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Journal ofMedkina1

Chemistry

Copyright 1978 by t he A mer i can Chemical Soc i e t y

Volume 22, Number 1

January

1979

The Benzodiazepine

Story’

Leo H. S te rnbach

Research Dioision, Hoffmann-La Roche

Inc.,

Nutley, New Jersey 07110 Received September 5 1978

Before star tin g with my lecture prop er, I would like to

express my deep fel t thanks to the M edicinal Chemistry

Division of the A merican Chem ical Society for choosing

me to receive this prestigious award. It is indeed an h onor,

gives me great sat isfact ion, and makes me very happ y.

In this lecture ,

I

would like to tell you abo ut th e chain

of events tha t started with the synthesis

of

a new chemical

en tity a nd culm inated in th e discovery of a new class of

biologically active agents. Specifically, I shall discuss the

development of the group of centrally acting 1,4-benzo-

diazepines that began with the discovery of a pharma-

cologically active com poun d, which received t he generic

name chlordiazepoxide and is the active ingredient of

Librium.

Th e story starts in the mid

1950s

when the tranquilizers,

a new class of therapeutic agents, were shown to have

considerable clinical value, and Roche decided to em bark

on a program concerned with the synthesis of pro ducts of

this type. T he pharmacological tests for the screening of

sedatives and tranquil izers were well in hand, and we

chemists were asked to produce a new compound which

would be superior to t he th en exist ing tranquilizers.

A chemist faced with a problem of this kind h as various

approaches a t his disposal. He can star t in a ra ther so-

phisticated mann er with a biochemical working hypothesis,

with othe r intelligent s peculations, or select a more prosaic

approach.

Our kn owledge of the processes occurring in the brain

was rather limited, and we could not thin k of an intelligent

working hypothesis. Therefo re, we decided to take th e low

road and to at tack this problem in a purely empirical

manner. Since our main interest was chemical synthesis,

we planned to select an approach which would be

chemically most attractive, challenging, and satisfying.

Th is left us essential ly with two al ternatives: to m odify

existing dru gs or to searc h for a new class of tranqu ilizers.

Molecular modification, sometimes disparagingly called

molecular m anipulat ion, of products known to have the

desired pro perties has prov en to be very successful in the

past. Th e modification or simplification of the molecular

stru cture of natural ly occurring alkaloids, hormones, and

antibio tics has given excellent results. Th e molecular

modification of man y s ynthetic dru gs, e.g., of the first sulfa

drug Pron tosil, the first M A 0 inhibitor, the first synthetic

diuretic, and many other synthetic biologically active

prod ucts has also led to vastly improved medicines. This

approach did n ot appear to be very promising, since the

0022-2623/79/1822-0001 01.00/0

then known tranquilizers were intensively studied by

several groups of investigators, e.g., meprobamate (Mil-

town) at Wallace Laboratories, reserpine by the Ciba

research group, and chlorpromazine by the SKF research

team.

We therefore considered it more attractive to pursue the

second approach a nd be guided mainly by our intere st in

synth etic chemical bench work. T he class of comp ounds

we were seeking would be ex pected t o fulfill the following

criteria: 1)be relatively unexplored, (2) be readily ac-

cessible, (3)give the possibility of a mu ltitude of variations

and transformations, (4) offer some challenging chemical

problems, and (5) “look” as if i t could lead t o biologically

active products. Our search led us to the benzheptox-

diazines, compounds

I

had worked with during my

postdoctoral assistantship years a t the U niversity of

Cracow.* These stud ies in th e early 1930swere concerned

with a search for new dyestuffs and dy estuff interme diates

and were te rmina ted a f te r we found tha t the benz-

heptoxdiazines did no t lend themselves to th e anticipated

uses. Comp ounds of this type now looked rathe r attractiv e

t o us and seemed to be well sui ted for a fa irly broad

synthetic program. Th e start ing materia ls were readily

accessible , and their t ransformation into benzheptox-

diazines seemed to be a reaction

of

general applicability.

Th e first compounds of this type were prepared in 1891

by Auwers and von Meyenburg3 by treatm ent of amino-

(1)

or acetaminoacetophenone oximes

(2)

with a Beckmann

NHCOCH3

C H 3 C 0 C ‘ -

=N

OH

CH3

CH3

1

2

CH3

3

mixture. Th e heptoxdiazine struct ure was “definite ly

established” in 1924.4

1978 American Chemical Society

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of

Medicinal Chemistry, 1979,

Vol.

22,

No.

I knew from my pa st experience th at these compounds

were readily form ed, crystallized very well, and could be

easily isolated an d purified. A literature search revealed

th at since our work in Cracow2 very little had been

published ab out t he chemistry of benzheptoxdiazines and

tha t no studies concerned with their biological properties

had been carried out. Thes e compounds therefore seemed

to be ideally suited for our purposes. We planned

to

synthesize a number of the relatively readily accessible

amino ketones

4

bearing various substi tuents

i n

the

Sternbach

the pharmacological properties were rather dis appointing.

Neither removal of th e N-oxide oxygen nor hydrogenation

a t t h e 3 ,4 p os it io n y ie ld ed an y th ing of i n t e r e ~ t . ~ , ~

A t tha t time (this was the second half of 1955) we had

to stop our work in the quinazoline field since other

problems seemed to be of greater importance. We became

involved with other synthetic projects and the isolation,

purification, and degradation of various antibiotics. This

inten sive work, of little practical value, finally led, in April

1957, t o an almost hopeless situation.

The laboratory

benche s were covered with dishes, flasks, an d beakers-all

containing various samples and mother liquors.

T h e

working area had shrunk almost to zero, and a major spring

cleaning was in order.

During this cleanup operation, my co-worker, Earl

Reeder, drew my attent ion to a few hu ndred m illigrams

of

two products, a nicely crystalline base and its hydro-

chloride.

Both the base, which had been prepared by

treating the quinazoline N-oxide

11

with methylamine, and

R2

4

R 2

5

R2

6

benzene ring an d acylate their oximes to products of type

5

By combining a variety of amino ketones an d acids, a

large number of new compounds of type

6

would be ex-

pected t o become available in the s hortest time a nd with

a minimum of difficulties.

Further transformations of 6 offered the promise of

addition al interesting possibilities. One of our first ob-

jectives was the sy nthe sis of new com pounds, e.g.,

7,

which,

by treatment with amines, could be converted into

products possessing basic side chains

as

in

8.

The reaction

CH,N(

R

I

C 6 H 5

7

I

C 6 H 5

8

products, we hoped, might have interesting properties,

since it is known that basic groups frequently impart

biological activity.

In the midst of our work, we began to have serious

dou bts abou t the stru cture of the heptoxdiazines of type

7

an d

8 .

In particular, the results of hydrogenation ex-

perim ents were quite revealing. Th e oxygen was removed

with great ease and the products, formed in good yield,

were quinazolines. Additional chemical studies showed

unequivocally that the so-called heptoxdiazines did not

possess the postulated struct ure but were in fact quin-

azoline 3-oxides5as shown in

9

an d

10.

The interesting

R

: q N \ O

N+fcH2c   N+fCH2N'R

C 6 H 5

9

1

C 6 H 5

10

novel struc ture of these compou nds an d their facile

for-

mation and transformations gave us additional incentive

to continue our work. We synthesized a numb er of

quinazolin e 3-oxides of t ype

9,

treated them with secondary

amines, and obtained the expected substitution products

of type 10. The reaction occurred readily with the for-

mation of nicely crystallized products, but u nfortunate ly

11

its hydrochloride had been ma de sometime in 1955. Th e

products were not s ubm itted for pharmacological testing

at that t ime because of our involvement with other

problems. Since the compounds were pure and ha d the

expected composition, we su bmitte d th e water-soluble salt

for pharmacolo gical evaluation in 1957. W e again expected

t o receive negative pharmacological results a nd thought

th at our work w ith quinazoline N-oxides would be finished

and lead to the publica tion of some chemically interes ting

material . Lit t le did we know that this was the st ar t

of

a

program which would keep us busy for many years.

Th e product was submitted for testing in May 1957 and

within a few days we received an e nthusias tic telephone

call from our pharmacologist, Dr. Lowell Rand all. He

informed us that this compound possessed unusually

interesting properties in th e six tests which were generally

used for the preliminary screening of tranquilizers and

sedatives. Table I shows the comparison of its pharma-

cological properties with those of the then most used

tranquilizers and the hypnotic, phe nob arb itd7 Mice were

used in all these tests with the exception of the th ird one

which was carried out with unanesthesized cats. Th e

inclined screen test indicates muscle relaxation and se-

dation an d the foot shock possibly a taming effect. Th e

test with th e unanesthesized ca t shows muscle relaxation

and is quite characteristic for this class of compounds as

is the pentylenetetrazole test which indicates sedative and

anticonvulsant properties. Th e two electroshock tests

are

a measure of their potency as anticonvulsants.'

Table I shows tha t the new compound was much more

effective tha n meprob amate in each of our six preliminary

tests. Compared with chlorpromazine, it was weaker in

the first two tests, of equal strength as a muscle relaxant

in the cat , and had a more pronounced anticonvulsant

activity in the mouse. As can be seen in the last line our

new compound was superior to phenobarbital in th e first

four tests but inferior in the two electroshock tests. Th e

absence of di rect hypnotic properties below the toxic dose

w s

another interesting feature which differentiated it very

characteristically from phenobarbital. It is also worth

noting tha t unlike chlorpromazine a nd reserpine i t had no

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Award Address

Table

I.

Pharmacological Propertiesa

of New

Compound , Meprobamate, Chlorpromazine,

a n d

Phenobarbital

Journal of Medicinal Chemistry, 1979, Vol. 22, No. 1

3

~~

anticonvulsant tests

pentylene- electroshock

inclined foot

compd

screen shock

cat tetrazole

max min

new

compound

100 40

2 18 92 150

meprobamate

250 250

100

150 200 167

chlorpromazine 17

20

2.5

42 150 600

phenobarbital 120 80

1 75 18 90

Dose

( m g / k g ) of orally

administered

drug required

to

achieve

the desired effect.

0

13

0

14

effect whatsoever on the autonomic nervous system. Th e

product had a pronounced taming effect on monkeys. Th e

low toxicity (620 mg/kg in mice) was particularly en-

couraging.

It

looked like an ideal compound.

While the compound underwent a whole gamut of

so-

phisticate d pharmacological tests by Dr. Randall a nd his

staff,7 we studi ed th e chemistry of this unusual produc t.

From the very beginning we had reservations about i ts

s t ruc ture s ince the

UV

and IR sp ectra were completely

different from those of th e s tar t ing material 11 or those

of other related quinazoline 3-oxides. Since at tha t time

NMR

or mass spectra were not yet used for the s tructure

determination of complicated heterocyclic molecules, we

resorted

to

classical methods. Th e analytical data showed

that the reaction product had the expected molecular

weight and elementary composition; the methylamino

group and the N-oxide function were also present. Th e

d eg ra da tiv e s t ~ d i e s , ~hich allowed us t o establish defi-

nitely that the compound had structure 13 rather than 12

are outlined in Scheme

I.

First we removed the N-oxide oxygen and then we

hydrolyzed compound

14

with acid. Th is gave the ami-

nobenzophenone used as starting material in quantita tive

yield. Th e acid-soluble residue gave, after benzoylation

by the Schotten-Baumann procedure, benzoylmethyl-

am ine and hippuric acid in greater than 60% yield. The

degradation products, glycine and methylamine, could

result only from the hydrolysis of the benzodiazepinone

13

via

14

and n ot from the quinazoline

12

or other con-

ceivable isomers.

This unusual transformation of a quinazoline 3-oxide

into a benzodiazepine 4-oxide promp ted us to investigate

the reaction in depth . Th e study of various reaction

conditions, solvents, and the behavior of a number of

analogues6 ed us to

conclude tha t the methylamine attacks

the quinazoline N-oxide at the 2 position due to ts residual

positive ch arge 1la) ather t ha n replacing the reactive

lla

- H C l

13

l N H C H 3

n N = ' C H pC

I

CI 7=N\OH

17

chlorine atom as might be expected.l0 Th is causes the

formation of an intermediate of type

16

which most

probably is ultimately transformed via

17

into th e 1,4-

benzodiazepine derivative 13. The in terest ing and

promising pharmacological properties of this compou nd

led us to synthesize a number of related products

(19)

N H R

R% NYCc - R 1 3 ;

18

19

obtained by causing quinazoline 3-oxides 18 to react with

ammonia and a variety of primary amines.

The synthesis of these analogues and homologues en-

abled us t o file a pate nt application in M ay 1958 claiming

2-amino-1,4-benzodiazepine-oxides bearing various

subs ti tuen ts in the benzo and phenyl r ings. Because of

the novelty of these products, th e p atentI 2 was granted

within a year (July 1959) and without difficulty.

Th e pharmacological evaluation of all the analogues and

homologues on hand showed tha t none were significantly

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Sternbach

Table

11.

Pharmacological Activitya of Chlordiazepoxide

and Its Transformation Products

anticonvulsant tests

pen-

tylene electroshock

n-

clined foot tetra-

compd screen shock cat zole max min

13 100

40

2 18 92 150

21 100

20 2 15 150

150

22 15

4 0

1 6

52 400

23

I 5

20

1

6

25

61

Dose mg/kg ) of orally administered drug required to

achieve the desired effect.

superior to the first product, the methylamino derivative

13.

It was therefore decided to intensify the stu dy of th is

compound and prepare it for clinical evaluation and

possible introductio n. Its pharmacological and psycho-

tropic prop erties in animals were thoroughly explored, the

toxicological studies were expanded, and an intensive

clinical investigation was starte d and conducted under th e

energetic direction of Dr. L . Hines.

It soon became a ppar ent th at this compound possessed

very valuable tranqu ilizing (anxiolytic) prope rties and t he

interest of the clinical investigators became so great tha t

within a short time thous ands of patients had been treate d

with this drug. Th ese extend ed successful studies enabled

us to f i le an NDA very quickly and to introduce the

compound

[7-chloro-2-(methylamino)-5-phenyl-3H-l,4-

benzodiazepine 4-oxidel in

1960

under the t rademark

Librium . Th e generic name which was later generally

accepted was chlordiazepoxide. Th e time elapsed between

the first pharmacological testing and introduction was only

l l

years.

Th is record time w as made possible by minimizing red

tape and by the enthusiasm a nd fr ictionless cooperation

of all the people involved in the chemical and pharma-

ceutical production an d pharmacological, toxicological, and

clinical testing of the new drug. T he favorable clinical

results and th e then existing positive attit ude of the FDA

were obviously of prime importance.

While this product was being prepared for introduction,

it

became desirable to find a form which would lend itself

to th e p reparation of a pharmaceutically acceptable elixir

or syrup for pediatric and geriatric use, because chlor-

diazepoxide hydrochloride, th e water-soluble clinically used

salt , was extremely bit ter . This was not at all surprising

since

it

is well known to m ost medicinal chem ists tha t

every useful drug is either b itter , hygroscopic, or unstable.

Since this com pound was rathe r valuable,

it

possessed all

three of these properties.

During these studies, we found tha t a suspension of the

qui te insoluble, finely pulverized base itself was unsuitable.

Moreover, the pharmacologically equipotent acetyl de-

rivative

20

also proved to be too bitter despite its low

solubility. No t unexpected ly, aqueous solutions or sus-

pensions of

13

a n d 20 were relatively unstab le. Th e en-

suing study led to th e very interesting f inding that the

substituent at the 2 position was the cause of the instability

an d was readily removed by acid hydrolysis.’’ T o our

pleasant surprise, the decomposition product

21

showed

the same pharmacological activity as 13 (Table

II ) . I4

A

further transformation of this product was the removal of

the N-oxide function to form

22.

Thi s change also did not

affect the pharmacological p roperties; quite the contra ry,

the activity even seemed to be sl ightly enhanced. Thus ,

i t turned out that some of the unique features which

seemed so characteristic for chlordiazepoxide were not at

all needed for its pharmacological activity. Th e N-oxide

CI‘

‘

0

21

function and particularly the basic substituent, which was

the co rnerst one of our initial working hy pothe sis, proved

to be only unnecessary adornments. Th e only features

which were common

to

these biologically active compounds

were the 1,4-benzodiazepine ring system bearing a chlorine

a t t h e 7 position and a phenyl group a t the 5 position.

Based on this knowledge, we started a broad program

of molecular modification, aiming at the discovery of

products which would be superior to chlordiazepoxide.

In order to facilitate our work, we first sou ght simple r

methods which would make compounds of type

21

and

22

more readily accessible.

We found th at N-oxides of type 21 could be prepared

easily by alkaline tre atm en t of

2-(chloromethyl)quinazoline

N-oxides 18.

18

\

r-

R 1 O j 3 ;

\

2 4

23

The results of the pharmacological study of these N-

oxides (24) were not very interesting, since different

substituents had only minimal effect on the biological

spectra and potencies of these compound s. Chemically,

however, they undergo an interesting reaction on tre atm ent

with acetic acid or anhydride. Thi s so-called Polonovsky

rearrangement results in the formation of th e 3-acetoxy

derivative

25

which on mild hydro lysis yields the bio-

21

A t 2 3

25 2 6

oxazepam)

logically active 3-hydroxy derivative 26. This rear-

rangement of benzodiazepine 4-oxides was studied by

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Vol. 22, No.

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5

’Pdble

111.

Comparison of the Pharmacological Activitf of Chlordiazepoxide with That of Diazepam

anticonvulsant tests

~

electroshock

inclined foot

pentylene-

compd screen

shock cat tetrazole max min

chlordiazepoxide

100

40 2 18 92 150

diazepam 3

10

0.2

1.4 6.4 64

a

Dose (mg/kg) of orally administered drug required to achieve the desired effe ct.

research team s a t Wyeth15 and also a t Roche.6

T he Wy eth investigators were rather successful. The y

discovered the biological activity first, obtained a p ate nt,

an d were able to introduce oxazepam in the Un ited States

in 1965 under t he trad e name Serax and under various

othe r names in other countries.

We concentrated our studies on simple benzodiazepi-

nones without th e N-oxide function. Th e search for a l-

ternativ e syn theses of these relatively simple compounds

resulted in a number of routes leading to the desired

prod ucts in good yields. Two meth ods which were used

most extensively are shown in Scheme II.16

In b oth cases, o-amino ketones

27

were used as startin g

materia ls . Tr eatm ent of the appropriately sub st i tute d

aminobenzophenone with a haloacetyl halide yielded a

compound of type 28, which, on treatm ent w ith ammonia,

gave the benzodiazepinone 30 via an am ino derivative

29.

The other method involved t rea tment of an amino-

benzophenone with an amino acid ester hydrochloride in

pyridine leading direct ly from 27 to 30. Th e first , mul-

t istep method general ly gave bet ter overal l yields, up to

70-80 of very pure products. Th e second method fa-

cilitated the synthesis of benzodiazepinones bearing

sub st i tue nts a t posi t ion 3, since many a-am ino acids

bearing a variety of subst i tu ents a t th e a carbon are

commercial ly available . W ith these two methods, we

prepared first a number of benzodiazepinones bearing

num erous s ubstitu ents a t different positions in ring A. A

subsequent modificat ion was the introduction of a sub-

s t i tuent in pos i t ion

1

which was readily achieved by

treatment with base and an alkylat ing agent .

Near the end of 1959, just before the introduction of

Librium , we were very much aware of its clinical value and

s ta r ted to look for a superior product. All th e compounds

which were the n on han d h ad similar activity spectra, but

one, the 1-methyl derivat ive

31 7-chloro-1,3-dihydro-l-

C H 3

31 (diazepam, Valium)

methyl-5-phenyl-2H-l,4-benzodiazepin-2-one),

as sig-

nificantly more potent tha n chlordiazepoxide. In the hop e

th at this higher potency would be connected with other

advantages in its clinical utility, we star ted a n intensive

stu dy of this substance. Th e compound was 3-10 t imes

as potent as chlordiazepoxide, as Table I11 indicates.

Fu rth er studies showed tha t the toxici ty was extremely

low. Its psychotropic and o ther pharmacological prope rties

were studied in d ep th with very favorable results. It was

given the generic name diazepam and, after the appro-

priate toxicological and extended clinical studies, was

in t roduced near the en d

of

1963 under the t rademark of

Valium. In th is case, the t ime elapsed between. the first

Scheme I1

R

R

--Pif”CoCH

 

R ”’a l - C O C H - H a I _

R i

-

o

I

-co

p y r i d i n e

A l k O C O

>CHR .

HCI

I

H2N

A

i

29

pharmacological test ing an d introd uction was

4

years.

Th e valuable clinical properties of this new com pound

led to an expansion of our synthe tic program. Th e

chemical staff was enlarged considerably and t he Ph ar-

macological De partm ent grew proport ionally.

As

soon as the Librium patent12 had appeared, other

research centers also started the investigation of benzo-

diazepine derivatives. Th is intensive activity led to a

num ber of valuable alternative ro utes for th e syn thesis of

benzodiazepinones.

With in a few years our intensive efforts resulted in the

synthesis an d pharmacological evaluation of well over

3000

1,bb enzo - and heterodiazepinones. Th is involved th e

preparation, identification, and pharmacological investi-

gation of about 4000 intermediates an d byproducts.

Th e large number of benzodiazepinones a t our disposal

enabled us to study thoroughly the structure-act ivi ty

relationships in this series. It became appar ent a t the very

beginning of our studies that the subst i tut ion pat tern

played an impo rtant role, of param ount importance being

t he subs t i tue n t a t t he

7

position (ring

A).

Subst i tuents

in rings

C

and also

B

had addit ional effects. Our most

significant findings are summarized in Chart

I”

(see also

ref 18).

These “rules” proved to be valuable guidelines in the

course of our further studies, which led to benzodiazep-

inones with over 80 different substituents at the 7 position

and wi th hundreds of subs t i tuents a t pos i t ion 1.

Of

part icular interest was the 1-ter t-bu tyl homologue1Qof

diazepam, which is almost completely inactive. Wherea s

other alkyl groups are readily removed by liver microsomes,

the tert-butyl group

is

no t attacked, as was shown by our

Me t a bo l i sm Group unde r t he d i r e c t i on o f Dr . M.

Schwartz.20 Based on these findings we synthesized a

compound which combined al l the features known to

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Chart

I.

Activity of Benzodiazepinones

Effects of Substituents on t he Biological

Sternbach

I

q2

4

32

a Ring

A :

(position 7 ) generally, increased by electron-

withdrawing groups, e.g ., halogens, NO,, and CF,, and

decreased by electron-releasing groups such as CH, and

OCH,; decreased by any substituents in any positions

other than

7 .

Ring B: increased by a methyl group at

position 1 ; decreased by larger substituents; tert-butyl

derivative is com plete ly inactive. Ring C : increased by

halogens at the 2' positi on (e.g ., C1 and F);very strongly

decreased by a substituent at the 4 position.

impa rt high activity: the CH 3 group at 1, he nitro group

at 7, and a f luorine at 2'.14J7 It proved to be, as expected,

one of th e pharmacologically most po ten t benzodiazepi-

nones, illustrating th e additive or potentiating prope rties

of pharmac ophoric groups in the benzodiazepine series. It

was introduced in Switzerland in

1975

as a poten t hyp-

notic, acting in 1-mg doses.

Thes e studies showed th at our six preliminary tests gave

a good indication of the potency of these compounds.

However, differences in the pharmacological spectrum were

not very significant since, to da te, they unfortunate ly have

not led to compounds which show effects going much

beyond thos e of othe r l,/i-benzodiazep ines. In every case,

muscle relaxation and sedation, anxiolytic, anticonvulsa nt,

and hypnotic properties are present to a varying degree.

Only the prepon derance of one or the other activity seems

to vary.

It

should be noted th at this discussion has been

limited

to

benzodiazepinones having a phenyl group at th e

5

position, because su ch com pounds w ere generally bio-

logically most active and also most readily accessible.

However, many benzodiazepinones bearing other sub-

st i tuen ts a t the 5 position were synthesized and studied

pharmacologically by m any research teams, including

ours.

Few were of inte rest an d some of them were rather difficult

to prepare. Only two benzodiazepinones bearing a sub-

st i tuen t o ther than phenyl a t the

5

position are currently

on the ma rket. One is an a-pyridyl derivative, broma-

zepam,21mark eted by Roche; the o ther is a cyclohexenyl

derivative, tetrazepam,22which was introduced by Clin-

Byla.

Research in the benzodiazepine series has been very

active and continues in m any industr ial centers, leading

to various modifications of the basic structure. Some of

the most interesting novel developments are derivatives

with additional rings joining the diazepine nucleus a t the

1

and 2 positions.

A t

the present time, the most interesting

are the t riazolobenzodiazepines

33,

which were syn-

C l

y

w

33,

R = H, C H , ; X = H, C1

Chart I1

N H C H j

chlordiazepoxide

(Librium, 1960)

C H 3

C I

f yf

N

diazepam

(Valium, 19 63 )

oxazepam

(Serax, 196 5)

flurazepamb

(Dalmane, 1970)

clorazepate clonazepam

(Tranxene, 1972)

(Clonopin, 1975)

0-c

lorazepam prazep am

(Ativan, 19 77 ) (Verstran, 19 77 )

Marketed mainly

as

the hydrochloride.

Marketed

as the hydrochloride.

thesized a nd investigated by TakedaZ 3 nd UpjohnZ4 e-

search teams. These compounds are generally more poten t

tha n the corresponding 1-methylbenzodiazepinones. Two

of

them are commercially available outside the U S .

Evidence

of

the intensive research in the benzodiazepine

field still in progress is indicated by the continuous flow

of new paten ts and scientific publications. In the las t five

years, over

1600

original patents have appea red, and over

1 2 papers concerned with the chemistry, pharmacology,

and clinical aspects have been published. One of the main

objectives is the discovery of products having a narrower

spec trum of biological activities. It is to be expected th at

this search will continue for years to come and might

ultimately lead

to

superior products with more specific

properties: anxiolytics, muscle relaxants, or anticonvul-

sants causing less sedation, compounds with pronounc ed

antidepressant properties, or even drugs acting in psy-

choses. Th e general acceptance of this class of compo unds

is illustrated by the widespread use of the eight benzo-

diazepine derivatives which are now marketed in the

U S .

They are shown in Chart I1 together with their generic

trade names and introduction dates. Six of them are

8/17/2019 Sternbach 1979

7/7

[ -Penicillamine,2- leucine]oxytoc in

anxiolytics, flurazep am is a hypnotic, and clonazepam is

an antiepileptic . Fourteen addit ional

1

Cbenzodiazepine

derivat ives are m arketed outside th e

US.,

any of them

under several t rade names.

Acknowledgment. I wish to express my appreciation

to al l my associates who contributed so great ly to the

dev elop me nt of th e chemistry of benzodiazepine s, in

particular to th e first group of chem ists who were involved

in th e earliest stages of our stud ies:

G.

A. Archer, M.

E.

Derieg, G.

F.

Field, R.

I.

Fryer,

W.

Metlesics, R.

Y.

Ning,

E.

Reeder,

G.

Saucy, R.

A.

Schm idt , N. Steiger, and

A.

Stempel. Th ank s are also due to our co-workers in Basle,

Switzerland, under the direction of Dr.

J.

Hellerbach.

I

also

wish to than k Dr. L.

0.

Randall and his staff for their

splendid cooperation.

References and Notes

Journal

of

Medicinal Chem istry, 1979, Vol. 22, No.

7

1961);L.

0

andall,

W.

Schallek, G. A. Heise, E.

F.

Keith,

and

R.

E.

Bagdon,J .

Pharmucol. Exp . Ther.,

129,163

(1960).

(8) For a description of these tests see ref

17.

(9) L. H. Sternbach and E. Reeder, J. Org. Chem., 26,

111

(1961).

(10)

L. H. Sternbach, Angew. Chem., 83, 0 (1971).

11) L. H . Sternbach,

E.

Reeder,

0.

Keller, and W. Metlesics,

J . Org. Chem.,

26,4488 (1961), nd add itional unpublished

results.

(12) L. H ternbach, U.S. Patent 2893992 July 7,1959).

(13)L. H. Sternbach and E. Reeder,

J. Org. Chem.,

26, 4936

(14)L. H. Sternbach and L. 0. Randall, CNS Drugs, Symp .,

(15) S. C. Bell and S . Childress,J .

Org. Chem .,

27,1691 1962).

(16) L. H ternbach, R. I. Fryer,

W.

Metlesics,

E.

Reeder, G.

Sach, G. Saucy, and A. Stempel,

J . Org. Chem.,

27, 3788

(1962).

(17)

L.H. Sternbach,

L.

0. Randall, R. Banziger, and H. Lehr,

“Medicinal Research Series”, Vol.2,A. Burger, Ed. , Marcel

Dekker, New York, N.Y., 1968, 237.

See also ref 14.

(18)

S. J. Childress and M.

I.

Gluckman, J .

Pharm. Sci.,

55,577

(1964).

(19) N.

W

ilman and L. H. Sternbach ,

J . Heterocycl. Chem.,

8, 297 (1971).

(20)M. Schwartz, unpublished results.

(21) R. I. Fryer, R. A. Schmidt, and L. H. Sternbach,J. Pharm.

Sci.,

53, 264 (1964).

(22)

J.

Schmidt,

P.

Comoy, M. Suquet, J. Boitard, J. LeMeur,

J. J.

Basselier, M. Brunaud, and

J.

Salle,

Chim. Ther.,

2,

254 (1967).

(23) K. Meguro

and

Y. Kuwada, Tetrahedron Lett., 4039 (1970).

(24) J. B. Hester, Jr., D. J. Duchamp, and C. G. Chidester,

(1961).

Hyderabad, India, 53 (1966).

Tetrahedron L ett.,

1609 (1971).

This is a condensed version of the Medicinal Chemistry

Award Address p resented a t the 16th Medicinal Chemistry

Symposium in Kalamazoo, Mich., June 20, 1978.

K. Dziewodski and L. Sternbach,

Bull. In t. Acad. Pol. Sci.

Lett., C1. Sci. Math. Nat., Ser. A,

416 (1933)

Chem.Abstr.,

28, 2717 (1934)l;

bid.,

33 (1935)

Chem. Abstr.,

30, 2971

(1936)l.

K. Auwers and F. von Meyenburg,

Chem. Ber.,

24, 2370

(1891).

J.

Meisenheimer and A. Diedrich,

Chem. Ber., 57,

1715

(1924);K. on Auwers,

ibid.,

57, 1723 (1924).

L.

H. Sternbach, S. Kaiser, and E. Reeder, J . Am . Chem.

Soc.,

82, 75 (1960).

E. Reeder and

L.

H. Sternb ach, unpublished results.

L.

0. Randall,

Dis. Nerv. Syst., Supp l.

7,22, ect. 2 July

[l-Penicillamine,2-leucine]oxytocin.

Synthesis and Pharmacological and

Conformational Studies of a Potent Peptide Hormone Inhibitor’

Victor

J.

Hruby,* K. K. Deb, Diane M. Yamamoto?

Department

of

Chemistry, University o f Arizona, Tucson , Arizona 85721

Mac

E.

Hadley,

Department

o f

General Biology, University

o f

Arizona, Tuc son, Arizona 85721

a n d W.

Y.

Chan

Department

of

Pharmacolog y, Cornel1 University Medical College, New Yor k, New York 10021. Received May

10,

1978

[

l-Penicillamine,2-leucine]oxytocin as synthesized by the solid-phase method of peptide syn thesis and purified

by partition chromatography on Sephadex G-25, ollowed by gel filtration . Th e peptide was found to be a very

potent competitive inhibitor of oxytocin in the oxytocic assay with a

pA2

of 7.14and an inhibitor of oxytocin in

the milk-ejecting assay. The compound showed no agonist activity in either of these assays, and its inhibitory activity

a t the u terus was of prolonged duration. Th e 13C nuclear magnetic resonance spectra l properties an d the 13C

T I

(spin-lattice) relaxation times of [Pen’,Leu2]oxytocinwere determined, and the results were compared with previous

studies of [Pen’loxytocin, a related competitive inhibitor , and oxytocin, the native hormone agonist. These studies

indicated tha t th e hormone inhibitors [Pen’,Leu2]oxytocin nd [Pen’loxytocin have similar conformationaland dynamic

prop erties which are differen t tha n those of the agonist, oxytocin.

Pept ide horm one competi t ive inhibitors (antagonists)

constitute a potentially useful class of organic compounds

in clinical applications an d for studying peptide-receptor

interact ions and the mechanisms of peptide hormone

action. Th ese applications derive from their ability to

interact with the receptor in a manner similar to the

hormone and their inabil i ty to t ransduce a biological

message to effect a change in t he target cells metabolism

or other properties. Th us a peptide horm one competitive

inhibitor can provide inform ation of the horm one-receptor

interact ion independent of the transduction event and

0022-2623/79/1822-0007 01.00/0

important clues

to

structural and dynamic features related

to both binding and transduction.

Recently we have shown tha t

[

1-penicillamine]oxytocin

([Pen’loxytocin, S-C(CH&CH(NH2)CO-Tyr-Ile-Gln-

Asn-Cys-Pro-Leu-Gly-NH,),

a competitive inhibitor of

oxytocin,3s4has considerably restricted dynamic properties

rel at ive t o t hose of o~ y t o c i n .~ ,~hese studies suggested

that certain specific differences in the conformational,

dynamic, and s tructu ral propert ies of the hormone an d

antagon ist were related

to

differen ces in biological activ ity.6

1978American Chemical Society