data obtained from radioligand

binding assays has been confirmed in functional assays

for CCK-B and CCK-A receptors. In the guinea-pig

myenteric plexus where both receptor subtypes are

found, a pK_Bof 8.9 ( 0.3 was determined for GV150013

against selective CCK-B agonists and 5.9 ( 0.2 against

a selective CCK-A agonist.⁴¹In the guinea-pig gallblad-

der, a CCK-A-selective tissue, GV150013 had a pK_Bof

5.8 ( 0.1. In the isolated rat gastric mucosa, an assay

for gastrin receptors, GV150013 was less potent as an

antagonist than in the neuronal assays and a pK_Bof

7.4 ( 0.2 was determined against pentagastrin-induced

acid secretion. This indicates that GV150013 may

discriminate between the classical CCK-B receptor and

the stomach gastrin receptor.

Finally, GV150013 has shown activity in a number

of animal models of anxiety as can been seen from the

ED₅₀values given in Table 4. In the mouse black/white

box test GV150013 increased the time that naive mice

remained in a brightly illuminated section of an activity

box. The effect was dose-related, and significant in-

creases were measured at 0.1, 0.3, and 1.0 µg/kg. Similar

anxiolytic effects were seen in the rat social interaction

test and the marmoset human threat test.²⁹In all of

the anxiolytic models used, GV150013 displayed similar

efficacy to PD134,308 and to a standard benzodiazepine

(diazepam in the mouse studies and chlordiazepoxide

in the rat and marmoset). GV150013 did not show

tolerance or rebound anxiogenesis upon withdrawal

after chronic treatment (7 days at 0.3 µg/kg, po) in the

mouse black/white box, while diazepam (2.5 mg/kg, po)

carried through in parallel exhibited a marked reduction

of effect and a significant rebound upon cessation of

dosing. In general pharmacological studies, GV150013

showed no effect up to 3 mg/kg, po in the rota-rod test

(motor function), in passive avoidance (learning and

memory), and on pentobarbitone sleeping time (interac-

tion with metabolic enzymes). No gross behavior effects

were seen with the compound up to a dose of 10 mg/kg,

po.

Gen er a l P r oced u r e for Alk yla tion of In ter m ed ia te 2

To Obta in Com p ou n d s of Gen er a l F or m u la 3: Rou te A

(Sch em e 1). 1-N-(Ad a m a n t -1-ylm et h yl)-2,4-d ioxo-5-N-

p h en yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (3m ).

Sodium hydride 80% dispersion in oil (1.18 g, 30 mmol) was

added to a solution of 2,4-dioxo-5-N-phenyl-2,3,4,5-tetrahydro-

1H-1,5-benzodiazepine (2)¹⁷(7.0 g, 20 mmol) in dry DMF (400

mL). The mixture was heated to 130 °C for 45 min under a

nitrogen atmosphere. Next, a solution of 1-adamantanemetha-

nol-methanesulfonate (7.58 g, 20 mmol) in dry DMF (70 mL)

was added dropwise. The mixture was stirred at 150 °C for 6

h, then continued at 23 °C for 48 h. The reaction mixture was

then diluted with ethyl acetate (400 mL), washed with brine

(4 × 400 mL) dried and concentrated in vacuo to an oil wich

was purified by flash chromatography (eluting in gradient from

CH-EA 80:20 to EA) to give 1.97 g of final compound 3m as

a white solid (18%): mp 180-2 °C; TLC R_f) 0.42 (EA/CH,

1:1); MS (FAB) m/e 402 (MH⁺); IR ν_max1695 and 1670 (CdO,

1

CdC) cm^-1; H NMR δ 7.50-7.10 (m, 8H); 6.95 (d, 1H); 4.53

(d, 1H); 3.32 (d), 3.50 (s, 2H); 1.89 (m, 3H); 1.70-1.40 (m, 12H).

Analytical data for representative compounds are as follows.

1-N-Bu tyl-2,4-d ioxo-5-N-p h en yl-2,3,4,5-tetr a h yd r o-1H-

Con clu sion

1

1,5-ben zod ia zep in e (3a ): TLC R_f) 0.53 (EA/CH, 3:7); H

A novel class of 1,5-benzodiazepines was explored

with the aim of identifying a new potent and selective

CCK-B antagonist. The molecular structure of com-

pounds belonging to this class can be efficiently ma-

nipulated to get potent and selective CCK-B antago-

nists. The substitution of the N-1 position with a

suitable side chain gave potent antagonists endowed

with nanomolar affinity at the CCK-B binding site.

Among them, GV150013 exhibits high affinity for the

CCK-B receptor, high selectivity against CCK-A recep-

tors, and anxiolytic activity in a number of animal

NMR δ 7.50-7.10 (m, 8H); 6.99 (d, 1H); 4.50 (m, 1H); 3.65 (m,

1H); 3.50 (s, 2H); 1.60 (m, 2H); 1.40 (m, 2H); 0.90 (t, 3H).

2,4-Dioxo-1-N-(3-m et h ylb u t -1-yl)-5-N-p h en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in e (3b): TLC R_f) 0.36

(EA/CH, 1:1); IR ν_max1695 and 1668 (CdO) and (CdC) cm^-1

;

¹H NMR δ 7.44-7.10 (m); 6.94 (d); 6.94 (d, 1H); 4.55 (m,); 3.63

(m); 3.47(s); 1.52 (m); 1.48 (m); 0.92 (d); 0.89 (d).

1-N-(2,3-Dim eth ylbu t-1-yl)-2,4-dioxo-5-N-ph en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in e (3e): TLC R_f) 0.40

1

(EA/CH, 1:1); IR ν_max1695, 1668 (CdO) and (CdC) cm^-1; H

NMR δ 7.46-7.36 (m, 3H); 7.35-7.2 (m, 3H);7.19-7.08 (m,

1H); 6.94 (dd, 1H); 4.65 and 4.52 (2dd, 1H); 3.58 and 3.38 (dd,

3604 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20

Ursini et al.

1H); 3.51 and 3.49 (2s, 1H); 1.8-1.6 (m, 2H); 0.91-0.82 (3d,

1-N-(2-Ad a m a n t-1-yleth yl)-3-a zid o-2,4-d ioxo-5-N-p h en -

yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (4n ): TLC R_f

) 0.68 (EA/CH, 1:1); MS (FAB) m/e 456 (MH⁺); IR ν_max2122

6H); 0.79 and 0.78 (2d, 3H).

1-N-(3,3-Dim eth ylbu t-1-yl)-2,4-dioxo-5-N-ph en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in e (3f): TLC R_f) 0.39 (EA/

1

(N₃), 1709, 1678 (CdO), 1601 (CdC) cm^-1; H NMR δ 7.50-

CH, 1:1); MS (FAB) m/e 337 (MH⁺); IR ν_max1713 (CdO) cm^-1

;

7.15 (m, 8H); 6.99 (dd, 1H); 4.49 (m, 1H); 4.19 (s, 1H); 3.72

(m, 1H); 1.97 (bs, 3H); 1.9-1.3 (m, 14H).

¹H NMR δ 7.48-7.08 (m, 8H); 6.95 (dd, 1H); 4.60-4.40 (m,

1H); 3.7-3.55 (m, 1H); 3.49 (s, 2H); 1.52-1.40 (m, 2H); 0.95

(s, 9H).

Gen er a l P r oced u r e To Obta in Com p ou n d s of Gen er a l

F or m u la 5 via Red u ction of Azid o In ter m ed ia te 4:

Rou te A (Sch em e 1). 1-N-(Ad a m a n t-1-ylm eth yl)-3-a m in o-

2,4-d ioxo-5-N-p h en yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod i-

a zep in e (5m ). 5% Pd/CaCO₃(0.51 g) was added to a solution

of the intermediate 4m (0.92 g, 2.08 mmol) in EA (50 mL) and

ethanol (50 mL) and the mixture was hydrogenated at 1 atm

for 5 h. The catalyst was filtered off and the solvent evaporated

in vacuo to small volume. The residue was diluted with

dichloromethane (50 mL), washed with brine (3 × 25 mL),

dried and concentrated in vacuo. Purification by flash chro-

matography (eluting with EA-MeOH 95:5) gave the title

compound 5m as a white foam (0.75 g, 1.8 mmol. 87%): TLC

R_f) 0.51 (MC/MeOH, 9:1); MS (FAB) m/e 416 (MH⁺); IR ν_max

3369 (NH₂), 1701-1672 (CdO) cm^-1; ¹H NMR δ 7.47 (dd, 1H);

7.40-7.30 (m, 5H); 7.23 (td, 1H); 7.15 (td, 1H); 6.94 (dd, 1H);

4.52 (d, 1H); 3.38 (d, 1H); 4.22 (s, 1H); 2.30-1.70 (m, 2H); 1.82

(m, 3H); 1.70-1.30 (m, 12H).

2,4-Dioxo-5-N-p h en yl-1-N-(2-p h en ylet h yl)-2,3,4,5-t et -

r a h yd r o-1H-1,5-ben zod ia zep in e (3l): TLC R_f) 0.27 (EA/

1

CH, 1:1); IR ν_max1695 and 1668 (CdO), 1599 (CdC) cm^-1; H

NMR δ 7.45-6.90 (m, 14H); 4.75 (m, 1H); 4.0-3.80 (m, 1H);

3.516 (s, 2H); 2.964 (t, 2H).

1-[2-(1-Ad a m a n tyl)eth yl]-2,4-d ioxo-5-p h en yl-2,3,4,5-tet-

r a h yd r o-1H-1,5-ben zod ia zep in e (3n ): TLC R_f) 0.42 (EA/

CH, 1:1); MS (FAB) m/e 415 (MH⁺); IR ν_max1695 and 1668

(CdO) cm^-1; ¹H NMR δ 7.42-7.36 (m, 3H); 7.30 (m, 1H); 7.26

(d, 1H); 7.19 (m, 2H); 7.11 (m, 1H); 6.93 (dd, 1H); 4.50 (m, 1H);

3.64 (m, 1H); 3.46 (s, 2H); 1.94 (bs, 3H); 1.74 (m, 6H); 1.5 (m,

6H); 1.37 (m, 2H).

Gen er a l P r oced u r e To Obta in Com p ou n d s of Gen er a l

F or m u la 4: Rou te A (Sch em e 1). 1-N-(Ad a m a n t-1-ylm eth -

yl)-3-azido-2,4-dioxo-5-N-ph en yl-2,3,4,5-tetr ah ydr o-1H-1,5-

ben zod ia zep in e (4m ). A solution of the intermediate 3 (1.69

g 4.29 mmol) in dry THF (40 mL) was added to potassium tert-

butoxide (0.7 g, 6.23 mmol) in dry THF (30 mL) cooled to -78

°C under a nitrogen atmosphere. The reaction mixture was

stirred at -78 °C for 30 min, then a cooled solution (-78 °C)

of 2,4,6-triisopropylbenzenesulfonyl azide (1.50 g, 5.08 mmol)

in dry THF (30 mL) was added. After 5 min glacial acetic acid

(0.24 mL) was added and the solution was allowed to warm to

23 °C and stirred for 24 h. The reaction mixture was diluted

with EA (200 mL) and washed with brine, saturated sodium

hydrogen carbonate solution, water, 10% hydrochloric acid

solution and brine (2 × 100 mL). The combined organic

extracts were dried and concentrated in vacuo to give after

flash chromatography on silica and EA/CH, 3:7 as eluants, the

final compound 4m as a white solid (0.98 g, 0.56 mmol, 52%):

TLC R_f) 0.73 (EA/CH, 1:1); IR ν_max2112 (N₃), 1690, 1666 (Cd

O) and (CdC) cm^-1; ¹H NMR δ 7.5-7.10 (m, 9H); 6.99(d, 1H);

4.53 (m, 1H); 4.20 (s, 1H); 3.39 (d, 1H); 1.90 (m, 3H); 1.7-1.35

(m, 12).

Analytical data for representative compounds are as follows.

3-Am in o-1-N-bu tyl-2,4-dioxo-5-N-ph en yl-2,3,4,5-tetr ah y-

d r o-1H -1,5-b en zod ia zep in e (5a ): TLC R_f) 0.25 (MC/

1

MeOH, 95:5); IR ν_max3710 (NH₂), 1701, 1668 (CdO) cm^-1; H

NMR δ 7.50-7.15 (m, 8H); 6.99 (d, 1H); 4.50 (m, 1H); 4.25 (s,

1H); 3.70 (m, 1H); 1.80-1.2 (m, 6H); 0.90 (t, 3H).

3-Am in o-2,4-d ioxo-1-N-(3-m eth ylbu t-1-yl)-5-N-p h en yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5b): TLC R_f)

0.55 (MC/MeOH, 95:5); MS (FAB) m/e 339 (MH⁺); IR ν_max3393

(NH); 1705-1670 (CdO), 1595 (CdC) cm^-1; ¹H NMR δ 7.45-

7.1(m, 8H); 6.95 (d, 1H); 4.54 (m, 1H); 3.67 (m, 1H); 4.22 (s,

1H); 1.92 (bs, 2H); 1.55 (m, 1H); 1.47 (m, 2H); 0.91(d, 3H); 0.88

(d, 3H).

3-Am in o-1-N-(2,3-d im eth ylbu tyl)-2,4-d ioxo-5-N-p h en yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5e): TLC R_f)

0.55 (EA/MeOH, 9:1); IR ν_max3371 (NH₂); 1701, 1668 (CdO),

1593 (CdC) cm^-1; ¹H NMR δ 7.46-7.12 (m, 8H); 6.94 (dd, 1H);

4.66 and 4.53 (2 dd, 1H); 4.24 and 4.22 (2 s, 1H); 3.64 and

3.44 (2 dd, 1H); 1.8-1.6 (m, 1H); 1.6-1.4 (m, 1H); 2.0-1.4 (bs,

2H); 0.9 and 0.84 (2d, 3H); 0.75 and 0.77 (2d, 3H); 0.81 and

0.84 (2 d, 3H).

3-Am in o-1-N-(3,3-d im eth ylbu tyl)-2,4-d ioxo-5-N-p h en yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5f): TLC R_f)

0.46 (MC/MeOH, 9:1); IR ν_max1701, 1670 (CdO), 1593 (CdC)

cm^-1; ¹H NMR δ 7.47-7.12 (m, 8H); 6.91 (dd, 1H); 4.58-4.40

(m, 1H); 3.80-3.63 (m, 1H); 4.24 (s, 1H); 1.54-1.45 (m, 2H);

1.85-1.55 (m, 2H); 0.96 (s, 9H).

3-Am in o-2,4-d ioxo-5-N -p h e n yl-1-N -(2-p h e n yle t h yl)-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5l): TLC R_f)

0.1 (MC/MeOH, 9:1); MS (FAB) m/e 372 (MH⁺); IR ν_max1707

(CdO), 1595 (CdC) cm^-1; ¹H NMR δ 7.50-7.15 (m, 13H); 7.03

(md, 2H); 6.95 (dd, 1H); 4.72 (m, 1H); 4.26 (s, 1H); 3.93 (m,

1H); 2.95 (t, 2H).

Analytical data for representative compounds are as follows.

3-Azid o-1-N-bu tyl-2,4-d ioxo-5-N-p h en yl-2,3,4,5-tetr a h y-

d r o-1H-1,5-ben zod ia zep in e (4a ): TLC R_f) 0.67 (EA/CH,

4:6); IR ν_max2114 (N₃), 1691-1666 (CdO) cm^{-1 1}H NMR δ

;

7.50-7.00 (m, 8H); 6.90 (d, 1H); 4.60 (m, 1H); 3.70 (m, 1H);

1.8-1.0 (m, 4H); 0.80 (t, 3H).

3-Azid o-2,4-d ioxo-1-N-(3-m et h ylb u t -1-yl)-5-N-p h en yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (4b): TLC R_f)

0.30 (EA/CH, 4:6); MS (FAB) m/e 364 (MH⁺); IR ν_max2122 (N₃),

1709 (CdO) cm^-1; ¹H NMR δ 7.45-7.00 (m, 8H); 6.98 (d, 1H);

4.54 (m, 1H); 4.20 (s, 1H); 3.70 (m, 1H); 1.62-1.45 (m, 3H);

0.93 (d, 3H); 0.91 (m, 3H).

3-Azid o-1-N-(2,3-d im eth ylbu t-1-yl)-2,4-d ioxo-5-N-p h en -

yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (4e): TLC R_f

) 0.73 (EA/CH, 1:1); IR ν_max2114 (N₃), 1691, 1666 (CdO) cm^-1

;

1-N-(2-Adam an t-1-yleth yl)-3-am in o-2,4-dioxo-5-N-ph en -

yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5n ): TLC R_f

) 0.62 (MC/MeOH, 9:1); MS (FAB) m/e 430 (MH⁺); IR ν_max

¹H NMR δ 7.46 7.14 (m, 8H); 6.98 (2d, 1H); 4.65 and 4.53 (2dd,

1H); 4.21 and 4.19 (2s, 1H); 3.64 and 3.44 (2dd, 1H); 1.82-

1.70 (m, 1H); 1.64-1.48 (m, 1H); 0.91 and 0.78 (2d, 3H); 0.84

and 0.83 (2d, 6H).

1

3447-2671 (NH₂), 1707,1686 (CdO) cm^-1; H NMR δ 7.48-

7.24 (m, 4H); 7.24-7.12 (m, 4H); 6.95 (dd, 1H); 4.56-4.4 (m,

1H); 4.23 (s, 1H); 3.78-3.64 (m, 1H); 2.0-1.3 (m, 19H).

Gen er a l P r oced u r e for Alk yla tion of Am in es 1 a n d 6

To Obta in Com p ou n d s of Gen er a l F or m u la 7: Rou te B,

Meth od A (Sch em e 2). 2-F lu or o-2′-(3-m eth ylbu t-1-yl)-

a m in od ip h en yla m in e (7c). Bromo-3-methylbutane (4.33

mL, 35 mmol) was added to a solution of 2-amino-2′-fluo-

rodiphenylamine⁴²(6) (7.0 g, 35 mmol) and sodium iodide (5.24

g, 35 mmol) in dimethylformamide (250 mL) under a nitrogen

atmosphere. The solution was stirred at 120 °C for 8 h, then

cooled to room temperature, diluted with water (300 mL) and

extracted with diethyl ether (2 × 250 mL). The combined

organic extracts were washed with brine (300 mL), dried and

3-Azid o-1-N-(3,3-d im eth ylbu t-1-yl)-2,4-d ioxo-5-N-p h en -

yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (4f): TLC R_f

) 0.73 (EA/CH, 1:1); MS (FAB) m/e 378 (MH⁺); IR ν_max2127

1

(N₃), 1693, 1666 (CdO), 1597 (CdC) cm^-1; H NMR δ 7.44-

7.40 (m, 3H); 7.38-7.31 (m, 2H); 7.24-7.17 (m, 3H); 6.999 (dd,

1H); 4.537-4.434 (m, 1H); 4.20 (s, 1H); 3.775-3.674 (m, 1H);

1.523 (m, 2H); 0.967 (s, 9H).

3-Azido-2,4-dioxo-5-N-ph en yl-1-N-(2-ph en yleth yl)-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in e (4l): TLC R_f) 0.57 (EA/

CH, 1:1); MS (FAB) m/e 398 (MH⁺); IR ν_max2122 (N₃), 1709,

1684 (CdO) cm^-^{1 1}H NMR δ 7.50-6.95 (m, 14H); 4.234 (s,

;

1H); 4.80-4.60 (m, 1H); 4.0-3.8 (m, 1H); 2.98 (m, 2H).

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3605

concentrated in vacuo to an oil, which was purified by flash

chromatography (eluting with CH-EA 95:5) to give 6.3 g of

title compound 7c as a yellow oil (66%): TLC R_f) 0.75 (CH/

EA, 9:1); MS (FAB) m/e 273 (MH⁺); IR ν_max3410 (NH) and

1620 (CdC) cm^-1; ¹H NMR δ 7.14-6.6 (m, 8H); 5.25 (bs, 1H);

4.09 (bs, 1H); 3.14 (t, 2H); 1.65 (m, 1H) 1.49 (m 2H); 0.91 (d,

6H).

was added portionwise. The resulting mixture was stirred at

23 °C for 30min, then diluted with water (150 mL) and

extracted with ethyl acetate (300 mL). The organic layer was

washed with brine (2 × 200 mL), dried and concentrated in

vacuo to an oil which was purified by flash chromatography

(eluting with CH-EA 9:1) to give the title compound as a

yellow oil (3.5 g, 46%): TLC R_f) 0.47 (CH/EA 9:1); MS (FAB)

m/e 279 (MH⁺); IR ν_max3373 (NH), 1601, 1512 and 1497 (Cd

Gen er a l P r oced u r e for Alk yla tion of Am in es 1 a n d 6

To Obta in Com p ou n d s of Gen er a l F or m u la 7: Rou te B,

Meth od B₁(Sch em e 2). 2-(3,3-Dim eth ylbu t-1-yl)a m in o-2′-

flu or od ip h en yla m in e (7g). Sodium borohydride (22.7 g, 600

mmol) was added portionwise to a mixture of 2-amino-2′-

fluorodiphenylamine⁴²(6) (8.0 g, 40 mmol), sodium acetate

trihydrate (16.33 g, 120 mmol) and 3,3-dimethylbutyraldehyde

(5 mL, 40 mmol) in acetic acid (12.8 mL), water (50 mL) and

ethanol (40 mL) cooled to 0 °C. The solution was stirred at 23

°C for 30 min, then diluted with ethyl acetate (300 mL). The

organic layer was washed with a 10% solution of sodium

hydroxide (3 × 200 mL) and brine (200 mL), dried and

concentrated in vacuo to an oil, which was purified by flash

chromatography (eluting with CH-EA 9:1) to give 7.44 g of

compound 7g as a yellow oil (65%): TLC R_f) 0.85 (CH/EA,

9:1); IR ν_max3408 (NH), 1618 and 1603 (CdC) cm^-1; ¹H NMR

δ 7.2-7.0 (m, 3H); 6.93 (dt, 1H); 6.8-6.6 (m, 4H); 6.26 (d, 1H);

4.07 (t, 1H); 3.15 (m, 2H); 1.6-1.5 (m, 2H); 0.96 (s, 9H).

Analytcal data for representative compounds are as follows.

2-(1,3-Dim eth ylbu t-1-yl)am in odiph en ylam in e(7d). Start-

ing from commercially available 2-aminodiphenylamine (1):

TLC R_f) 0.79 (CH/EA, 9:1); MS (FAB) m/e 268 (MH⁺); IR ν_max

3420 (NH), 1599, 1514 and 1497 (CdC) cm^-1; ¹H NMR δ 7.3-

7.05 (m, 3H); 6.85-6.6 (m, 6H); 5.01 (bs, 1H); 3.97 (b, 1H),

3.56 (m, 1H); 1.68 (m, 1H); 1.51-1.37 (m, 1H), 1.14 (d, 3H);

1.3-1.15 (m, 1H); 0.91 (d, 3H); 0.88 (d, 3H).

C) cm^-^{1 1}H NMR δ 7.24-7.14 (m, 2H); 7.14-7.04 (m, 2H);

;

6.81 (t, 1H); 6.76-6.62 (m 4H); 5.04 (bs, 1H); 4.29 (bs, 1H);

3.68 (m, 1H); 2.48 (m, 1H); 2.20 (bs, 1H); 2.10 (m, 1H); 1.58-

1.42 (m, 2H); 1.40-1.1 (m, 4H); 0.74 (m, 1H).

Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s of

Gen er a l F or m u la 8: Rou te B (Sch em e 2). 2,4-Dioxo-5-

N-(2-flu or op h en yl)-1-N-(3-m et h ylb u t -1-yl)-3-p h en ylh y-

d r a zon o-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (8c).

The intermediate 7c (6.3 g, 23 mmol) and the 2-phenylhydra-

zonomalonyl dichloride¹⁸(6.8 g, 27.7 mmol) were each taken

up in THF (150 mL) and dropped in a flask containing THF

(200 mL) maintained at -5 °C under a nitrogen atmosphere.

After complete addition the solution was allowed to warm to

room temperature and then heated to 50 °C for 2-3 h. The

solution was concentrated in vacuo to an oil, which was

purified by flash chromatography (eluting with CH-EA 8:2)

to give the title compound as a yellow solid (5.8 g, 57%): TLC

1

R_f) 0.59 (CH/EA 7:3); IR ν_max1700 (CdO) cm^-1; H NMR δ

11.34 and 11.15 (2d, 1H); 7.7 (m., 1H); 7.5-6.9 (m, 13H); 4.58

(m, 1H); 3.65 (m, 1H); 1.8-1.5 (m, 3H); 0.95 and 0.94 (2d, 3H);

0.81 (d, 3H).

Analytical data for representative compounds are as follows.

1-N -(1,3-Dim e t h ylb u t -1-yl)-2,4-d ioxo-5-N -p h e n yl-3-

p h e n ylh yd r a zon o-2,3,4,5-t e t r a h yd r o-1H -1,5-b e n zod i-

a zep in e (8d ): TLC R_f) 073 (CH/EA 7:3); MS (FAB) m/e 441

(MH⁺); IR ν_max1668, 1653 (CdO), 1591 (CdC) cm^-1; ¹H NMR

δ 11.21, 10.96, 10.95 (3bs, 1H); 7.52-6.93 (m, 14H); 4.06, 4.31

(2m, 1H); 1.8-1.4 (m, 3H); 1.72, 1.72, 1.70, 1.61 (4d, 3H); 1.01-

0.85 (d, 6H).

2-(3-Cyclopen tylpr open -2-yl)am in odiph en ylam in e (7h ).

Starting from commercially available 2-aminodiphenylamine

(1): TLC R_f) 0.58 (CH/EA 3:1); IR ν_max3373 (NH), 1599 (Cd

C) cm^-^{1 1}H NMR δ 7.19-7.14 (m, 2H); 7.11-7.06 (m, 2H);

;

6.78 (t, 1H); 6.71-6.6 (m, 4H); 4.99 (bs, 1H); 3.97 (bs, 1H);

3.49 (m, 1H); 1.88 (m, 1H); 1.70 (m, 1H); 1.58 (m, 1H); 1.64-

1.00 (m, 6H); 1.13 (d, 3H).

2-(2-C y c lo p e n t y le t h y l)a m i n o -2′-flu o r o d i p h e n y l-

a m in e (7i). Starting from 2-amino-2′-fluorodiphenylamine⁴²

(6): TLC R_f) 0.78 (CH/EA 9:1); IR ν_max3398 (NH); 1618-

1605 (CdC) cm^-1; ¹H NMR δ 7.18-7.07 (m, 2H); 7.03 (m, 1H);

6.9 (m, 1H); 6.72 (m, 1H); 6.76-6.58 (m, 3H); 5.25 (bs, 1H);

4.12 (bs, 1H); 3.13 (t, 2H); 1.90-1.05 (m, 11H).

1-N-(3,3-Dim eth ylbu t-1-yl)-2,4-dioxo-5-N-(2-flu or oph en -

yl)-3-p h en ylh yd r a zon o-2,3,4,5-tetr a h yd r o-1H-1,5-ben zo-

d ia zep in e (8g): mp 112-114 °C; TLC R_f) 0.40 (CH/EA 8:2);

MS (FAB) m/e 459 (MH⁺); IR ν_max1670 and 1653 (CdO) cm^-1

;

¹H NMR δ 11.31 and 11.14 (2bs, 1H); 7.72 (dt, 1H); 7.54-6.88

(m, 12H); 4.66-4.48 (m, 1H); 3.64-3.56 (m, 1H); 1.6-1.5 (m,

2H); 0.99 (s, 9H).

1-N-(3-Cyclop en tylp r op en -2-yl)-2,4-d ioxo-5-N-p h en yl-

3-p h en ylh yd r a zon o-2,3,4,5-t et r a h yd r o-1H -1,5-b en zod i-

a zep in e (8h ): TLC R_f) 0.75 (CH/EA 3:1); IR ν_max3300 (NH);

2-(Ad a m a n t-2-yl)a m in od ip h en yla m in e (7o). Starting

from commercially available 2-aminodiphenylamine (1): TLC

1

1666 (CdO); 1637-1591 (CdC) and (CdN) cm^-1; H NMR δ

R_f) 0.73 (CH/EA 9:1); IR ν_max3400 (NH); 1605 (CdC) cm^-1

;

11.20 and 10.94 (bs, 1H); 7.60-6.80 (m, 14 H); 4.56 and 4.30

¹H NMR δ 7.18 (m, 2H); 7.07 (m, 2H); 6.79 (t, 1H); 6.72 (m,

2H); 6.67-6.6 (m. 2H); 5.05 (bs, 1H); 4.51 (bs, 1H); 3.53 (bs,

1H); 2.00-1.4 (m, 14H).

(m, 1H); 2.60 (m, 1H); 2.05-1.1 (m, 13H).

1-N-(2-Cyclop en tyleth yl)-2,4-d ioxo-5-N-(2-flu or op h en -

yl)-3-ph en ylh ydr azon o-2,3,4,5-tetr ah ydr o-1H-1,5-ben zodi-

a zep in e (8i): TLC R_f) 0.71 (CH/EA, 1:1); mp 147-50 °C; IR

2-(Ad a m a n t -1-ylm et h yl)a m in od ip h en yla m in e (7m ).

Starting from commercially available 2-aminodiphenylamine

(1) (55%): TLC R_f) 0.59 (CH/EA 8:2); MS (FAB) m/e 332

(MH⁺); IR ν_max3427, 3379 (NH); 1599 (CdC) cm^-1; ¹H NMR δ

7.18 (m, 2H); 7.07 (m, 2H); 6.80 (dt, 1H); 6.72 (d+m, 3H) 6.62

(dt, 1H); 5.07 (bs, 1H); 4.19 (bs, 1H); 2.78 (d, 2H); 1.92 (m,

3H); 1.74-1.40 (m, 12H).

ν_max3250 (NH); 1670-1659 (CdO), 1610-1595 (CdC) cm^-1

;

¹H NMR δ 11.33-11.31 (bs, 1H); 7.70-6.88 (m, 13H); 4.68-

4.50 (m, 2H); 3.78-3.6 (m, 2H); 1.90-1.1 (m, 9H).

1-(Ad a m a n t-1-m eth yl)-2,4-d ioxo-5-p h en yl-3-p h en ylh y-

d r a zon o-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (8m ):

93%; TLC R_f) 0.39 (CH/EA, 8:2); MS (FAB) m/e 505 (MH⁺);

IR ν_max1732 (CdO), 1663, 1637, 1601 (CdC) and (CdN) cm^-1

;

2-(Adam an t-2-ylm eth yl)am in odiph en ylam in e (7q). From

2-adamantanecarboxaldehyde⁴³and 2-aminodiphenylamine

(1): TLC R_f) 0.86 (CH/EA 8:2); MS (FAB) m/e 332 (MH⁺); IR

¹H NMR δ 11.24 and 11.21 (2bs, 1H); 7.60-6.88 (m, 14 H);

4.74 and 4.62 (2d, 1H); 3.35 (d, 1H); 1.94 (m, 3H); 1.74-1.46

(m, 12H).

1

ν_max3436 (NH); 1599 (CdC) cm^-1; H NMR δ 7.25-7.07 (m,

4H); 6.85-6.6 (m, 5H); 6.67-6.6 (m); 5.027 (s, 1H); 4.10 (s,

1-(Ad a m a n t -2-yl)-2,4-d ioxo-5-p h en yl-3-p h en ylh yd r a -

zon o-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (8o): TLC

R_f) 060 (CH/EA 80:20); IR ν_max1664 and 1632 (CdO), 1589

1H); 3.22 (d, 2H); 1.95-1.5 (m, 15H).

Gen er a l P r oced u r e for Alk yla tion of Am in es 1 a n d 6

To Obta in Com p ou n d s of Gen er a l F or m u la 7: Meth od

B₂(Sch em e 2). 2-[Bicyclo[2.2.1]-2-h ep tyl]a m in od ip h en -

yla m in e (7p ). A mixture of 2-aminodiphenylamine (1) (5.0

g, 27 mmol), norcamphor (3.0 g, 27 mmol) and molecular sieves

in dry toluene (200 mL) was heated to 120 °C for 6 h. The

mixture was allowed to cool to room temperature, filtered and

the solution concentrated in vacuo. The residue was dissolved

in ethanol (200 mL), then sodium borohydride (3.0 g, 81 mmol)

1

(CdC) cm^-1; H NMR δ 12.41 and, 11.21 (2s, 1H); 7.54-6.88

(m, 14H); 4.50 and 4.42 (2m 1H); 3.12 and 2.93 (2m, 1H); 2.30-

2.20 (m, 1H); 2.06-1.26 (m, 12H).

1-[Bicyclo[2.2.1]-2-h ep tyl]-2,4-d ioxo-5-p h en yl-3-p h en -

ylh yd r a zon o-2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in e

(8p ): mp 110-111 °C; TLC R_f) 0.72 (CH/EA, 7:3); MS (FAB)

m/e 451 (MH⁺); IR ν_max1668 (CdO), 1639 and 1591 (CdC)

1

cm^-1; H NMR δ 12.33, 12.13, 11.38, 11.28 (4 bs, 1H); 7.58-

3606 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20

Ursini et al.

6.9 (m, 14H); 4.63 and 4.4 (2m, 1H); 3.44 and 3.26 (m, 1H);

2.6 and 2.5 (m, 1H); 2.6-1.8 (m, 8H).

yl-2,3,4,5-tetr ah ydr o-1H-1,5-ben zodiazepin e (5q): mp 209-

210 °C; TLC R_f) 0.38 (EA/MeOH, 20:1); MS (FAB) m/e 416

(MH⁺) IR ν_max1697 and 1664 (CdO) cm^-1;¹H NMR δ 7.5-7.15

(m, 8H); 6.94 (dd, 1H); 5.06 (dd, 1H); 4.27 (s, 1H); 3.60 (dd,

1H); 2.3-1.5 (m, 15H).

1-N-(Adam an t-2-ylm eth yl)-2,4-dioxo-5-N-ph en yl-3-ph en -

ylh yd r a zon o-2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in e

(8q): mp 135-6 °C dec; TLC R_f) 0.48 (CH/EA, 8:2); MS (FAB)

m/e 505 (MH⁺); IR ν_max1736 and 1668 (CdO), 1653 and 1600

Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s of

Gen er a l F or m u la 5 Usin g Ca ta lic Hyd r ogen a tion : Rou te

B (Sch em e 2). 1-N-(Ad a m a n t -1-ylm et h yl)-3-a m in o-2,4-

d ioxo-5-N -p h e n yl)-2,3,4,5-t e t r a h yd r o-1H -1,5-b e n zod i-

a zep in e (5m ). 10% Pd/C (1.51 g) and concentrated hydro-

chloric acid (10 mL) were added to a solution of the intermedi-

ate 8m (3.01 g, 5.96 mmol) in methanol (100 mL) and the

mixture was hydrogenated at 1 atm. for 8 h. The catalyst was

filtered over Celite and the filtrate concentrated in vacuo. The

residue was dissolved in ethyl acetate (200 mL), washed with

a 10% sodium hydroxide solution (3 × 100 mL), water (100

mL) and brine (2 × 100 mL), dried and concentrated in vacuo.

Purification by flash chromatography (eluting with EA-MeOH

95:5) gave the title compound as a white foam (1.92 g, 4.62

mmol, 78%).

Gen er a l P r oced u r e To Obta in Com p ou n d s of Gen er a l

F or m u la 9 (Sch em e 3). 1-N-(Ad a m a n t-2-yl)-2,4-d ioxo-3-

isocya n a to-5-N-p h en yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zo-

d ia zep in e (9o). Phosgene in toluene (1.93 M solution, 10 mL)

was added to a solution of the intermediate 5 (0.285 g, 0.68

mmol) in dichloromethane (10 mL). The resulting solution was

stirred at 23 °C for 4 h, then concentrated in vacuo at 50 °C

for 2.5 h to give the title compound as a white foam (0.29 g,

0.67 mmol, 98%): IR ν_max2220 (NdC), 1697 and 1676 (CdO)

cm^-1; ¹H NMR δ 7.50-7.15 (m, 8H); 7.05-6.95(m, 1H); 4.7 (s,

1H); 4.55 (m, 1H); 3.05 (m, 1H); 2.35 (m, 1H); 1.95-1.1 (m,

12H).

(CdC) cm^-^{1 1}H NMR δ 11.27 and 11.24 (2bs, 1H); 7.5-6.9

;

(m, 14H); 5.12-5.04 and 5.02-4.94 (2dd, 1H); 3.67-3.61 (dd,

1H); 2.1-1.5 (m, 15H).

Gen er a l P r oced u r e for P r ep a r a tion of Com p ou n d s of

Gen er a l F or m u la 5 Usin g Zn /AcOH: Rou te B (Sch em e

2). 3-Am in o-2,4-d ioxo-5-N-(2-flu or op h en yl)-1-N-(3-m eth -

ylbu t-1-yl)-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5c).

A solution of the intermediate 8c (5.8 g, 13 mmol) in glacial

acetic acid (70 mL) was added, dropwise, to a suspension of

zinc dust (6.37 g, 97.5 mmol) in glacial acetic acid (20 mL)

cooled to 0 °C. The mixture was stirred at 23 °C for 3 h, then

diluted with water (200 mL) and decanted from zinc. Solid

sodium carbonate was added until pH ) 9 and the mixture

extracted with ethyl acetate (2 × 300 mL). The combined

organic extracts were washed with brine (300 mL), dried and

concentrated in vacuo to an oil which was purified by flash

chromatography (eluting in gradient from CH-EA 2:1 to EA)

to give compound 5c as a white solid (2.8 g): mp 125-6 °C;

TLC R_f) 0.38 (MC/MeOH, 30:1); MS (FAB) m/e 356 (MH⁺);

1

IR ν_max1709 and 1672 (CdO), 1599 (CdC) cm^-1; H NMR δ

7.46-7.14 (m, 7H); 6.94 (dd, 1H); 4.48 (m, 1H); 4.28 (s, 1H);

3.71 (m, 1H); 1.59 (m, 1H); 1.50 (m, 2H); 0.92 (d, 3H); 0.91 (d,

3H).

Analytical data for representative compounds are as follows.

3-Am in o-1-N-(1,3-dim eth ylbu t-1-yl)-2,4-dioxo-5-N-ph en -

yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5d ): TLC R_f

) 0.53 (MC/MeOH, 9:1); MS (FAB) m/e 352 (MH⁺); IR ν_max

Analytical data for representative compounds are as follows.

2,4-Dioxo-5-N-(2-flu or oph en yl)-3-isocyan ato-1-N-(3-m e-

t h ylb u t -1-yl)-2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in e

(9c): mp 167-8 °C; IR ν_max2243 (CdNdO), 1717 and 1684

(CdO), 1601 (CdC) cm^-1; ¹H NMR δ 7.46 (dd, 1H); 7.44-7.32

(m, 2H); 7.3-7.15 (m, 4H); 7.0 (dd, 1H); 4.64 (s, 1H); 4.52-4.4

(m, 1H); 3.8-3.68 (m, 1H); 1.7-1.45 (m, 3H); 0.94 (d, 3H); 0.91

(d, 3H).

3500-3000 (NH₂), 1703 and 1672 (CdO), 1593 (CdC) cm^-1

;

¹H NMR δ 7.46-7.36 (m, 3H); 7.36-7.14 (m, 5H); 6.95 (dt,

1H); 4.5-4.3 (m, 1H); 4.42-4.39 (m, 1H); 2.11-1.7 (m, 1H);

1.64-1.44 (m, 2H); 1.57-1.55 (d, 3H); 0.92-0.83 (4d, 6H).

3-Am in o-1-N-(3,3-dim eth ylbu t-1-yl)-2,4-dioxo-5-N-(2-flu o-

r op h e n yl)-2,3,4,5-t e t r a h yd r o-1H -1,5-b e n zod ia ze p in e

(5f): mp 98-100 °C; TLC R_f) 0.30 (MC/MeOH); MS (FAB)

m/e 370 (MH⁺); IR ν_max3371-3314 (NH); 1701 and 1670 (Cd

O), 1593 (CdC) cm^-1; ¹H NMR δ [[7.42 (dd); 7.4-7.3 (m); 7.32

(dt)] 13H]; 7.26-7.12 [[(m); 7.18 (dt)] 3H]; 6.96 (dd, 1H); 4.50-

4.40 (m, 1H); 4.36 (s, 1H); 3.76-3.66 (m, 1H); 2.47 (bs, 2H);

1.50 (m, 2H); 0.95 (s, 9H).

1-(3,3-Dim eth ylbu tyl)-2,4-d ioxo-3-isocya n a to-5-p h en yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (9f): mp 205-7

°C; IR ν_max2218 (NdCdO); 1693 and 1668 (CdO) cm^{-1 1}H

;

NMR δ 7.48-7.18 (m, 8H); 7.01 (dd, 1H); 4.57 (s, 1H); 4.54-

4.42 (m, 1H); 3.80-3.68 (m, 1H); 1.60-1.46 (m, 2H); 0.96 (s,

9H).

3-Am in o-1-N-(3-cyclop en t ylp r op -2-yl)-2,4-d ioxo-5-N-

ph en yl-2,3,4,5-tetr ah ydr o-1H-1,5-ben zodiazepin e (5h ): TLC

R_f) 0.80 (MC/MeOH, 9:1); IR ν_max3366-3200 (NH₂), 1699

1-(2-Cyclop en tyleth yl)-2,4-d ioxo-5-(2-flu or op h en yl)-3-

isocyan ato-2,3,4,5-tetr ah ydr o-1H-1,5-ben zodiazepin e (9i):

TLC R_f) 0.63 (MC/MeOH, 9:1); IR ν_max2232 (NdC), 1715-

1670 (CdO) cm^-1; ¹H NMR δ 7.46 (dd, 1H); 7.44-7.15 (m, 6H);

7.00 (dd, 1H); 4.63 (s, 1H); 4.44 (m, 1H); 3.75 (m,1H); 1.86-

1.4 (m, 9H); 1.20-1.06 (m, 2H).

1

and 1663(CdO), 1591 (CdC) cm^-1; H NMR δ 7.48 7.12 (m,

8H); 6.98 and 6.90 (2dd, 1H); 4.46-4.36 and 4.58-4.50 (2m,

1H); 4.20 and 4.18 (s, 1H); 2.30-2.20 (m, 1H); 2.00-1.10 (m,

10H); 1.57 and 1.45 (2d, 3H).

3-Am in o-1-N-(2-cyclopen tyleth yl)-2,4-dioxo-5-N-(2-flu o-

r op h en yl)-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5i):

TLC R_f) 0.63 (MC/MeOH, 9:1); IR ν_max1709 and 1672 (Cd

O), 1597 (CdC) cm^-1; ¹H NMR δ 7.44 (dd, 1H); 7.42-7.28 (m,

3H); 7.26-7.14 (m, 3H); 6.95 (dd, 1H); 4.45 (m, 1H); 3.71(m,

1H); 4.29(s, 1H); 2.20-1.90 (bs, 2H); 1.86-1.68 (m, 3H); 1.68-

1.42 (m, 6H); 1.20-1.04 (m,2H).

Gen er a l P r oced u r e To Obta in Com p ou n d s of Gen er a l

F or m u la 10 (Sch em e 3). 2,4-Dioxo-5-N-(2-flu or op h en yl)-

1-N -(3-m e t h ylb u t -1-yl)-3-(p h e n yloxyca r b on yla m in o)-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (10c). Pyridine

(0.137 mL, 1.7 mmol) and phenyl chloroformate (0.21 mL, 1.7

mmol) were added to a solution of the intermediate 7c (0.3 g,

0.85 mmol) in dichloromethane (15 mL) under a nitrogen

atmosphere. The resulting solution was stirred at 23 °C for

30 min, then washed with a 1% solution of hydrochloric acid

(15 mL), a 5% solution of sodium hydrogen carbonate (15 mL)

and brine (20 mL). The organic layer was dried and concen-

trated in vacuo to a solid which was triturated with ethyl

acetate to give the title compound as a white solid (0.3 g,

74%): mp 226-7 °C; TLC R_f) 075 (CH/EA, 1:1); C₂₇H₂₆FN₃O₄;

MS (FAB) m/e 476 (MH⁺); IR (Nujol) ν_max3275 (NH), 1734,

1707 and 1684 (CdO), 1593 (CdC) cm^-1; ¹H NMR δ 7.46 (dd,

1H); 7.44-7.14 (m, 11H); 7.00 (dd, 1H); 6.46 (d, 1H); 5.17 (d,

1H); 4.55-4.47 (m, 1H); 3.77-3.68 (m, 1H); 1.6 (m, 1H); 1.56-

1.46 (m, 2H); 0.94 (d, 3H); 0.92 (d, 3H).

1-N -(Ad a m a n t -2-yl)-3-a m in o-2,4-d ioxo-5-N -p h e n yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (5o): mp 231-3

°C dec; TLC R_f) 0.61 (MC/MeOH, 9:1); IR ν_max3379 (NH₂),

1697 and 1663 (CdO), 1591 (CdC) cm^-^{1 1}H NMR δ 7.46-

;

7.20 (m, 8H); 7.0-6.9 (m, 1H); 4.52 (bs, 1H); 4.24 (s, 1H); 2.96

(bs, 1H); 2.33 (bs, 1H); 2.2-1.1 (m, 14H).

3-Am in o-1-N-[b icyclo[2.2.1]h ep t -2-yl]-2,4-d ioxo-5-N-

ph en yl-2,3,4,5-tetr ah ydr o-1H-1,5-ben zodiazepin e (5p): mp

172-3 °C; TLC R_f) 0.30 (EA/MeOH, 95:5); MS (FAB) m/e 362

(MH⁺); IR ν_max1691 and 1666 (CdO), 1595 (CdC) cm^{-1 1}H

;

NMR δ 7.5-7.1 (m, 8H); 6.98 and 6.95 (2dd, 1H); 4.50-4.42

(m, 1H); 4.27 (s, 1H); 3.49 and 2.66 (2m, 1H); 2.5 and 1.96

(2m, 2H); 2.40 and 1.64 (2bs, 2H); 2.28 and 2.18 (2t, 1H);

[1.56-1.4, 1.4-1.1, 1.02, 0.86 (4m, 7H)].

Analytical data for representative compounds are as follows

1-N-(3,3-Dim eth ylbu t-1-yl)-2,4-dioxo-5-N-ph en yl-3-(ph en -

yloxyca r bon yla m in o)-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod i-

1-N-(Adam an t-2-ylm eth yl)-3-am in o-2,4-dioxo-5-N-ph en -

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3607

a zep in e (10f): mp 170-2 °C; TLC R_f) 0.80 (CH/EA, 1:1); MS

(FAB) m/e 472 (MH⁺); IR ν_max3250 (NH), 1736 and 1695 (Cd

7.46 (dd, 1H); 7.4-7.1 (m, 10H); 7.03 (m, 1H); 6.99 (dd, 1H);

6.93 (bs, 1H); 6.35 (d, 1H); 5.37 (d, 1H); 4.46 (m, 1H); 3.70 (m,

1H); 1.6-1.4 (m, 3H); 0.90 (d, 3H); 0.89 (d, 3H).

1

O), cm^-1; H NMR δ 7.46-7.14 (m, 13H); 7.10 (dd, 1H); 6.46

(d, 1H); 5.12 (d, 1H); 4.94 (m, 1H); 3.71 (m, 1H); 1.50 (m, 2H);

0.95 (s, 9H).

N-[1-(1,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-p h en ylu r ea

(16): TLC R_f) 0.53 (CH/EA, 1:1); C₂₈H₃₀N₄O₃; MS (FAB) m/e

471 (MH⁺); IR ν_max3370 (NH), 1701 and 1670 (CdO), 1651

1-N-(3,3-Dim eth ylbu t-1-yl)-2,4-dioxo-5-N-(2-flu or oph en -

yl)-3-(p h en yloxyca r bon yla m in o)-2,3,4,5-tetr a h yd r o-1H-

1,5-ben zod ia zep in e (10g): mp 199-200 °C; TLC R_f) 0.82

(CH/EA, 1:1); MS (FAB)m/e 490 (MH⁺); IR (Nujol) ν_max3290

(NH), 1740, 1707 and 1686 (CdO), 1593 (CdC) cm^-1; ¹H NMR

δ 7.5-7.1 (m, 12H); 7.00 (dd, 1H); 6.45 (d, 1H); 5.17 (d, 1H);

4.48-4.41 (m, 1H); 3.78-3.71 (m, 1H); 1.52 (m, 2H); 0.96 (d,

9H).

1-N-(2-Cyclopen tyleth yl)-2,4-dioxo-5-N-(2-flu or oph en yl)-

3-(p h en yloxyca r bon yla m in o)-2,3,4,5-tetr a h yd r o-1H-1,5-

ben zod ia zep in e (10i): mp 205-7 °C; TLC R_f) 0.68 (CH/EA,

1:1); MS (FAB) m/e 502 (MH⁺); IR ν_max3280 (NH), 1736, 1709

and 1682 (CdO) cm^-1; ¹H NMR δ 7.46 (dd, 1H); 7.44-7.28 (m,

5H); 7.28-7.08 (m, 6H); 6.99 (dd, 1H); 6.46 (d, 1H); 5.17 (d,

1H); 4.47 (m, 1H); 3.72(m, 1H); 1.86-1.70(m, 3H); 1.70-1.44

(m, 6H); 1.12 (m, 2H).

1-N-(2-Ad a m a n t yl-1-ylet h yl)-2,4-d ioxo-5-N-p h en yl-3-

(ph en yloxycar bon ylam in o)-2,3,4,5-tetr ah ydr o-1H-1,5-ben -

zod ia zep in e (10n ): TLC R_f) 0.77 (CH/EA, 1:1); IR ν_max1742,

1707 and 1674 (CdO) cm^-1; ¹H NMR δ 7.43 (t, 3H); 7.38-7.30

(m, 4H); 7.25-7.14 (m, 5H); 6.99 (dd, IH); 6.46 (d, 1H); 5.06

(d, 1H); 4.51 (m, 1H); 3.72 (m, 1H); 1.966 (bs, 3H); 1.67 (bq,

6H); 1.54 (d, 6H); 1.36 (2d, 2H).

1

and 1601 (CdC) cm^-1; H NMR δ 7.44-7.35 (m, 3H); 7.34-

7.24 (m, 2H); 7.24-7.15 (m, 8H); 6.98 (m, 2H); 6.54 and 6.53

(2d, 1H); 5.33 and 5.32 (2d, 1H); 4.58 and 4.44 (mq +q, 1H);

2.11 and 1.74-1.64 (2m, 1H); 1.64-1.44 (m, 2H); 1.54,1.44 (2d,

3H); 0.89, 0.88, 0.87, 0.83 (4d, 6H).

N-[1-(2,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-ph en ylu r ea (17):

TLC R_f) 0.49 (CH/EA, 1:1); C₂₈H₃₀N₄O₃; MS (FAB) m/e 471

(MH⁺); IR ν_max3300 (NH), 1707 and 1641 (CdO); 1558 and

1541 (CdC) cm^-1; ¹H NMR δ 7.46-7.10 (m, 11H); 6.9 (m, 4H);

6.4 (2d, 1H,); 5.32 and 5.29 (2d, 1H); 4.61 and 4.48 (2dd, 1H);

3.60 and 3.42 (2dd, 1H); 1.8 (m, 1H); 1.4 (m, 1H); 0.86 and

0.80 (2d, 3H); 0.77 and 0.75 (2d, 3H); 0.73 and 0.70 (2d, 3H).

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-ph en ylu r ea (18):

mp 236 °C; TLC R_f) 0.57 (CH/EA, 1:1); C₂₈H₃₀N₄O₃; MS (FAB)

m/e 471 (MH⁺); IR ν_max3431-3350 (NH), 1705-1668 (CdO),

1

1599 (CdC) cm^-1; H NMR δ 7.48-7.16 (m, 13H); 7.04-6.96

(m, 2H); 6.52 (d, 1H); 5.35 (d, 1H); 4.51-4.40 (m, 1H); 3.73-

3.63 (m, 1H); 1.47 (t, 2H); 0.92 (s, 9H).

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-dioxo-5-(2-flu or oph en yl)-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-p h en yl-

Gen er a l P r oced u r e To Obta in Com p ou n d s of Gen er a l

F or m u la I Dir ectly fr om Am in es 5 (Sch em e 3). N-[1-

(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-tetr a h y-

dr o-1H-1,5-ben zodiazepin -3-yl]-N′- ph en ylu r ea (23). Phen-

yl isocyanate (0.033 mL, 0.25 mmol) was added to a solution

of the intermediate 6o (0.1 g, 0.24 mmol) in dichloromethane

(5 mL) under a nitrogen atmosphere. The mixture was stirred

at 23 °C for 1 h, then concentrated in vacuo. The residue was

triturated with acetonitrile to give compound 23 (0.112 g, 0.21

mmol, 87%) as a white solid: mp 194-6 °C; TLC R_f) 0.77

(CH/EA 1:1); C₃₃H₃₄N₄O₃1H₂O; MS (FAB) m/e 535 (MH⁺); IR

u r ea (19): mp 271-2 °C; TLC R_f) 0.32 (CH/EA, 7:3); C₂₈H₂₉

-

FN₄O₃; MS (FAB) m/e 489 (MH⁺); IR ν_max3310 (NH), 1718,

1668 and 1639 (CdO), 1601 and 1556 (CdC) cm^-1; ¹H -NMR

δ [[7.45 (dd); 7.4-7.10 (m), 11H]; 7.06-6.97 (m, 3H); 6.41 (d,

1H); 5.36 (d, 1H); 4.48-4.37 (m, 1H); 3.76-3.66 (m 1H); 1.50

(m, 2H); 0.92 (s, 9H).

N-[1-(Cyclop en tylp r op -2-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-ph en ylu r ea (20):

TLC R_f) 0.51 (CH/EA, 1:1); C₃₀H₃₂N₄O₃; MS (FAB) m/e 497

(MH⁺); IR ν_max3400-3300 (NH), 1701 and 1670 (CdO), 1651

_max3294 (NH), 1717, 1705 and 1680 (CdO); 1643 (CdC) cm^-1

;

and 1597 (CdC) cm^-^{1 1}H NMR δ 7.50-7.00 (m, 13H); 6.90

;

ν

¹H NMR δ 7.5-6.96 (m, 14H); 7.08 (bs, 1H); 6.50 (d, 1H); 5.31

(d, 1H); 4.49 (d, 1H); 3.37 (d, 1H); 1.84 (m, 3H); 1.6-1.3 (m,

12H).

(2m, 1H); 6.4 (m, 1H); 5.29 (d, 1H); 4.60-4.50 and 4.50-4.40

(2m, 1H); 2.20-1.10 (m, 11H); 1.42 (d, 3H).

N-[1-(2-Cyclop en tyleth yl)-2,4-d ioxo-5-(2-flu or op h en yl)-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-p h en -

Analytical data for representative compounds are as follows.

N-[1-Bu t yl-2,4-d ioxo-5-p h en yl-2,3,4,5-t et r a h yd r o-1H -

1,5-ben zod ia zep in -3-yl]-N′-p h en ylu r ea (11): TLC R_f) 0.65

(MC/MeOH, 95:5); C₂₆H₂₆N₄O₃; MS (FAB) m/e 443 (MH⁺); IR

ylu r ea (21): mp 255-7 °C; TLC R_f) 0.58 (CH/EA, 1:1); C₂₉H₂₉

-

FN₄O₃; MS (FAB) m/e 501 (MH⁺); IR ν_max3400 (NH), 1718 and

1650 (CdO), 1600 (CdC) cm^-1; ¹H NMR δ 7.46 (dd, 1H); 7.4-

7.1 (m, 11H); 7.0 (t, 1H); 6.98 (d, 1H); 6.52 (d, 1H); 5.38 (d,

1H); 4.44 (m, 1H); 3.66 (m, 1H); 1.84-1.40 (m, 9H); 1.20-1.00

(m, 2H).

ν

_max3431 (NH); 1707-1670 (CdO), 1599 (CdC) cm^-1; ¹H NMR

δ 7.40-7.00 (m, 14H); 6.66 (bs, 1H); 6.22 (d, 1H); 5.3 (d, 1H);

4.55 (m, 1H); 3.70 (m, 1H); 1.53 (m, 2H); 1.3 (m, 2H); 0.88 (t,

3H).

N-[2,4-Dioxo-5-ph en yl-1-(2-ph en yleth yl)-2,3,4,5-tetr ah y-

d r o-1H-1,5-ben zod ia zep in -3-yl]-N′-p h en ylu r ea (22): TLC

R_f) 0.45 (CH/EA, 1:1); C₃₀H₂₆N₄O₃; MS (FAB) m/e 491 (MH⁺);

IR ν_max3310 (NH), 1707 and 1678 (CdO), 1643, 1603 and 1556

N-[2,4-Dioxo-5-p h en yl-1-(3-m eth ylbu t-1-yl)-2,3,4,5-tet-

r a h y d r o -1H -1,5-b e n zo d ia ze p in -3-y l]-N ′-p h e n y lu r e a

(12): TLC R_f) 0.87 (MC/MeOH, 95:5); C₂₇H₂₈N₄O₃; MS (FAB)

m/e 457 (MH⁺); IR ν_max3440-3350 (NH), 1701 and 1680 (Cd

O), 1616 and 1599 (CdC) cm^-1; ¹H NMR δ 7.44-7.16 (m, 14H);

7.00 (m, 1H); 6.4 (bs, 1H); 5.33 (d, 1H); 4.53 (m, 1H); 3.68 (m

1H); 1.6-1.4 (m, 3H); 0.89 (d, 3H); 0.86 (d, 3H).

(+)-N-[2,4-Dioxo-5-p h en yl-1-(3-m eth ylbu t-1-yl)-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-ph en ylu r ea (13):

mp >254 °C; TLC R_f) 0.87 (MC/MeOH, 95:5); [R]_D) +116

(CH₂Cl₂c ) 8.48 mg/mL); C₂₇H₂₈N₄O₃; MS (FAB) m/e 457

(MH⁺); for IR and ¹H NMR data see compound 12.

(-)-N-[2,4-Dioxo-5-p h en yl-1-(3-m eth ylbu t-1-yl)-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-ph en ylu r ea (14):

TLC R_f) 0.87 (MC/MeOH, 95:5); [R]_D) -104.88 (CH₂Cl₂c )

5.035 mg/mL); TLC R_f) 0.87 (MC/MeOH, 95:95); C₂₇H₂₈N₄O₃;

MS (FAB) m/e 457 (MH⁺); for IR and ¹H NMR data see

compound 12.

(CdC) cm^-^{1 1}H NMR δ 7.43 (dd, 1H), 7.36-7.12 (m, 14H);

;

7.07-6.94 (m, 4H); 6.48 (d, 1H); 5.36 (d, 1H); 4.78-4.66 (m,

1H); 3.98-3.86 (m, 1H); 2.92 (m, 2H).

N -(+)-[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-p h en yl-

u r ea (24): mp 265-6 °C; TLC R_f) 0.77 (CH/EA 1:1); [R]_D

)

+42.5 (CHCl₃c ) 10.05 mg/mL); C₃₃H₃₄N₄O₃; MS (FAB) m/e

535 (MH⁺); for IR and ¹H NMR data see compound 23.

N -(-)-[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-p h en -

ylu r ea (25): 75%; mp 265-6 °C; TLC R_f) 0.77 (CH/EA, 1:1);

[R]_D) -39.4 (CH₂Cl₂c ) 6.08 mg/mL); C₃₃H₃₄N₄O₃; MS (FAB)

m/e 535 (MH⁺); for IR and ¹H NMR data see compound 23.

N-[1-(2-Ad a m a n t-1-yleth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-p h en ylu r ea

(26): TLC R_f) 0.55 (CH/EA, 1:1); MS (FAB) m/e 549 (MH⁺);

N-[2,4-Dioxo-5-(2-flu or op h en yl)-1-(3-m et h ylb u t -1-yl)-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-p h en -

ylu r ea (15): mp 254-5 °C; TLC R_f) 0.65 (CH/EA, 1:1);

C

₃₄H₃₇N₄O₃; IR ν_max3312 (NH), 1701, 1668 and 1645 (CdO),

1

1601 and 1580 (CdC) cm^-1; H NMR δ 7.46-7.14 (m, 12H);

7.02-6.96 (m, 3H); 6.56 (d, 1H); 5.35 (d, 1H); 4.45 (m, 1H);

3.70 (m, 1H); 1.93-1.28 (m, 17H).

C

₂₇H₂₇FN₄O₃; MS (FAB) m/e 475 (MH⁺); IR ν_max3450 (NH),

1707 and 1670 (CdO), 1601 and 1533 (CdC) cm^-1; ¹H NMR δ

3608 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20

Ursini et al.

N-[1-(Ad a m a n t-2-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-tetr a h y-

d r o-1H-1,5-ben zod ia zep in -3-yl]-N′-p h en ylu r ea (27): mp

191-4 °C; TLC R_f) 0.76 (CH/EA, 1:1); C₃₂H₃₂N₄O₃; MS (FAB)

m/e 521 (MH⁺); IR ν_max3306 (NH), 1713 and 1705 (CdO), 1641

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(3-br om op h en -

yl)u r ea (50): mp 254-6 °C; TLC R_f) 0.53 (CH/EA, 2:1);

C₃₃H₃₃BrN₄O₃; MS (FAB) m/e 416 (MH⁺); IR ν_max3290 (NH),

1

1717 and 1672 (CdO) cm^-1; H NMR δ 7.56-7.15 (m, 10H);

and 1601 (CdC) cm^-1

;

¹H NMR δ 7.44-7.20 (m, 13H); 7.08

7.03-6.88 (m, 2H); 6.99 (dd, 1H); 6.93 (dd, 1H); 6.73 (d, 1H);

5.29 (d, 1H); 4.49-3.38 (m, 2H); 1.83 (m 3H); 1.64-1.30 (m,

12H).

(m, 1H); 7.02-6.9 (m, 1H); 6.39 (d, 1H); 5.34 (d, 1H); 4.50 (m,

1H); 2.95 (m, 1H); 2.32 (m, 1H); 1.9-1.1 (m, 11H).

N-[1-[Bicyclo[2.2.1]h ept-2-yl]-2,4-dioxo-5-ph en yl-2,3,4,5-

t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-p h en ylu r ea

(28): mp 267-8 °C; TLC R_f) 0.62 (CH/EA, 1:1); C₂₉H₂₈N₄O₄;

MS (FAB) m/e 481 (MH⁺); IR ν_max3300 (NH), 1705, 1678 and

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(3-eth oxyca r -

bon ylp h en yl)u r ea (51): mp 246-8 °C; TLC R_f) 0.37 (CH/

EA, 2:1); C₃₆H₃₈N₄O₅; MS (FAB) m/e 607 (MH⁺); IR ν_max1709,

1690 and 1670 (CdO) cm^-1; ¹H NMR δ 7.93 (t, 1H); 7.64-7.50

(m, 2H); 7.44-7.39 (m, 5H); 7.38 (bs, 1H); 7.35-7.27 (m, 2H);

7.24-7.14 (m), 6.89 (dd, 1H); 6.58 (d, 1H); 5.31 (d, 1H); 4.50

(d, 1H); 4.34 (m, 2H); 3.38 (d, 1H); 1.85 (m, 3H); 1.61-1.51

(2m, 6H); 1.45-1.37 (2m, 6H); 1.35 (t, 3H).

1

1645 (CdO), 1599 and 1556 (CdC) cm^-1; H NMR δ [[7.46-

7.12 (m); 7.03-6.94 (m)] 15H]; 6.42 and 6.44 (2d, 1H); 5.33

and 5.32 (2d, 1H); 4.5-4.4 (m, 1H); 3.46 and 2.64 (2s, 1H);

2.18 (m, 1H); 2.40 and 1.96 (2m, 1H); [[1.6 (m); 1.54-1.38 (m);

1.38-1.1 (m); 0.99 (m); 0.86 (m), 7H].

N-[1-(Ad a m a n t-2-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-ph en ylu r ea (29):

mp 192-3 °C; TLC R_f) 0.73 (CH/EA, 1:1); C₂₉H₂₈N₄O₄; MS

(FAB) m/e 535 (MH⁺); IR ν_max3306 (NH), 1717 and 1701 (Cd

O), 1643 and 1620 (CdC) cm^-1; ¹H NMR δ 7.5-7.14 (m, 12H);

7.00 (dd+t, 2H); 7.05 (bs, 1H); 6.47 (d, 1H); 5.33 (d, 1H); 5.05

(dd, 1H); 3.59 (dd, 1H); 2.02 (m, 1H); 1.84-1.36 (m, 14H).

N-[2,4-Dioxo-5-(2-flu or op h en yl)-1-(3-m et h ylb u t -1-yl)-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(N,N-

d im eth yla m in o)p h en yl]u r ea (30):⁴⁴mp 252-3 °C; TLC R_f

) 0.50 (CH/EA, 1:1); C₂₉H₃₂FN₅O₃; MS (FAB) m/e 518 (MH⁺);

IR (Nujol) ν_max3312 (NH), 1707,1676 and 1639 (CdO), 1593

and 1558 (CdC) cm^-1; ¹H NMR δ 7.45 (dd, 1H); 7.41-7.28 (m,

2H); 7.25-7.1 (m, 5H); 7.134 (t 1H); 6.98 (dd, 1H); 6.82 (t, 1H);

6.63 (s, 1H); 6.60 (dd, 1H); 6.46 (dd, 1H); 6.36 (d, 1H); 5.36 (d,

1H); 4.51-4.41 (m, 1H); 3.74-3.64 (m, 1H); 2.92 (s, 6H); 1.6-

1.42 (m, 3H); 0.91 (d, 3H); 0.90 (d, 3H).

(+)-N-[2,4-Dioxo-5-(2-flu or op h en yl)-1-(3-m eth ylbu t-1-

yl)-2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-[3-

(N,N-d im eth yla m in o)p h en yl]u r ea (31):⁴⁴mp 252-3 °C;

TLC R_f) 0.50 (CH/EA, 1:1); [R]_D) +109.6 (CH₂Cl₂c ) 0.1

mg/mL); C₂₉H₃₂FN₅O₃; MS (FAB) m/e 518 (MH⁺); for IR and

¹H NMR data see compound 30.

(-)-N-[2,4-Dioxo-5-(2-flu or op h en yl)-1-(3-m eth ylbu t-1-

yl)-2,3,4,5,2-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-

(N,N-d im eth yla m in o)p h en yl]u r ea (32):⁴⁴mp 252-3 °C;

TLC R_f) 0.50 (CH/EA, 1:1); [R]_D) -112.3 (CH₂Cl₂c ) 0.7

mg/mL); C₂₉H₃₂FN₅O₃; MS (FAB) m/e 518 (MH⁺); for IR and

¹H NMR data see compound 30.

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-(3-car boxyph en -

yl)u r ea (52). An aqueous 0.1 M solution of lithium hydroxide

(6.6 mL) was added to a solution of intermediate 51 (0.2 g,

0.33 mmol) in THF (15 mL) previously cooled to 0 °C. The

solution was stirred at 23 °C for 16 h, then heated at 60 °C

for 1 h and at 80 °C for 13 h. The solution was cooled to 23 °C,

neutralized with acetic acid, concentrated in vacuo and the

residue purified by flash chromatography (eluting in gradient

from CH-EA 3:1 to MC and finally to MC-MeOH 10:1) to

give compound 52 as a white solid (0.183 g), still containing

traces of inorganic salts. This material was further purified

by dissolution in MC and washing with 10% HCl; the organic

layer was dried, concentrated in vacuo and the residue

triturated with diethyl ether to give the pure title compound

(0.150 g, 78%): mp 260-70 °C dec; TLC R_f) 0.64 (EA);

C

₃₄H₃₄N₄O₅; MS (FAB) m/e 579 (MH⁺); IR ν_max3383, 3319 and

1

3184 (NH and OH), 1760 and 1650 (CdO) cm^-1; H NMR δ

8.34 (s, 1H); 8.31 (d, 1H); 7.84 (s, 1H); 7.69-7.63 (m, 2H); 7.52

(d, 1H); 7.47-7.16 (m, 8H); 7.03 (m, IH); 5.24 (d, 1H); 4.55 (d,

1H); 3.43 (d, 1H); 1.92 (m, 3H); 1.7-1.3 (m, 12H).

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(N,N-d im e-

th yla m in o)p h en yl]u r ea (53): mp 263-5 °C; TLC R_f) 0.52

(CH/EA, 1:1); C₃₅H₃₉N₅O₃; MS (FAB) m/e 578 (MH⁺); IR ν_max

1

3300 (NH), 1717 and 1674 (CdO) cm^-1; H NMR δ 7.48 (dd,

1H); 7.45-7.24 (m, 6H); 7.19-7.10 (m, 2H); 6.98 (dd, 1H); 6.93

(dd, 1H); 6.61 (s, 1H); 6.58-6.45 (m, 2H); 6.38 (d, 1H); 5.29 (d,

1H); 4.49-3.37 (m, 2H); 2.92 (s, 6H); 1.87 (m, 3H); 1.63-1.53

(m, 6H); 1.44-1.34 (m, 6H).

(+)-N -[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-(3-h y-

(+)-N -[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-(3-h y-

d r oxym eth ylp h en yl)u r ea (54): mp 204-6 °C; TLC R_f) 0.50

(CH/EA 1:2); [R]_D) +70.8 (c ) 7.40 mg/mL CHCl₃); C₃₄H₃₆N₄O₄;

MS (FAB) m/e 565 (MH⁺); IR ν_max3287 (NH), 1699 and 1670

d r oxyp h en yl)u r ea (47): TLC R_f) 0.20 (CH/EA, 2:1); [R]_D

)

+76.9 (DMSO c ) 8.90 mg/mL); C₃₃H₃₄N₄O₄; MS (FAB) m/e

551 (MH⁺); IR ν_max3450-3310 (NH), 1693 and 1639 (CdO)

cm^-1; ¹H NMR δ 9.22 (bs, 1H); 9.03 (bs, 1H); 7.82 (d, 1H); 7.48

(t, 2H); 7.38 (m, 2H); 7.29 (d, 2H); 7.27 (m, 1H); 6.97 (t, 1H);

6.94 (dd, 1H); 6.88 (t, 1H); 6.87 (d, 1H); 6.70 (d, 1H); 6.29 (dd,

1H); 4.97 (d, 1H); 4.25 (d, 1H); 3.60 (d, 1H); 1.84 (bs, 3H); 1.66-

1.25(m, 12H).

1

(CdO), 1634 and 1560 (CdC) cm^-1; H NMR δ 7.49 (dd, 1H);

7.44 (m, 4H); 7.24 (m, 2H); 7.22 (m, 2H); 7.12 (m, 1H); 7.40-

6.96 (m, 3H); 6.46 (d, 1H); 5.27 (d, 1H); 4.57 (t, 2H); 4.50 (d,

1H); 3.38 (d, 1H); 2.8-2.2 (m, 1H); 1.89 (bs, 3H); 1.70-1.40

(m, 12H).

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-(3-m eth ylph en -

yl)u r ea (48): mp 213-5 °C; TLC R_f) 0.33 (CH/EA, 2:1);

C₃₄H₃₆N₄O₃; MS (FAB) m/e 548 (MH⁺); IR ν_max3300 (NH), 1715

and 1672 (CdO), 1645 and 1616 (CdC) cm^-1; ¹H NMR δ 7.49

(dd, 1H); 7.45-7.35 (m); 7.35-7.25 (m, 6H); 7.21-7.15 (m, 2H);

7.14 (t, 1H); 7.03 (m, 1H); 6.99 (dd, 1H); 6.85 (m, 1H); 6.75 (s,

1H); 6.32 (d, 1H); 5.29 (d, 1H); 4.50 (d, 1H); 3.38 (d, 1H); 2.29

(s, 3H); 1.86 (s, 3H); 1.68-1.3 (m, 12H).

3-(tert-Butyldiphenylsilyloxymethyl)phenyl isocyanate was

prepared from commercially available 3-aminobenzyl alcohol

by reaction with tert-butyldiphenyl chlorosilane; the obtained

intermediate was reacted with phosgene to give the final

3-(tert-butyldiphenylsilyloxymethyl)phenyl isocyanate.

(+)-N -[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(m or -

p h olin -4-ylm eth yl)p h en yl]u r ea (55): mp 175-7 °C; TLC

R_f) 0.38 (EA); [R]_D) +39.8 (c ) 6.45 mg/mL CHCl₃);

C₃₈H₄₃N₅O₄; MS (FAB) m/e 634 (MH⁺); IR ν_max3292 (NH); 1701

and 1676 (CdO) cm^-1; ¹H NMR δ 7.49 (dd, 1H); 7.46-7.14 (m,

10H); 7.03 (bs, 1H); 6.99 (dd, 1H); 6.74 (d, 1H); 6.25 (m, 1H);

5.28 (d, 1H); 4.49 (d, 1H); 3.69 (m, 4H); 3.43 (s, 2H); 3.38 (d,

1H); 2.42 (m, 4H); 1.87 (m, 3H); 1.70-1.30 (m, 12H).

3-(Morpholinomethyl)phenyl isocyanate was prepared ac-

cording to known procedure starting from commercially avail-

able 3-chloromethylnitrobenzene.⁴⁵

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(3-n itr op h en -

yl)u r ea (49): mp 244-6 °C; TLC R_f) 0.32 (CH/EA, 2:1);

C₃₃H₃₃N₅O₅; MS (FAB) m/e 580 (MH⁺); IR ν_max3296 (NH), 1713

1

and 1645 (CdO), cm^-1; H NMR δ 8.25 (bs, 1H); 8.15 (t, 1H);

7.64 (m, 1H); 7.52 (dd, 1H); 7.45 (m, 4H); 7.36-7.29 (m, 2H);

7.24-7.17 (m, 2H); 7.13 (t, 1H); 7.06 (d, 1H); 7.02 (dd, 1H);

5.27 (d, 1H); 4.51 (d, 1H); 3.40 (d, 1H); 1.86 (bs, 3H); 1.66-

1.34 (m, 12H).

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

(+)-N -[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3609

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(4-br o-

m op h en yl)u r ea (56): mp 297 °C dec; TLC R_f) 0.53 (CH/EA

2/1); [R]_D) +47.4 (CHCl₃c ) 10.25 mg/mL); C₃₃H₃₃BrN₄O₃;

MS (FAB) m/e 615 (MH⁺); IR ν_max3200 (NH), 1705 and 1684

n-hexane/THF 45/55); C₄₀H₄₅N₅O₆; MS (FAB) m/e 692 (MH⁺);

IR ν_max3400 (NH), 1718 (CdO) cm^-1; ¹H NMR δ 7.91 (bs, 1H);

7.58 (d, 1H); 7.54-7.06 (m, 11H); 7.00 (dd, 1H); 6.65 (m, 1H);

5.27 (m, 1H); 4.54-4.38 (m, 3H); 3.73 (t, 4H); 3.38 (d, 1H);

2.79 (t, 2H); 2.61 (m, 4H); 1.87 (m); 2.2-1.3 (m, 15H).

1

(CdO) cm^-1; H NMR δ 7.48 (d, 1H); 7.45-7.15 (m, 9H); 7.07

(d, 2H); 7.00 (dd, 1H); 6.70 (d, 1H); 5.30 (bs, 1H); 5.28 (d, 1H);

(+)-N -[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(3-a m i-

n op h en yl)u r ea (62). 5% Pd/C (0.30 g) was added to a solution

of (+)-(1-adamant-1-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tet-

rahydro-1H-1,5-benzodiazepin-3-yl]-N′-(3-nitrophenyl)urea (1.0

g 1.72 mmol) in dry THF (50 mL) and EtOH (50 mL) under a

nitrogen atmosphere. The mixture was hydrogenated at 23 °C

and 1 atm for for 2 h, then filtered and concentrated in vacuo.

The residue was purified by flash chromatography (eluting

with CH/EA 9/1) to give the title compound as a white solid

(0.67 g, 1.22 mmol): mp 188-90 °C; TLC R_f) 0.44 (EA/MeOH,

3/1); [R]_D) +38.3 (CHCl₃c ) 9.65 mg/mL); C₃₃H₃₅N₅O₃; MS

(FAB) m/e 550 (MH⁺); IR ν_max3356 (NH), 1707, 1674 and 1639

(CdO) cm^-1; ¹H NMR δ 7.5-7.24 (m, 7H); 7.15 (t, 1H); 7.00 (t,

2H); 6.85 (bs, 1H); 6.82 (t, 1H); 6.56 (dd, 1H); 6.42 (d, 1H);

6.35 (dd, 1H), 5.29 (d, 1H); 4.49 (d, 1H); 3.37 (d, 1H); 3.62 (bs,

2H); 1.86 (m, 3H), 1.7-1.3 (m., 12H).

4.49 (d, 1H); 3.37 (d, 1H); 1.84 (m, 3H); 1.66-1.3 (m, 12H).

(+)-N -[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(3-br o-

m op h en yl)u r ea (57): TLC R_f) 0.53 (CH/EA, 2:1); [R]_D

)

+61.7 (CHCl₃c ) 9.60 mg/mL); C₃₃H₃₃BrN₄O₃; MS(FAB) m/e

613 (MH⁺); IR ν_max3300 (NH), 1709 and 1676 (CdO), 1595

(CdC) cm^-1; ¹H NMR δ 7.52 (bs, 1H); 7.56-7.38 (m, 4H); 7.36-

7.26 (m, 4H); 7.17 (dt, 1H); 7.08-6.95 (m, 4H); 6.69 (bd, 1H);

5.27 (d, 1H); 4.50 (d, 1H); 3.39 (d, 1H); 1.86-1.3 (m, 15H).

(+)-4-[4-(Adam an t-1-ylm eth yl-2,4-dioxo-5-ph en yl-2,3,4,5-

tetr a h yd r o-1H-ben zo[b][1,4]d ia zep in -3-yl)u r eid o]p h en -

oxy]bu tyr ic a cid , eth yl ester (58): mp 255.5-6.5 °C dec;

TLC R_f) 0.55 (CH/EA, 1:1); [R]_D) +25.7 (CHCl₃c ) 8.3 mg/

mL); C₃₉H₄₄N₄O₆; MS (FAB) m/e 664 (MH⁺); IR ν_max3400-

3333 (NH), 1736, 1699 and 1651 (CdO) cm^-1; ¹H NMR δ 7.48

(dd, 1H); 7.45-7.2 (m, 8H); 7.16 (tt, 1H); 6.99 (dd, 1H); 6.83

(d, 2H); 6.39 (bs, 1H); 6.1 (d, 1H); 5.25 (d, 1 H); 4.48 (d, 1H);

4.14 (q, 2H); 3.97 (t, 2H); 3.38 (d, 1H); 2.51 (t, 2H); 2.09 (m,

2H); 1.87 (m, 3H); 1.68-1.34 (m, 12H); 1.26 (t, 3H).

(+)-4-[4-(Adam an t-1-ylm eth yl-2,4-dioxo-5-ph en yl-2,3,4,5-

tetr a h yd r o-1H-ben zo[b][1,4]d ia zep in -3-yl)u r eid o]p h en -

oxy]bu tyr ic Acid (59). Aluminum triiodide (1.656 g) was

added to the solution of ethyl ester 58 (0.513 g,0.77 mmol) in

dry acetonitrile (50 mL). The reaction mixture was stirred at

reflux for 2 h, then concentrated in vacuo and the residue

dissolved in MC (100 mL) and washed with 10% hydrochloric

acid solution (80 mL), 5% sodium hydrogen carbonate solution,

10% hydrochloric acid solution (80 mL), water (2 × 80 mL),

brine (2 × 80 mL) 5% sodium sodium dithionite (2 × 80 mL)

and brine (2 × 80 mL). The organic extracts were dried and

concentrated in vacuo and the residue purified by flash

chromatography (eluting with CH-EA 3:2, then with MC-

MeOH 9:10) to give the title compound as a white solid (0.182

g, 0.28 mmol): mp 195-205 °C dec; TLC R_f) 0.39 (EA); [R]_D

) 35.6 (CHCl₃c ) 8.55 mg/mL); C₃₇H₄₀N₄O₆; MS (FAB) m/e

637 (MH⁺); IR ν_max3281 (NH and OH), 1695 and 1668 (CdO)

cm^-1; ¹H NMR δ 12.1 (m, 1H); 8.96 (s, 1H); 7.82 (m, 1H); 7.49

(t, 2H); 7.37 (m, 2H); 7.28 (m, 3H); 7.22 (d, 2H); 6.94 (dd, 1H);

6.79 (d, 3H); 4.98 (d, 1H); 4.28 (d, 1H); 3.88 (t, 2H); 3.60 (d,

1H); 2.32 (t, 2H); 1.87 (m, 2H); 1.84 1.22 (m, 15H).

Continuing elution with MC-MeOH 4:1 a pure sample of

(+)-N-[1-(a d a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-(4-h ydr oxyph en -

yl)u r ea (60) was isolated and characterized: [R]_D) +35.6

(CHCl₃c ) 8.6 mg/mL); C₃₃H₃₄N₄O₄; MS (FAB) m/e 551(MH⁺);

IR ν_max3306 (OH), 3198 (NH), 1703 and 1670 (CdO) cm^-1; ¹H

NMR δ 7.47 (dd, 1H); 7.42-7.23 (m, 6H); 7.15 (td, 1H); 7.05

(d, 2H); 6.99 (dd, 1H); 6.94 (bs, 1H); 6.62 (s, 2H); 6.42 (bd, 1H);

6.25 (bs, 1H); 5.27 (d, 1H); 4.47 (d, 1H); 3.38 (d, 1H); 1.87 (s,

3H); 1.70-1.20 (m, 12H).

(+)-N -[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-[3-(2-

m or p h olin -4-yleth oxy)ca r bon yl]p h en ylu r ea (61). To a

solution of (+)-1-adamant-1-ylmethyl-2,4-dioxo-3-(3-hydroxy-

carbonylphenyl)aminoarbonylamino-5-phenyl-2,3,4,5-tetrahy-

dro-1H-1,5-benzodiazepine (0.10 g) in dry THF (5 mL) N,N′-

carbonyldiimidazole (0.056 g) was added and the reaction

mixture was stirred at 20 °C for 20 h. The solvent was

evaporated and the residue taken up in toluene; N-(2-hydroxy-

ethyl)morpholine (0.069 g) was then added and stirring was

continued for 16h at 20 °C and at reflux for 4 h. The reaction

mixture was dried, concentrated in vacuo and the residue was

taken up with MC (50 mL) and washed with saturated

ammonium chloride solution (30 mL) and brine (2 × 40 mL)

to give a crude compound (0.15 g) which was purified by

preparative TLC using CH/MeOH 95/0.5 as eluant to give the

title compound as a white solid (0.030 g, 0.43 mmol): TLC R_f

) 0.2 (CH/EA, 2:1); HPLC t_R) 5.2 min (Pirkle DNBPG S5,

(+)-N -[1-(Ad a m a n t -1-ylm e t h yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-(3-(^D-

1,2-d ih yd r oxyp r op yla m in o)p h en yl)u r ea (63). To the so-

lution of glyceraldehyde (0.02 g) and compound 62 (0.13 5 g,

0.24 mmol) in ethanol (3 mL) and dichloromethane (2 mL) at

23 °C, acetic acid (0.013 mL), sodium acetate trihydrate (0.040

g) and water (1 mL) were added. Sodium borohydride was then

added portionwise during 30 min. and stirring continued for

3 h at 23 °C. After evaporation under vacuum the residue was

treated with the same quantities of reagents under the same

conditions. The reaction mixture was concentrated in vacuo,

the residue taken up in dichloromethane (50 mL) and washed

with water (20 mL) and brine (20 mL). The organic solution

was dried, concentrated in vacuo and the residue was purified

by flash chromatography on silica using CH/EA 1/1 and then

methanol to give the title compound as a white solid (0.053 g,

0.08 mmol): TLC R_f) 0.64 (EA/MeOH, 7/3); C₃₆H₄₁N₅O₅; MS

(FAB) m/e 624 (MH⁺); IR ν_max3377 (NH, OH), 1705 and 1659

(CdO), 1610 (CdC) cm^-^{1 1}H NMR δ 7.53 (bs, 1H); 7.46 (d,

;

1H); 7.42-7.2 (m, 7H); 7.14 (m, 1H); 6.97 (m, 2H); 6.74 (d, 1H);

6.64 (s 1H); 6.62 (d, 1H); 6.26 (d, 1H); 5.26 (d, 1H); 4.44 (d,

1H); 3.80 (m,1H); 3.64-3.44 (m, 2H); 3.35 (d, 1H); 3.20-2.98

(m, 2H); 1.86 (m, 3H); 1.7-1.3 (m, 12H).

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-(3-(1,2-d ih y-

d r oxyp r op yla m in o)p h en yl)u r ea (64): mp 267-8 °C; TLC

R_f) 0.20 (CH/EA, 2:1); C₃₆H₄₁N₅O₅; IR ν _max3302 (NH), 1713,

1674 and 1641 (CdO), 1612 and 1558 (CdC) cm^-1; ¹H NMR δ

7.52 (bt, 1H); 7.47 (d, 1H); 7.42-7.2 (m, 7H); 7.14 (t, 1H); 6.98

(d, 1H); 6.97 (m, 1H); 6.76 (m, 1H); 6.62 (m, 2H); 6.26 (d, 1H);

6.16 (d, 1H); 5.26 (d, 1H); 4.44 (d, 1H); 4.1 (bs,2H); 3.81 (m,

1H); 3.59 (bd, 1H); 3.49 (dd, 1H); 3.35 (d, 1H); 3.17 (d, 1H)),

1.86 (m, 3H); 1.7-1.3 (m, 12H).

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

t e t r a h yd r o-1H -1,5-b e n zod ia ze p in -3-yl]-N ′-(3-a ce t a m i-

d op h en yl)u r ea (65). Acetyl chloride (0.011 g) was added to

the racemic 3-amino derivative (0.07 g, 0.12 mmol) in MC (4

mL) and triethylamine (0.010 g). The mixture was stirred at

23 °C for 1 h, then filtered. The solid obtained was dissolved

in MC (70 mL) and washed with water (30 mL), 20% sodium

hydroxide solution (30 mL), 5% hydrochloric acid (30 mL) and

water (30 mL), dried and concentrated in vacuo, to give the

title compound as a gum (0.050 g, 0.08 mmol): TLC R_f) 0.82

(EA/MeOH, 9/1); C₃₅H₃₇N₅O₄; MS (FAB) m/e 592 (MH⁺); IR

3346 (NH), 1701 and 1684 (CdO), 1607 and 1558

max

(CdC)cm^-^{1 1}H NMR δ 9.83 (bs, 1H), 9.17 (bs, 1H); 7.83 (d,

;

1H); 7.64 (bs, 1H); 7.54 (t, 2H); 7.36 (t, 2H); 7.34 (m, 3H); 7.06

(m, 3H); 6.98-6.90 (m, 2H); 4.99 (d, 1H); 4.30 (d, 1H); 3.60 (d,

1H); 1.99 (s, 3H); 1.84 (bs, 3H); 1.70-1.2 (m, 12H).

N-[1-(Ad a m a n t-1-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(3-for m ila m i-

n op h en yl)u r ea (66). To a solution of racemic 1-adamantan-

3610 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20

Ursini et al.

t ylm et h yl-2-dioxo-5-ph en yl-2,3,4,5-t et r a h ydr o-1H -1,5-

benzodiazepin-3-yl]-N′-(3-aminophenyl)urea (0.175 g, 0.32 mmol)

in formic acid (2 mL), acetic anhydride (0.7 mL) was added,

and the reaction mixture was stirred at 15 °C for 3 h then at

20 °C for 20 h. The reaction mixture was concentrated in vacuo,

taken up with MC (50 mL) and purified by flash chromatog-

raphy, using CH/EA 1/1 as eluant to give a residue which was

crystallized using MC/petroleum to give the title compound

as a white solid (0.097 g, 0.16 mmol): TLC R_f) 0.54 (CH/EA,

1674 and 1641 (CdO); 1607 (CdC) cm^-1

7.10 (m, 10H);7.02-6.90 (m, 3H); 6.82 (s, 1H); 6.30 (d, 1H);

5.30 (d, 1H); 4.46 (m, 1H); 3.70 (m, 1H); 2.44 (s, 3H); 1.48 (t,

2H); 0.93 (s, 9H).

;

¹H NMR δ 7.48-

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-dioxo-5-(2-flu or oph en yl)-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-(3-d i-

m eth yla m in o)p h en ylu r ea (41): mp 255-6 °C; TLC R_f) 0.28

(CH/EA); C₃₀H₃₄FN₅O₃; MS (FAB) m/e 530 (MH⁺); IR ν_max3308

(NH), 1717 (CdO), 1637 (CdC) cm^-^{1 1}H NMR δ 7.48-7.10

;

1:9); MS (FAB) m/e 578 (MH⁺); IR ν

3341 (NH), 1703 and

max

(m, 8H); 6.98 (dd, 1H); 6.81 (t, 1H); 6.66-6.56 (m, 2H); 6.46

(dd, 1H); 6.34 (d, 1H); 5.36 (d, 1H); 4.41 (m, 1H); 3.70 (m, 1H);

2.94 (s, 3H); 2.92 (s, 3H); 1.49 (t, 2H); 0.93 (s, 9H).

1

1645 (CdO), 1609 (CdC) cm^-1; H NMR δ 8.58 (m, 1H); 8.10

(bs, 1H); 7.78 (bs, 1H); 7.76-7.69 (bs, 1H); 7.50-7.42 (m, 1H);

7.43-7.22 (m, 1H); 7.20-7.04 (m, 8H); 7.00-6.96 (dd, 1H);

6.88-6.60 (dd, 2H); 5.27 (d, 1H); 4.47 (m, 1H); 3.35 (m, 1H);

1.82-1.30 (m, 15H). Anal. (C₃₄H₃₅N₅O₄) H, N; C: calcd, 70.7;

found, 67.86.

N-[1-(Ad a m a n t -1-ylet h yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-(3-N,N-d im e-

th yla m in op h en yl)u r ea (67): TLC R_f) 0.37 (CH/EA 1:1);

C₃₆H₄₁N₅O₃; MS (FAB) m/e 592; IR ν_max3373 (NH), 1707, 1682

and 1660 (CdO); 1595 and 1580 (CdC) cm^-1; ¹H NMR δ 7.45-

6.35 (m, 3H); 7.34-7.26 (m, 2H); 7.22-7.15 (m, 3H); 7.12 (t,

1H); 6.98 (dd, 1H); 6.84 (t, 1H); 6.74 (bs, 1H); 6.56 (dd, 1H);

6.44 (dd, 1H); 6.42 (d, 1H); 5.31 (d, 1H); 4.52-4.42 (m, 1H);

3.72-3.62 (m, 1H); 2.91 (s, 6H); 1.94 (bs, 3H); 1.67 (bq, 6H);

1.50 (d, 6H); 1.33 (t, 2H).

N-[1-(Bicyclo[2.2.1]h ep-2-tyl)-2,4-dioxo-5-ph en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(N,N-d im e-

th yla m in o)p h en yl]u r ea (71): mp 258-9 °C; TLC R_f) 0.62

(CH/EA, 1:1); C₃₁H₃₃N₅O₃; MS (FAB) m/ e 524 (MH⁺); IR ν_max

3302 (NH), 1713, 1680 and 1637 (CdO), 1616 and 1558 (Cd

C) cm^-1; ¹H NMR δ 7.46-7.10 (m, 9H); 7.00 (m, 1H); 6.82 (dt,

1H); 6.58 (bd, 1H); 6.49 (bs, 1H); 6.46 (dd, 1H); 6.23 (bd, 1H);

5.29 (d, 1H); 4.45 (m, 1H); 3.47 and 2.65 (2bs, 1H); 3.93 and

3.92 (2s, 6H); 2.44 and 1.96 (2m, 1H); 2.25 and 2.17 (2bt, 1H);

[[1.65-1.4 (m); 1.4-1.1 (m); 1.02 (m); 0.86 (m)] 7H].

N-[1-(Adam an t-1-yleth yl)-2,4-dioxo-5-ph en yl -2,3,4,5-tet-

rahydro-1H-1,5-benzodiazepin-3-yl]-N′-(3-methylthiophenyl)-

u r ea (68): TLC R_f) 0.75 (CH/EA, 1:1); MS (FAB) m/e 595

(MH⁺); C₃₅H₃₈N₄O₃S; IR ν_max3430 (NH), 1701 and 1670 (Cd

1

O); 1595 (CdC) cm^-1; H NMR δ 7.5-6.88 (m, 13H); 6.42 (d,

N -[1-(Bicyclo[2.2.1]-2-h e p t -2-yl)-2,4-d ioxo-5-p h e n yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(3-ch lo-

r op h en yl)u r ea (72): mp 193-4 °C; TLC R_f) 0.62 (CH/EA,

1:1); C₂₉H₂₇ClN₄O₃; MS (FAB) m/e 515 (MH⁺); IR ν_max3294

1H); 5.31 (d, 1H); 4.48 (m, 1H); 3.70 (m, 1H); 2.43 (s, 3H); 2.09-

1.3 (m, 18H).

N-[1-(Ad a m a n t-2-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-tetr a h y-

d r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(N,N-d im eth yla m i-

n o)p h en yl]u r ea (69): TLC R_f) 0.72 (MC/MeOH, 95:0.5);

(NH), 1715, 1673 and 1649 (CdO), 1601 and 1551 (CdC) cm^-1

;

¹H NMR δ [[7.64-7.14 (m,); 7.06-6.98 (m); 6.98-6.84 (m),

14H]; 6.64 (2d, 1H); 5.29 (2d, 1H); 4.45 (m, 1H); 3.45 and 2.63

(2s, 1H); 2.35 (m, 1H); 2.16 (m, 1H); 1.97 (m, 1H); 1.65-0.87

(m, 7H).

C

₃₄H₃₇N₅O₃; IR ν_max3300 (NH), 1713 and 1676 (CdO), 1637

1

and 1610 (CdC) cm^-1; H NMR δ 7.4-7.1 (m, 9H); 6.99 (m,

1H); 6.80 (t, 1H); 6.62 (m, 1H); 6.56 (dd, 1H); 6.45 (dd, 1H);

6.31 (d, 1H); 5.31 (d, 1H); 4.52 (m, 1H); 2.91 (m, 7H); 2.32 (m,

1H); 2.0-1.1 (m, 12H).

N-[1-(Ad a m a n t-2-ylm eth yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(N,N-d im e-

th yla m in o)p h en yl]u r ea (73): mp 229-30 °C; TLC R_f) 0.55

(CH/EA, 1:1); C₃₅H₃₉N₅O₃; MS (FAB) m/e 578 (MH⁺); IRν_max

Gen er a l P r oced u r e To Obta in Com p ou n d s of Gen er a l

F or m u la I via Isocia n a to 9 (Sch em e 3). N-[1-(3-Cyclo-

p en t ylp r op -2-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-t et r a h yd r o-

1H -1,5-b en zod ia zep in -3-yl]-N′-[3-(t et r a zol-5-yl)p h en yl]-

u r ea (42). Phosgene in toluene (1.93 M solution, 5 mL) was

added to a solution of the intermediate 5h (0.130 g, 0.34 mmol)

in dry dichloromethane (10 mL). The resulting solution was

stirred at 23 °C for 7 h, then concentrated in vacuo at 50 °C

for 3 h to give the 1-(3-cyclopentylprop-2-yl)-2,4-dioxo-3-isocya-

nato-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine as

crude. 5-(3-Aminophenyl)tetrazole (0.40 mg) was added to a

solution of the above intermediate in acetonitrile (8 mL) under

nitrogen atmosphere and stirring was continued for 7 h, then

concentrated in vacuo and purified by flash chromatography

(eluting with MC increasing polarity to MC methanol (9:1) to

give the title compound (0.025 g, 0.04 mmol) as a white solid:

TLC R_f) 0.43 (MC/MeOH, 9:1); C₃₁H₃₂N₈O₃; MS (FAB) m/e

565 (MH⁺); IR ν_max3335 (NH), 1693 and 1647 (CdO, CdN)

3310 (NH), 1715 and 1668 (CdO), 1641 and 1614 (CdC) cm^-1

;

¹H NMR δ 7.5-7.11 (m, 9H); 6.98 (m, 1H); 6.83 (t, 1H); 6.58

(m, 1H); 6.46 (m, 1H); 6.50 (m, 1H); 6.31 (d, 1H); 5.29 (d, 1H);

5.05 (m, 1H); 3.58 (m, 1H); 2.92 (s, 6H); 2.04 (m, 1H); 1.9-1.4

(m, 14H).

Gen er a l P r oced u r e To Obta in Com p ou n d s of Gen er a l

F or m u la I via Ca r ba m a te 10 (Sch em e 3). N-[2,4-Dioxo-

5-(2-flu or oph en yl)-1-(3-m eth ylbu t-1-yl)-2,3,4,5-tetr ah ydr o-

1H -1,5-b en zod ia zep in -3-yl]-N′-(3-(N,N-d im et h yla m in o)-

p h en yl)u r ea (30). Triethylamine (0.32 mL, 2.31 mmol) and

3-N,N-dimethylaminoaniline dihydrochloride (0.24 g, 1.15

mmol) were added to a suspension of the intermediate 10c

(0.22 g, 0.46 mmol) in dry dimethylformamide (5 mL) under a

nitrogen atmosphere. The resulting mixture was heated at 160

°C for 2 h, then cooled to room temperature, diluted with water

(20 mL) and extracted with ethyl acetate (2 × 20 mL). The

combined organic extracts were dried, concentrated in vacuo

and the residue was triturated with acetonitrile to give the

title compound as a white solid (0.12 g, 50%): mp 252-3 °C;

TLC R_f) 0.50 (CH/EA 1:1); C₂₉H₃₂FN₅O₃. Analytical data in

agreement with those obtained following method iii.

Analytical data for representative compounds are as follows.

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-(3-N,N-d im e-

th yla m in op h en yl)u r ea (34): TLC R_f) 0.31 (CH/EA, 1:1);

mp 221-3 °C; C₃₀H₃₅N₅O₃; MS (FAB) m/e 514; IR ν_max3500

(NH), 1794, 1707 and 1666 (CdO); 1607 (CdC) cm^-1; ¹H NMR

δ 7.46-7.10 (m, 9H); 6.99 (dd, 1H); 6.82 (t, 1H); 6.60 (m, 1H);

6.46 (m, 1H); 6.53 (bs, 1H); 6.31 (d, 1H); 5.31 (d, 1H); 4.47 (m,

1H); 3.69 (m, 1H); 2.94 (s, 3H); 2.93 (s, 3H); 1.47 (m, 2H); 0.94

(s, 9H).

1

cm^-1; H NMR δ 8.82-8.66 (m, 1H); 7.48 (m, 3H); 7.42-6.80

(m, 13H); 5.29 (m, 1H); 4.53 (m, 1H); 2.20-1.20 (m, 9H); 1.16-

0.80 (m, 2H); 1.36 (d, 3H).

N-[2,4-Dioxo-5-(2-flu or op h en yl)-1-(3-m et h ylb u t -1-yl)-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(3-m eth -

ylth iop h en yl)u r ea (33): mp 246-7 °C; TLC R_f) 0.65 (CH/

EA,1:1); C₂₇H₂₇FN₄O₃; MS (FAB) m/e 475 (MH⁺); IR ν_max1711,

1691, 1680 and 1670 (CdO), 1595 (CdC) cm^-1; ¹H NMR δ 7.46

(dd, 1H); 7.4-7.30 (m, 3H); 7.26-7.10 (m, 4H); 7.04-6.9 (m,

3H); 6.82-6.76 (bm, 1H); 6.26 (d, 1H); 5.33 (d, 1H); 4.46 (m,

1H); 3.70 (m, 1H); 2.44 (s, 3H); 1.6-1.4 (m, 3H); 0.91 (d, 3H);

0.89 (d, 3H).

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr ah ydr o-1H-1,5-ben zodiazepin -3-yl]-N′-(3-cyan oph en yl)-

u r ea (36): mp 268-70 °C; TLC R_f) 0.55 (CH/EA, 1:1);

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

t e t r a h yd r o-1H -1,5-b e n zod ia ze p in -3-yl]-N ′-(3-m e t h yl-

th iop h en yl)u r ea (35): TLC R_f) 0.62 (CH/EA, 1:1); mp 247-9

°C; C₂₉H₃₂N₄O₃S; MS (CI) m/e 517; IR ν_max3300 (NH), 1705,

C₂₉H₂₉N₅O₃; IR ν_max3319 (NH), 2230 (CdN), 1711 and 1647

(CdO) cm^-1; ¹H NMR δ 7.91 (bs, 1H); 7.52-7.12 (m, 12H); 7.01

(dd, 1H); 6.88 (d, 1H); 5.34 (d, 1H); 4.52-4.38 (m, 1H); 3.80-

3.68 (m, 1H); 1.51 (m, 2H); 0.91 (s, 9H).

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3611

1

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(tetr a zol-5-

yl)p h en yl]u r ea (37): TLC R_f) 0.44 (MC/MeOH, 80:20); MS

(CI) m/e 538 (MH⁺); C₂₉H₃₀N₈O₃₊10% mol TEA; IR ν_max3310

(CdO and CdN), 1593 (CdC) cm^-1; H NMR δ 9.26 (s, 1H);

7.99 (m, 1H); 7.67 (m, 1H); 7.56-7.46 (m, 3H); 7.42-7.32 (m,

5H); 7.28 (m, 1H); 7.24 (d, 1H); 6.98 (m, 1H); 6.89 (d, 1H); 5.05

(d,1H); 4.53 (m, 1H); 2.91 (m, 1H); 2.30 (m, 1H); 1.94-1.04

(m, 12H).

(NH), 1691, 1657 and 1641 (CdO) cm^-^{1 1}H NMR δ 9.46 (s,

;

1H); 8.16 (bs, 1H); 7.78 (dd, 1H); 7.58 (dt, 1H); 7.52-7.28 (m,

8H); 7.21 (d, 2H); 7.01 (m, 2H); 5.04 (d, 1H); 4.38 (m, 1H); 3.83

(m, 1H); 1.40 (t, 2H); 0.92 (s, 9H).

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-[2-(2,2-d im e-

th yleth yl)tetr a zol-5-yl]p h en yl]u r ea (38): mp 266-8 °C;

TLC R_f) 0.13 (CH/EA, 7:3); MS (FAB) m/ e (MH⁺) 595;

Gen er a l P r oced u r e for Resolu tion . 1-(Ad a m a n t-1-yl-

m et h yl)-3-a m in o-2,4-d ioxo-5-p h en yl-2,3,4,5-t et r a h yd r o-

1H -1,5-b en zod ia zep in e (1S)-(+)-10-Ca m p h or su lfon a t e

(74m ). A solution of (1R)-(-)-10-camphorsulfonic acid (0.347

g, 1.49 mmol) in ethyl acetate (11 mL) was added to a hot

solution of the racemic amine 5m (0.74 g, 1.78 mmol) in ethyl

acetate (1 mL). The resulting precipitate was filtered, washed

with cold ethyl acetate to give a (+):(-) 60:40 mixture of

diastereomeric salts (0.836 g, 1.29 mmol). Recrystallization

from chloroform-methanol (50:50, 6 mL) gave a (+):(-) 88:12

mixture of diastereomeric salts (0.195 g, 0.30 mmol) as white

crystals. The mother liquors were concentrated in vacuo to give

an enriched mixture of diastereomeric salt (0.93 g, 1.43 mmol).

A solution of this material in dichloromethane (40 mL) was

washed with a 5% ammonia solution (2 × 30 mL) and brine

(2 × 30 mL). The organic layer was dried and concentrated in

vacuo to give an enriched mixture of amines (0.55 g). To a hot

solution of this material in chloroform (25 mL) (1S)-(+)-10-

camphorsulfonic acid (0.277 g, 1.19 mmol) was added; the

mixture was concentrated to a small volume (5 mL), then

methanol was added dropwise (5 mL). The resulting solid was

filtered off and washed with cold methanol to give the title

compound (0.34 g, 0.52 mmol) as white needles: [R]_D) -18.4

(CH₂Cl₂c ) 0.7.565); C₃₆H₄₅N₃O₆S; MS (FAB) m/e 416 (MH⁺);

IR ν_max1734, 1714 and 1684 (CdO) cm^-1; ¹H NMR δ 7.52 (dd,

1H); 7.44- -7.24 (m, 6H); 7.18 (dt, 1H); 7.00 (dd, 1H); 4.93 (s,

1H); 4.49(d, 1H); 3.44 (d, 1H); 3.19 (d, 1H); 2.75 (d, 1H); 2.46-

1.20 (m, 20H); 0.99 (s, 3H); 0.78 (s, 3H).

C

₃₃H₃₈N₈O₃; IR ν_max3320 (NH), 1715, 1668 and 1645 (CdO),

1

1599 (CdC) cm^-1; H NMR δ 8.03 (t, 1H); 7.81 (dt, 1H); 7.46

(dd, 1H); 7.44-7.15 (m, 10H); 7.00 (dd, 1H); 6.48 (d, 1H); 5.36

(d, 1H); 4.54-4.42 (m, 1H); 3.78-3.64 (m, 1H); 1.77 (s, 9H);

1.54-1.44 (m, 2H); 0.91 (s, 9H).

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-

t e t r a h yd r o-1H -1,5-b e n zod ia ze p in -3-yl]-N ′-(3-t r iflu o-

r om eth oxyp h en yl)u r ea (39): mp 234-5 °C; TLC R_f) 0.57

(CH/EA, 60:40); MS (CI) m/e 555 (MH⁺); C₂₉H₂₉F₃N₄O₄; IR

ν_max3317 (NH), 1717 and 1650 (CdO); 1609 and 1558 (CdC)

1

cm^-1; H NMR δ 7.53 (bs, 1H); 7.46 (dd, 1H); 7.45-7.18 (m,

8H); 7.10 (t, 1H); 7.00 (dd, 1H); 6.88 (m, 1H); 6.77 (m, 1H);

6.66 (d, 1H); 5.35 (d, 1H); 4.45 (m, 1H); 3.70 (m, 1H); 1.54-

1.42 (m, 2H); 0.91 (s, 9H).

N-[1-(3,3-Dim eth ylbu t-1-yl)-2,4-dioxo-5-(2-flu or oph en yl)-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-(m eth -

ylth iop h en yl)u r ea (40): mp 249-50 °C; TLC R_f) 0.33 (CH/

EA, 7:3); C₂₉H₃₁FN₄O₃S; MS (FAB) m/e 536 (MH⁺); IR ν_max

3308 (NH), 1707, 1676 and 1643 (CdO), 1607 (CdC) cm^-1; ¹H

NMR δ 7.48-6.90 (m, 12H); 6.83 (bs, 1H); 6.29 (d, 1H); 5.34

(d, 1H); 4.41 (m, 1H); 3.71 (m, 1H); 2.44 (s, 3H); 1.50 (m, 2H);

0.93 (s, 9H).

N-[1-(2-Cyclop en tyleth yl)-2,4-d ioxo-5-(2-flu or op h en yl)-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-[3-(d i-

m eth yla m in o)p h en yl]u r ea (43): mp 238-40 °C; TLC R_f)

0.90 (MC/MeOH, 9:1); C₃₁H₃₄FN₅O₃; MS (FAB) m/e 544 (MH⁺);

IR ν_max3400 (NH), 1707, 1676 and 1637 (CdO and CdN), 1600

(CdC) cm^-1; ¹H NMR δ 7.46 (dd, 1H); 7.42-7.10 (m, 6H); 7.14

(t, 1H); 6.98 (dd, 1H); 6.82 (t, 1H); 6.61 (dd, 1H); 6.56 (bs, 1H);

6.46 (dd, 1H); 6.33 (d, 1H); 5.36 (d, 1H); 4.49-4.39 (m, 1H);

3.74-3.64 (m, 1H); 2.92 (s, 6H); 1.66-1.54 (bm, 3H); 1.66-

1.40 (bm, 6H); 1.16-1.04 (bm, 2H).

N-[1-(2-Cyclop en tyleth yl)-2,4-d ioxo-5-(2-flu or op h en yl)-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-[4-(d i-

m eth yla m in o)p h en yl]u r ea (44): TLC R_f) 0.81 (MC/MeOH,

9:1); C₃₁H₃₄FN₅O₃; MS (FAB) m/e 544 (MH⁺); IR ν_max3304

(NH), 1718-1641 (CdO), 1605-1549 (CdC) cm^-1; ¹H NMR δ

7.46 (dd, 1H); 7.40-7.10 (m, 8H); 6.98 (dd, 1H); 6.68 (d, 2H);

6.28 (bs, 1H); 6.07 (d 1H); 5.32 (d, 1H); 4.41 (m,1H); 3.66 (m,

1H); 2.91 (s, 6H); 1.84-1.00 (m, 11H).

N-[1-(2-Cyclop en tyleth yl)-2,4-d ioxo-5-(2-flu or op h en yl)-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(m e-

th ylth io)p h en yl]u r ea (45): mp 220-3 °C; TLC R_f) 0.69 (EA/

CH, 1:1); C₃₀H₃₁FN₄O₃S; MS (FAB) m/e 547 (MH⁺); IR ν_max

3300 (NH), 1703, 1674 and 1639 (CdO), 1607 (CdC) cm^-1; ¹H

NMR δ 9.23 (s, 1H); 7.78 (d, 1H); 7.54-7.38 (m, 7H); 7.04-

6.94 (m, 3H); 7.16 (t, 1H); 6.80 (m, 1H); 5.07 (d, 1H); 4.42-

4.32 (m, 1H); 3.86-3.77 (m, 1H); 2.41 (s, 2H); 1.80-1.6 (m,

3H); 1.6-1.36 (m, 6H); 1.14-1.00 (m, 2H).

1-(Ad a m a n t -1-ylm et h yl)-3-a m in o-2,4-d ioxo-5-p h en yl-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in e (1R)-(-)-10-

Ca m p h or su lfon a te (75m ). The mother liquors recovered

after the crystallization of the above intermediate 74m were

concentrated in vacuo to give an enriched mixture of diaster-

eomeric salt (0.421 g, 0.64 mmol). A solution of this material

in dichloromethane (40 mL) was washed with a 5% ammonia

solution (2 × 25 mL) and brine (2 × 20 mL). The organic layer

was dried and concentrated in vacuo to give an enriched

mixture of amines (0.256 g, 0.61 mmol). To a hot solution of

this material in chloroform (10 mL) (1R)-(-)-10-camphorsul-

fonic acid (0.13 g, 0.55 mmol) was added; the mixture was

concentrated to a small volume (3 mL), then methanol was

added dropwise (3 mL). The resulting solid was filtered off and

washed with cold methanol to give the title compound as white

needles (0.216 g, 0.33 mmol): [R]_D) +21.27 (CH₂Cl₂c )

0.6500); C₃₆H₄₅N₃O₆S; MS (FAB) m/e 416 (MH⁺); IR ν_max1734,

1

1711 and 1684 (CdO) cm^-1; H NMR δ 7.52 (dd, 1H); 7.44-

7.24 (m, 7H); 7.19 (m, 1H); 7.01 (dd, 1H); 5.00 (s, 1H); 4.48 (d,

1H); 3.45 (d, 1H); 3.18 (d, 1H); 2.75 (d, 1H); 2.40-2.22 (m, 2H);

2.04-1.24 (m, 20H); 0.99 (s, 3H); 0.78 (s, 3H).

3-Am in o-2,4-dioxo-1-(3-m eth ylbu t-1-yl)-5-ph en yl-2,3,4,5-

tetr a h yd r o-1H-1,5-ben zod ia zep in e (1S)-(+)-10-Ca m p h or -

su lfon ic Sa lt (74b). To the racemic amine 5b (2.05 g, 6.07

mmol) dissolved in hot ethyl acetate (35 mL), (1S)-(+)-10-

camphorsulfonic acid (0.95 g, 4.08 mmol) was added. The

resulting salt was crystallized out from the cooled solution by

dropwise addition of cyclohexane; the precipitate was filtered

off and washed with cold cyclohexane to give a (+)/(-) 3/97

mixture of diastereomeric salt (1.1 g, 1.94 mmol). Recrystal-

lization from 2-propanol afforded the pure title compound (0.49

g, 0.86 mmol): [R]_D) -68.11 (CH₂Cl₂c ) 1.0055). Recrystal-

lization from methanol gave the title compound (0.34 g, 0.52

mmol) as white needles: [R]_D) -18.4 (CH₂Cl₂c ) 0.7.565);

C₃₀H₃₉N₃O₆S; MS (FAB) m/e 570 (MH⁺); IR ν_max2750-2600

N-[1-(2-Cyclop en tyleth yl)-2,4-d ioxo-5-(2-flu or op h en yl)-

2,3,4,5-t et r a h yd r o-1H -1,5-b en zod ia zep in -3-yl]-N′-[3-(5-

tetr a zol-5-yl)p h en yl]u r ea (46): TLC R_f) 0.55 (MC/MeOH,

8:2); C₃₀H₂₉FN₈O₃; MS (FAB) m/e 569 (MH⁺); IR ν_max3330-

3200 (NH), 1697, 1664 and 1637 (CdO and CdN), 1595 (Cd

C) cm^-1; ¹H NMR δ 9.46 (bs, 1H); 8.19 (bs, 1H); 7.79 (dd, 1H);

7.62-7.28 (m, 10H); 7.06 (d, 1H); 7.02 (dd, 1H); 5.10 (d, 1H);

4.38 (m, 1H); 3.81 (m, 1H); 1.82-1.62 (m, 3H); 1.60-1.36 (m,

6H); 1.16-1.00 (m, 2H).

N-[1-(Ad a m a n t-2-yl)-2,4-d ioxo-5-p h en yl-2,3,4,5-tetr a h y-

d r o-1H-1,5-ben zod ia zep in -3-yl]-N′-[3-(tetr a zol-5-yl)p h en -

yl]u r ea (70): TLC R_f) 0.58 (MC/MeOH, 8:2); C₃₃H₃₂N₈O₃; MS

(FAB) m/e 589 (MH⁺); IR ν_max3325 (NH), 1684 (CdO), 1661

1

(NH₃), 1736,1713 and 1700 (CdO) cm^-1; H NMR δ 9.0-7.4

(bm, 2H); 7.5 (d, 1H): 7.45-7.2 (m, 6H); 7.18 (t, 1H); 6.97 (d,

1H); 5.05 (s, 1H); 4.58 (m, 1H); 3.68 (m, 1H); 3.20 (m, 2H);

2.72 (m, 1H); 2.42 (m, 1H); 2.22 (m, 1H); 2.0 (m, 6H); 1.2 (m,

2H); 1.0-0.7 (m, 12H).

3-Am in o-2,4-dioxo-1-(3-m eth ylbu t-1-yl)-5-ph en yl-2,3,4,5-

3612 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20

Ursini et al.

tetr a h yd r o-1H-1,5-ben zod ia zep in e (1R)-(-)-10-Ca m p h or -

su lfon ic Sa lt (75b). The mother liquors obtained after

precipitation of the above compound 74b were evaporated to

dryness to give an enriched mixture of diastereomeric salt (2.19

g,). The residue was taken up in ethyl acetate (30 mL),

extracted with a 5% ammonia solution (20 mL) and washed

with brine (20 mL). The organic layer was dried and evapo-

rated in vacuo, to give the enriched mixture of amine (1.0 g,

2.96 mmol). (1R)-(-)-10-Camphorsulfonic acid (0.47 g, 2.04

mmol) in ethyl acetate (6 mL) was added to the solution of

the above amine (1 g) in ethyl acetate (5 mL) and the resulting

solution was stirred at 0 °C for 2 h. The obtained precipitate

was filtered off, washed with EA (20 mL) and dried to give

the title compound (0.97 g, 1.70 mmol): [R]_D) +71 (CH₂Cl₂c

) 0.606). Recrystallization from methanol gave the title

compound (0.34 g, 0.52 mmol) as white needles: [R]_D) -18.4

(CH₂Cl₂c ) 0.7.565); C₂₀H₂₃N₃O₂‚C₁₀H₁₆O₄S; MS (FAB) m/e

(td, 1H); 6.94 (dd, 1H); 4.52 (d, 1H); 3.38 (d, 1H); 4.22 (s, 1H);

2.30-1.70 (m, 2H); 1.82 (m, 3H); 1.70-1.30 (m, 12H).

(+)-1-(Ad a m a n t-1-ylm eth yl)-3-a m in o-2,4-d ioxo-5-p h en -

yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (77m ): TLC

R_f) 0.33 (EA/MeOH 95:5); [R]_D) +31 (CH₂Cl₂c ) 0.496); MS

(FAB) m/e 416 (MH⁺); IR ν_max3369 (NH₂), 1701-1672 (CdO)

cm^-1; ¹H NMR δ 7.5 (dd, 1H); 7.40-7.30 (m, 5H); 7.23 (td, 1H);

7.15 (td, 1H); 6.94 (dd, 1H); 4.52 (d, 1H); 3.38 (d, 1H); 4.22 (s,

1H); 2.30-1.70 (m, 2H); 1.82 (m, 3H); 1.70-1.30 (m, 12H).

(-)-3-Am in o-2,4-d ioxo-1-(3-m et h ylb u t -1-yl)-5-p h en yl-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (76b): TLC R_f)

0.55 (MC/methanol, 95:5); [R]_D) -114 (CH₂Cl₂c ) 0.5805);

MS (FAB) m/e 338 (MH⁺); IR ν_max3377 (NH₂), 1705-1670 (Cd

O), 1593 (C-C) cm^-^{1 1}H NMR δ 7.5-7.1 (m, 8H); 6.95 (dd,

;

1H); 4.55 (m, 1H); 4.23 (s, 1H); 3.7 (m, 1H); 1.8 (m, 2H); 1.64-

1.4 (m, 3H); 0.92 (d, 3H); 0.89 (d, 3H).

(+)-3-Am in o-2,4-d ioxo-1-(3-m et h ylb u t -1-yl)-5-p h en yl-

1

569 (MH⁺); H NMR δ 9.0-7.4 (bm, 2H); 7.5 (d, 1H): 7.45-

2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (77b): [R]_D

)

7.2 (m, 6H); 7.18 (t, 1H); 6.97 (d, 1H); 5.05 (s, 1H); 4.58 (m,

1H); 3.68 (m, 1H); 3.20 (m, 2H); 2.72 (m, 1H); 2.42 (m, 1H);

2.22 (m, 1H); 2.0 (m, 6H);1.2 (m, 2H); 1.0-0.7 (m, 12H).

+107.5 (CH₂Cl₂c ) 5.355 mg/mL); IR ν_max3375 (NH₂), 1715-

1661 (CdO), 1591 (C-C) cm^-^{1 1}H NMR δ 7.5-7.1 (m, 8H);

;

6.95 (dd, 1H); 4.6-4.5 (m, 1H); 4.24 (s, 1H); 3.8-3.65 (m, 1H);

1.8 (bs, 2H); 1.62-1.4 (m, 3H); 0.92 (d, 3H); 0.89 (d, 3H).

3-(-)-Am in o-2,4-d ioxo-5-(2-flu or op h en yl)-1-(3-m eth yl-

bu t-1-yl)-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (76c):

3-Am in o-2,4-d ioxo-5-(2-flu or op h en yl)-1-(3-m eth ylbu t-

1-yl)-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (1R)-(-)-

10-Ca m p h or su lfon a te (74c). A hot solution of (1R)-(-)-10-

camphorsulfonic acid (1.685 g, 7.26 mmol) in ethyl acetate (15

mL) was added, dropwise over 30 min, to a solution of the

amine 5c (3.0 g, 8.44 mmol) in ethyl acetate (7 mL) previously

heated at 90 °C under a nitrogen atmosphere. The resulting

solution was heated at 90 °C for 10 min, then concentrated in

vacuo. The residue was triturated with EE-petroleum gave a

(+)/(-) 50/50 mixture of diastereomeric salt (4.65 g). Recrys-

tallization from 2-propanol gave the title compound (0.9 g, 1.5

96%; mp 125-6 °C; TLC R_f) 0.38 (MC/MeOH, 30:1); [R]_D

)

-117.4 (CH₂Cl₂c ) 2.9 mg/mL); MS (FAB) m/e 356 (MH⁺); IR

(Nujol) ν_max1717 and 1701 (CdO), 1600 (CdC) cm^-1; ¹H NMR

δ 7.42 (dd, 1H); 7.40-7.18 (m, 6H); 6.94 (dd, 1H); 4.54 (m, 1H);

4.28 (s, 1H); 3.70 (m, 1H); 2.8-1.6 (m, 2H); 1.78-1.4 (m, 3H);

0.92 (d, 3H); 0.90 (d, 3H).

3-(+)-Am in o-2,4-d ioxo-5-(2-flu or op h en yl)-1-(3-m eth yl-

bu t-1-yl)-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (77c):

97%; mp 125-6 °C; TLC R_f) 0.38 (MC/MeOH, 30:1); [R]_D

)

3 mmol): [R]_D) +67.8 (CH₂Cl₂c ) 0.52); mp 216-7 °C; C₂₀H₂₂

-

+115.2 (CH₂Cl₂c ) 2.75 mg/mL); MS (FAB) m/e 356 (MH⁺);

IR (Nujol) ν_max3375 and 3317 (NH), 1699 and 1666 (CdO),

1591 (CdC) cm^-1; ¹H NMR δ 7.42 (dd, 1H); 7.40-7.18 (m, 6H);

6.94 (dd, 1H); 4.54 (m, 1H); 4.28 (s, 1H); 3.70 (m, 1H); 2.8-1.6

(m, 2H); 1.78-1.4 (m, 3H); 0.92 (d, 3H); 0.90 (d, 3H).

FN₃O₂‚C₁₀H₁₆O₄S; MS (FAB) m/e 588 (MH⁺); IR (Nujol) ν_max

1736, 1717 and 1700 (CdO) cm^-1; ¹H NMR δ 7.8-7.7 (bs, 3H);

7.47 (d, 1H); 7.4-7.03 (m, 6H); 7.00 (dd., 1H); 5.08 (s, 1H);

4.47 (m, 1H); 3.69 (m, 1H); 3.19 (d, 1H); 2.71 (d, 1H); 2.4 (m,

1H); 2.24 (d, 1H); 2.00-1.36 (m, 8H); 0.97 (s, 3H); 0.89 (d, 3H);

0.87 (d, 3H); 0.76 (s, 3H).

Ack n ow led gm en t. The authors thank Mr. B. La-

mont and Mr. Sean Lynn for the determination of CD

and X-ray structures, Dr. Beatrice Oliosi for providing

the binding data, and all our colleagues who provided

3-Am in o-2,4-d ioxo-5-(2-flu or op h en yl)-1-(3-m eth ylbu t-

1-yl)-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (1S)-(+)-

10-Ca m p h or su lfon a te (75c). The mother liquors obtained

after precipitation of the above intermediate 74c were con-

centrated in vacuo to dryness to give an enriched mixture of

diastereomeric salt (3.7 g, 6.3 mmol). A solution of this

material in ethyl acetate (100 mL) was washed with a 5%

ammonia solution (2 × 60 mL) and brine (100 mL). The organic

layer was dried and evaporated in vacuo to give the enriched

mixture of amine (1.88 g, 84%). A hot solution of (1S)-(+)-10-

camphorsulfonic acid (1.01 g, 4.35 mmol) in ethyl acetate (9

mL) was added dropwise over 15min to a solution of the above

mixture (1.8 g, 5 mmol) in ethyl acetate (4 mL) previously

heated at 90 °C under a nitrogen atmosphere. The resulting

solution was heated to 90 °C for 10 min, then concentrated in

vacuo. The residue was triturated with EE-petroleum to give

a (+)/(-) 55/45 mixture of diastereomeric salt (2.8 g). Recrys-

tallization from 2-propanol gave the title compound (0.5 g, 1.00

mmol): mp 216-7 °C; [R]_D) -73.1 (CH₂Cl₂c ) 0.59); MS

(FAB) m/e 588 (MH⁺); IR (Nujol) ν_max1736, 1717 and 1688

1

mass spectra and IR and H NMR spectra.

Su p p or tin g In for m a tion Ava ila ble: Crystallographic

data. This material is available free of charge via the Internet

at http://pubs.acs.org.

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1

(CdO) cm^-1; H NMR δ 7.8 (m, 2H); 7.5 (d, 1H); 7.4-7.1 (m,

7H); 7.00 (d, 1H); 5.09(s, 1H); 4.49 (m, 1H); 3.70 (m, 1H); 3.20

(d, 1H); 2.72 (d, 1H); 2.40 (m, 1H); 2.25 (m, 1H); 2.00-1.3 (m,

8H); 0.98 (s, 3H); 0.90 (d, 3H); 0.88 (d, 3H); 0.77 (s, 3H).

(-)-1-(Ad a m a n t-1-ylm eth yl)-3-a m in o-2,4-d ioxo-5-p h en -

yl-2,3,4,5-tetr a h yd r o-1H-1,5-ben zod ia zep in e (76m ). A so-

lution of the intermediate 74m (0.311 g, 0.74 mmol) in

chloroform (40 mL) was washed with a 5% ammonia solution

(3 × 25 mL) and brine (3 × 20 mL). The organic layer was

dried and concentrated in vacuo to give the title compound as

a white foam (0.19 g, 0.45 mmol, 95%): 95%; TLC R_f0.33 (EA/

MeOH 95:5); [R]_D) -36.8 (CH₂Cl₂c ) 0.4945); MS (FAB) m/e

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potent, orally effective non peptidal antagonists of the peptide

hormone cholecystokinin. Proc. Natl. Acad. Sci. U.S.A. 1986, 83,

4918-22.

1

416 (MH⁺); IR ν_max3369 (NH₂), 1701-1672 (CdO), cm^-1; H

NMR δ 7.47 (dd, 1H); 7.40-7.30 (m, 5H); 7.23 (td, 1H); 7.15

Synthesis/ SAR of 5-Phenyl-3-ureido-1,5-benzodiazepines

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J M990967H

Article Doi

Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazephines as cholecystokinin-B receptor antagonists

DOI: 10.1021/jm990967h

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