C8-substituted derivatives of 2-(dipropylamino)tetralin: Palladium-catalyzed synthesis and interactions with 5-HT1A-receptors

0960-894X,91 $3.00 + .00 @ 1991 lb8m.X k=S PlC

BioorgmicdrMedicinalChemistry Letters,Vol.1. No.5, pp.257-262. 1991 Rited inGreatBritain

CB-SUBSTITUTED PALLADIUM-CATALYZED

Ye Liu,a Svante

DERIVATIVES SYNTHESIS AND

OF Z-(DIPROPYLAMINO)TETRALIN: INTERACTIONS WITH 5-HTlA-RECEPTORS

Bjijrn E. Sv~nsson,~ B. Ross,b

Tommy

Hong

131,~ Lourdes

Lewander,=

Cortizo,a

and Uli Hacksellar*

a Department of Organic Pharmaceutical Chemistry, Box 574, Uppsala Biomedical Centre, Uppsala University, S-751 23 Uppsala, Sweden, b Research and Development Laboratories, Astra Research Centre, S-151 Sodertalje, Sweden, C Department of Psychiatry, Ulleraker, Uppsala University, S-750 17 Uppsala, Sweden

85

(Received 18 April 1991) Abstract: A series of C8-modified analogues of 8-OH-DPAT (1) have been prepared by facile palladium-catalyzed reactions of the triflates of the enantiomers of 1. Several of the new compounds have high affinity for 5HT lA-receptors and some are potent agonists. Drugs

are

receptors

and

interacting

the

enantiomers being

a

of

1 are

enantiomers poor

of

is

1

ten

years,

which

the

receptors

to

a

of

only

few

of

some

1

treatment

of

pass

of

1

seem

appeared

in the

modified.5 leading

with

of high

high

the

affinity as

~...\Nw7h

5-HT

(R)-1: (R)

257

to

the

C8of 1 the in

present

enantiomers C8-position. to

5-HTlA-

5-HTlA-receptor

agonists.

HyJyW2

during

literature

In

in

potency

due

profile

phenolic

to pure

substituents

bind

to be

the

1 nor

the structure

been

various

mainly

efforts

protocol

has

derivatives

although

(N-1

racemic

pharmacokinetic

of research

have

a synthetic

them

that

result

derivatives

neither

of

iS

Both

5-HTIA-receptors

development,

poor

1)3

potency,'l

at

conjugation

surprising as the

agonist

drug

anxiety

agonist.

considerable

the

of

(5-HT)

(8-OH-DPAT,

However,

for

likely,

first

containing

new

of

cyclase.4c

Most

considerably

these

and

in the

partial

considered

fast

we describe

derivatives

Several

been

C8-substituent

communication of

to adenylate

a

serotonin

of

5-HTIA-receptor

agonists

(S)-1

It is, therefore,

varied

past

and

have

related

substituent.

interest

examined

selective

bioavailability.

has been

5-HTIA-subtype1

clinical

thoroughly

agonist

coupled

their

the

8-Hydroxy-2-(dipropylamino)tetralin

most

full

negatively the

of potential

depression.2

probably

with

R=H

-2: R=CH3

Y. Lw et al.

258

SchemeI* OH NGH,),

(.9-l

W3W2

mNcc3H7J2 a

W$-b)2

S30CH,

(3 -8

(9 -6

(a-7 *Reagents: Triflic anhydride, CH2C12; (a) (b) (CH3)4Sn, K2CO3, PdCl2(Ph3P)2, LiCl, 1,4-dioxane, DMF; (c) PhSn(n-C4Hg)3, Pd(Ph3P)4, LiCl, 1,4-dioxane, DMF; d) DMF; PdCl2(dppf), CO, LiCl, (e) i: (CR3)4Sn, butylvinylether, % HCl; DMF. ii: 10 Pd(OAc)z, (f) N(QH5)3, dppp, Pd(OAc)z, dppf, N(C2H5)3, CH30H, CO, DMSO; (g) Pd(OAc)z, dppf, N(C2H5)3, HCOOH, DMF.

In the

syntheses

of the

novel

derivatives

palladium-catalyzed

transformations

derivative

I). An advantage

3

the

optical

are

retained

(Scheme purities

and

absolute

in the C8-modified

3 were produced

from

the

readily

of with

of

available

utilized

enantiomers

this

synthetic

configurations

analogues.

1 we

the

of the

strategy

triflate is that

enantiomers

Key intermediates enantiomers

efficient

of

(S)- and

of

1

(RI-

of l6 by treatment

Derivatives of2-(dipropylamino)tetra)in

259

Table I. Yields of the Compounds Synthesized and Their Apparent Ki Values and Hill Coefficients for Inhibiting the Binding of [3H]8-OH-DPAT to Membranes from Rat Cerebral Cortex.

yield compda

R

(%)b

recrystn mp,"C

solvent=

[a]Dd

Ki (nM)e

(range)

"H

1.8

(1.6-2-O)

0.86

f

(S)-1g

OH

(R)-19

OH

1.3

(1.1-1.5)

0.97

(S)-29

OCH3

2.8

(2.7-3.0)

0.96

(R)-24

OCH3

1.5

(1.4-1.7)

1.11

(S)-3 (W-3

OSO2CF3

94

114-116

A

-58.9

9.5

(7.4-13.2)

0.83

98

113-115

A

+59.6

3.8

(2.8-5.7)

0.79

(S)-4

OSO2CF3 H

77

129-130

B

-71.5

56

(46-71)

0.83

(W-4

H

41

127-128

B

+71.1

17

15-19)

0.85

129-131

C

-72.5

62

56-69)

1.04

129-131

C

f68.8

34

32-38)

1.13

22-26)

1.04

(S)-5

CH3

56

(W-5

CR3

57

(S)-6

C6H5

88

115-117

D

-25.2

24

115-116

D

+24.1

7.7

7.2-8.3)

1.00

(S)-7

C6H5 COCH3

83 44

114-116

A

-123.2

0.7

(0.6-1.0)

0.71 0.96

(W-6 (W-7

COCH3

52

115-116

A

+122.7

1.8

(1.6-2.0)

(S)-8

COOCH3

149-150

A

-115.1

1.7

(1.4-2.1)

1.01

(W-8

COOCH3

59 71

148-150

A

+115.4

4.3

(3.7-4.9)

0.90

(f)-9

COOH

97

245-241

C

> 300

a All compounds were obtained and tested as the hydrochlorides except (S)and (RI-6 which were obtained and tested as the oxalates. b Yields refer to recrystallized compounds. All compounds described have been characterized with lH and 13C NMR-spectroscopy and give an acceptable elemental analysis. c Recrystallization solvent: (A) Chlorofordm/ether; (B) Acetonitrile/ether; (C) Methanol/ether; (D) Acetone/ether. (c 1.0, MeOH), 22°C. * Binding of [3H] 8-OH-DPAT (2nM) to rat cerebral cortical membranes was determined as described previously (ref 13). Ki values and approximate standard errors (ranqes) were determined from displacement curves based on 6-10 different confcentrations in duplicate by using the computer program LIGAND (ref 18). The Hill coefficients were determined from log-logit plots of the inhibition between 10 and 90 %. g Included for comparison. with

triflic

anhydride

in

the

presence

of

base.7

Palladium-catalyzed

couplings8 of (R)- or (S)-3 with tetramethyltin and phenyltributylstannane produced the corresponding C8-methylated (5) and arylated (6) derivatives, respectively. Introduction of methoxycarbonyl and acetyl groups were accomplished by palladium catalyzed carbonylations in the presence of methanol9 or tetramethyltin.19 Alternatively, the acetyl group was intro-

Y. LIU etal.

260

duced

by

a

Heck

hydrolysis. removed

The

by

with

Hydrolysis

carboxylic

of

3

CB-substituent

treatment

catalyst.12

Table

coupling

acid

9

with of

formic

of

(Scheme

the

vinyl

etherll of

enantiomers

acid

in the

racemic

the II).

butyl

Yields

the

was

of

new

subsequent

conveniently

a palladium(I1)

ester

methyl

of

3

presence

and

8

afforded

compounds

are

the

given

in

I.

Scheme

II

COOH

NW7)2

NW-&)2

NaOH/H20/CH30H

(*)-8

The

(?)-9

ability

receptors for

the

than

substituted

any

with

CS-position

unsubstituted whereas

4

affinity

of

but the

5-HT

(3)

seems

It

in Table

1 reported the

CS-substituent

(S)-enantiomers

appear

to

potent

in this

Derivatives group

5-HTIA-receptor. are

substituted that

weak

with

in

The CS-

less

potent

derivatives

only

one

(6)

derivative,

stereoselectivity

possess

a methoxycarbonyl

have

higher

the

or

affinity

(about In

5-HTIA-receptors.

(R)-enantiomers is

affinity

for 5-HTlA-receptors.

a fairly

the

5-HTlA-

high

1.

(5) derivatives

phenyl

interactions to date,

more

compound

is noteworthy

I show

their

from

have

or a methoxycarbonyl

for the

substituted the

to be

lead

of acetyl

affinity

and

compounds

acetyl

an

than

most

higher (R)-

the

(Table I).

via

synthesis

subsequent experiments as

(Table II).

that

activation

rate

aminoacid

behave

high

methyl

It is well-known14 of

enantiomers methoxy,

[3H]-S-OH-DPAT

of the

(+)-9, has low affinity

in

when

displace

(S)-7

fact,

affinity.

acid

fold)

antipodes

the

exhibit

derivatives

derivatives

group,

all

intermediate

-

In

triflates

the carboxylic

The

of

to

I.13 Most

a hydroxy,

(4) and

the

display

1.5

derivatives

in Table

5-HTlA-receptors.

respect

the

of the

is given

may

be

of

in

agonists

autoreceptors.

measured

decarboxylase analysis

5-HT lA-receptor somatodendritic

of

the

non-pretreated

receptor Since

agonists, none

indirectly

(with

after

decrease

inhibition

3-hydroxybenzylhydrazine;

5-HTP

levels.15

rats, similar

the in

of the enantiomers

In

such

enantiomers potency

to

of 7 affect

in of the

the

synthesis

The

decrease

of

aromatic

L-

NSD

1015)

and

vivo

biochemical

(S)-

and

enantiomers

the DOPA

in

(R)-7 of

accumulation

1

Derivatives of2-(dipropylamino)tetralin

in the

brain

receptors

areas

at

potencies

the

as

activity

dose

the

such

behavioral

studied,

as

they

tested.

syndrome,

which

preliminary

availability

of 7 is increased

Table

II. Biochemical

1

body

in

Effects

5-HTP

appear

to

corroborates

about

in

and

Striatum

(S)-I

55.8 * 4.9**

of

that

the

5-HT

results-l6

biochemical

in vivo of the Enantiomers

similar

5-HTlA-receptor

induction

indicate

the

oral

to that

bio-

of I.

of 1 and 7

(O-32

Rats.=

DOPA

(rig/g tissue)

Compound

for

fold as compared

in Non-Pretreated

dopaminergic

(S)-7 exhibit

tests

the

dogs

five

activate

(R)- and

other

temperature

experiments

s.c.)

wol/kg,

of

of

Furthermore,

not

In addition,

enantiomers reduction

do

(rig/g tissue) Limbic

Striatum

Limbic

112 * 4.2""

1136 f 94

445 f 14

(R)-I

51.2 f 2.6**

102 f 6.2**

1280 rf:43

414 f 17

(S)-7

58.5 5 7.5"

89.0 * 8.0""

1098 + 32

365 + 19

(R)-7

62.1 + 3.1*

111 + 2.9**

1101 f 48

399 f 25

171 z!z7.2

1212 f 39

440 + 16

Control

104 * 4.8

a Rats were given test compounds 60 min and benzylhydrazine.HCl (287 /lmol/ The values are means f SEM (n=14 and 4-7 kg, s.c.) 30 min before sacrifice. in the control and experimental groups, respectively). Sta*tistics: On$*way ANOVA followed by Tukey's studentized range (HSD) test; p I 0.05, p I 0.01 compared with saline treated controls.

The

set

refinement provided

of

compounds

of a recently that

addition,

the

several

presented reported

intrinsic of

the

here

may

3D-model

activities

for

of

the

compounds

new

help

in

the

evaluation

and agonists, 17

5-HTIA-receptor compounds

may

are

evaluated.

leads

provide

for

In drug

development.

Acknowledgment.

by grants f~cmie~~~ Support for this study was provided Natural Swedish Board Swedish for Technical Development, the Research Council and Astra Research Centre. L.C. was supported by a grant from DGICYT of the Ministerio de Educaci6n y Ciencia of Spain. We thank Dr Seth-Olov Thorberg for the data on the bioavailability of I and 7.

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