prostaglandin endoperoxide receptor antagonist

Tetrahedron Letters,Vol.30,No.l8,pp Printed in Great Britain

oo40-4039/89 $3.00 Pergamon Press plc

2399-2402,1989

+ .OO

THE SYNTHESIS OF POTENT THROMBOXANE AZ/ PROSTAGLANDIN ENDOPEROXIDE RECEPTOR ANTAGONIST Nobuyuki

HAMANAKA,* Minase

Takuya

Research

SEKO,

Institute,

Shimamoto,

Department

of Applied

A design

SUMMARY:

In diseases a very

treat such TXA2 and ONO-3708

such

important

as angina role.1

We

and the compound

experimental pharmacological on induced by STA27 (TXA;! agonist),

I Thromboxane

4

Nagoya

antagonist

diseases by synthesizing PG endoperoxide. During 33,

Pharmaceutical Osaka

and Hisashi

Chemistry,

MIYAZAKI,

618,

A2

and Masao NAKA Co., Ltd.

Japan

YAMAMOTO University,

Nagoya

of new and ‘most potent thromboxane

endoperoxide

plays

ON0

Mishima,

Kyoji FURUTA

Tohru

461- 1, Japan

A2lprostaglandin

is reported.

pectoris have

and

been

compounds the course 44,516 have

thrombosis,

working

proved

2 ONO- 11720

d/form

2399

development

which antagonize the of such investigations,

Az(TXA2)

1

of drugs

to

actions _ of both ONO-11120 22,

to be particularly effective based inhibition of platelet aggregation

properties, e. g., and inhibition of smooth

5 6

thromboxane

on the

muscle

construction

3 ONO-3708

7 X&H3 8 X=Br

2400

induced

by

activity

was

improved orally

U-466198

agonistic describe

in

The strategies

accompanied

the

above

structures

with

of the ring

system

as that

about

20

of the

concluded

be

designed

now

2 or 3, it was

transient

and

weak

communication we TXA2 antagonists

and

synthesized

according

to the

5,

times

more

and

that the ring

to

consequently

potent

than

6.

to

acid since

was

only

compound This

suppress

I and

resulted

in

racemic

its

its

activity

was

however, one-tenth

6, as

7, the enantiomeric

result

should

on

the

be are

the

form.

twice

as

absolute as

isomer

its

of 6,

only

by

analysis,

we

not essential

conformational

in the

potent

interpretable

conformational

bulkiness

the

II. Relocation

terminal

even

Surprisingly, 4,

and its structural

act

in Table

to 4

isomer

4 and 7. Based

of

only

carboxylic

potency

dl-mixture.

skeleton

but

the

optical

equivalent

similarity

activity

toward

a preferred is

mixture

isomer

comparable

corresponding

which

conformational

biological

of

smooth muscle. In this and synthesis of potent

of 5, 6, 7, and 8 are listed

showed

should of

enantiomeric

Although

than

properties.

optical

of 4 by sliding

which

configuration

property

was

in 4.

activity

biological

system

of preferred

activities

4

unfavorable

the

2 in water

below.

biological

Compound

compounds,

of compound

in inhibitory

agonistic

The

5,

of

of 3 was improved

potent

vascular design

of the side chain

of the ring

series solubility

duration

an

3) modification

structure

this

lower

of 5, 6, 7, and 8 were

shown

1) relocation

the

more

unfavorable

2) confirmation

was

4 was

In

the

3 and short

compound

activity on platelets and our efforts in the rational

from

potent

agonist).

as follows:

significantly active

unfortunately

free

(PGH2

strengthened

mobility

for

the

of

the

molecule. Further tosyl

group

with

TABLE I

but

a variety

simple

modifications

of benzenesulfonyl

Inhibition of Human Aggregation*

Compound 3 4 5 6 7 8 * Induced by STA2

IC5o (M) 4x10-7 7x10-8 9x10-8 9x10-7 5x10-8 9x1 o-9 (lo-6M)

Platelet

of the

side

derivatives

TABLE

chain were

II

Compound 4 7 8 ** Induced

by replacement made.

Among

Inhibition of Rabbit Aorta Constriction** IC5o (M) 3x10-9 3x10-9 1x10-9 by U-46619

(lo-6M)

of the them,

2401

compound

8

was

administration inhibiting

an

related

will of

in

the

work

be

to

reported

Compound reaction

in

at the

platelet

ee).

gave

100

ug/kg

vivo),

these

undesirable

by the

following

action

is

synthesized fumarate

an optically

of 12

and

9 with

reaction

with

pure

cyclopentadiene(1

iodo-lactone

methanol

and

sequences.9 eq)

in

toluene

by hydrolysis with with KI3 and

12 (69% from 9, [a]~

hydrogen

chloride

followed

84%

oxalyl

yield

chloride

by

a two

step

in

methylene

reaction chloride

and

i. e.,

subsequent

in

+53.3’, by

the

>99%

zinc-acetic

sequence,

with

the

4N KOH (40 then single

to the formation

in

Diels-Alder

After hydrogenation carboxylic acid was

15 in

oral

also

continuing

acid reduction produced the half ester 14 quantitatively. atm H2, MeOH) of the double bond of 14, the resulting amide

by

but

however,

eliminate

di-D-menthyl

Esterification

of (ex

response (in vivo) caused by various stimulants weak and transient agonistic activities still

pressor

1 h) followed presence of 1.2 eq stannic chloride(-78*, h, reflux) gave the di-acid 11. Iodolactonization recrystallization

amount

aggregation

elsewhere.

8 was

the

even

inhibiting

Unfortunately,

Further

results

to be effective

only

increase

to TXA2.

remain.

proved

not

acid

treatment

(Pd-C, 1 converted chloride with

0 Roo%OOR

SnCI+toluene c -78%

9 R=D-menthyl

11

10

OOH KI - I2

HCI / MeOH

Zn , AcOH

reflux, 30min

rt, lhr

14

1) H2-Pd-C

1)LAH

ammonia.

lithium

Simultaneous

aluminum

Br

16

15

with

-8 2) Ph3P(CH2)&OOH -ferf-E&K

2) BsCl

2) (C@J)2 3) NH3

gaseous

1) Swem Ox.

-)

hydride

reduction in

THF

of at

both reflux

amide and ester moieties in 15 for 3 h, followed by selective

sulfonylation of amino function with p-bromobenzenesulfonyl from 15). The a-side chain was introduced by the following

chloride gave 16 (60% sequence. After Swern

2402

oxidation

of

16, the resulting

crude

aldehyde

(4-carboxybutyl)triphenylphosphonium to afford

the

crude

was

bromide

8 (63%

from

16),

treated

and

which

contained

isomer. Recrystallization via the cyclohexylamine amine, the optically pure 8: oil, [a]~ +20.4” (EtOH). Compounds corresponding

5, 6, and starting

7 were

also

reviews:

M. Lefer

2)

M.

a)

Jr. ibid. 46,

Katsura,

T.

Kawasaki

and

salt

synthesized

M. L. Ogletree,

and H. Darious,

L. Saussy

9%

of the

afforded,

in

ylide

derived

terr-butoxide

THF

(E)-double

after

a similar

from

in

bond

removal

manner

of the

from

the

and

Notes

Fed. Am. Sot.

ibid. 46 144 (1987).

Exp.

Biol., 46,

133 (1987).

c) P. V. Halushka,

b) A.

D. E. Mais and D.

149 (1987).

Miyamoto,

N.

Hamanaka,

M. Tsuboshima,

Adv.

K.

Prostagl.

Kondo,

T.

Terada,

Thrombox.

Y.

Leukotri.

Ohgaki,

Res.,

A,

11,

319

j.

(1983 3)

H. Suga, N. Hamanaka,

4)

Adv. Prostagl. Thrombox. Leukotri. Res., 17, A sulfonyl amide containing non-prostanoid by

the

materials. References

Recent

with

potassium

Boehringer

Haemostas., 5)

K. Furuta,

6)

The

K. Kondo,

Manheim 33,

277

H. Miyake,

company:

H.

S. Ohuchida,

Y. Arai and A. Kawasaki,

799 (1987). TXA2 antagonist

Patscheke

and

K.

was

Stegmeir,

first

reported

Thrombos.

(1984).

S. Hayashi,

Y. Miwa

and

H. Yamamoto,

Tetrahedron

Lett.,

28,

5841

(1987). compound

4 and

Narisada,

M. Ohtani,

Kakushi,

K. Ohtani

its

F. Watanabe,

N. Hamanaka

8)

G. L. Bundy,

Tetrahedron

9)

All

new

compounds

IR,

NMR

spectral

(Received

in

Japan

were

Lett., and

1975,

here

were

elemental

13 March

1989)

reported H. Arita,

Chem., 31,

and M. Hayashi,

reported data

also

K. Uchida,

and S. Hara, J. Med.

S. Ohuchida,

7)

analogs

by

Shionogi

M. Doteuchi,

company:

M.

K. Hanasaki,

H.

1847 (1988).

Tetrahedron,

39,

4269

(1983).

1957. fully

characterized

analysis/high

resolution

on

the mass

basis

of their

spectrum.