DuP 747: sar study

DuP 747: sar study

096&894X/92 $5.00 + .OO 0 1992 Pcrgamon Press Ltd Bioorgat~ic & Medicinal Chemistry Lelters, Vo1.2. No.7, pp. 721-126, 1992 Printed in Great Britain ...

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096&894X/92 $5.00 + .OO 0 1992 Pcrgamon Press Ltd

Bioorgat~ic & Medicinal Chemistry Lelters, Vo1.2. No.7, pp. 721-126, 1992 Printed in Great Britain

DuP

747:

SAR

STUDY’

P. Rajagopalan’, R. M. Scribner, P. Pennev, P. L. Mattei, H. S. Kezar, C. Y. Cheng, R. S. Cheeseman, V. R. Ganti2 A. L. Johnson, M. A. Wuonola, W. K. Schmidt, S. W. Tam, G. F. Ste’infels and L. Cook. CNS Diseases Research. The Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0353

(Received 20 April 1992)

Abstract: The results of a detailed study of the structure-activity represented by DuP 747 are described.

The synthesis and pharmacology

of racemic trans-3,4-dichloro-N-methyI-N-[5-methoxy-2-(pyrrolidin-l-yl)-l

tetrahydronaphthalen-l-yl]benzeneacetamiUe letter

relationships in the series of compounds

methanesulfonate

,2,3,4-

(DuP 747, 1) was described in the preceding

A number of analogues of this novel, kappa selective analgesic was prepared to develop a structure-activity

relationship

in this series of compounds

represented

by the general structure 2. The result of the study is the

subject of this letter

OMe 1 (DuP

747)

a;$&

.(COO” COOH

3 (U-50,488

CHEMISTRY:

H\

The methods employed for the synthesis of compounds of the type 2 are depicted in Scheme 1

and are fairly strarghtforward epoxide route (5*7),

The preferred route to the amrnoalcohols 7 was through the bromohydrins 6

The

thcugh successful In a few cases, was not dependable in that the epoxrdation of the alkenes

of the type 4 was capncrous.berng sensitive to the substituent on the benzene nng to the diamrnes (7+8*9)

the aminoalcohols 7 was secondary because the alternate route (7*9) lead, In this case, to a sulfonamrde useless for further elaboration 9,10-dihydrophenanthrene4

The chlorosuifonic acid route3

was clean and of general applicabrlity. It was parkcularly useful when the amino group of rnvolving methanesuifonyl chloride would

The starting material for 12 was 9,10-epoxy-

and that for 13 was 3,4_drhydrophenanthrene 5

721

The resolution of DuP 747 (1) was

P. RAJAO~PALAN

et&.

SCHEME 1

per acid

W)n 3

I

NBS,

Hz0

R; -NH-R2

solvent

i

6 C1S03H

/.

I

i. CH3S02CI 2. RNHp

Rt-NH-R2

2 cl

When R’=CI, a base was used When RkOH,

DGC or CDt was used

DuP 747: SAR study

carried out using (+)- and (-)- dibenzoyitartaric

acids.

723

The structure of the analogues 10 to 13 are shown in Chart 1

and the other analogues are listed in Table 1 under the general structure 2.

Chart

1

11

10 R = 3,4-dlchlorobenzyl

0

0 Me.N.kR

3 PHARMACOLOGY:

.HCI .HCI

For SAR purposes the tests employed were limited in vitro to kappa and mu receptor

binding and in vivo to the mouse phenylquinone writhing (PQW) antagonism6 tests. The standards chosen for comparison were the selective mu receotor agonist morphine and the selective kappa receptor agonist U-50.488H (31

The data are shown In Table 2.

STRUCTURE-ACTIVITY

RELATIONSHIP:

Early in our SAR study, it was decided, on the basis of the

structure 01 U-50.48~ _, to restnct the amide and amino functions at the l- and 2- positions of the tetralin system of 2 to the N-(3,4-dichlorophenylacetyl)-N-methylamino

and the pyrrokdino groups, respectively.

It

was then quickly demonstrated that transposrng the amrde and the amine functions at the l- and 2- position, respechvely, resulted in undesrrable mu selectrvrty (entry 10) and that movrng the amide group from the l- to the 3posihon

led to reduced mu selectivrty and analgesic actrvdy only by the s c route (entry 11)s

Mono- or

disubstitution at the cl-position of 2 (entries 17 and 16, respectively) reduced kappa selectivity and destroyed analgesic actrvity

Annelation of a benzene ring to the 3,4-posrtions (entry 12) of 2 eliminated both kappa

affinity and in vwo activity whrle fusing it to the 5,6-posrtions (entry 13) retained both, albeit to a lesser extent. Also, any substituent on the benzene ring of the tetrakn moiety other than alkyl. alkoxy, hydroxymethyl

or

hydroxy groups and their esters generally brought about a reduction or complete elimination of both kappa binding and rn vrvo activity (entries 18 to 42)

Although the 6-hydroxy derivative (entry 22) was by far the

most potent both rn terms of afllnity to the kappa receptor and analgesic potency, rt exhibrted a high degree of afhnity to the mu receptor as well selectivity and analgesrc potency

A methoxy substituent at the 5positron

seemed to be ideal for kappa

The optimal substituents and the substitution pattern on the aromatic and

aliphatic rings of structure 2 havmg thus been established, the variations of the ammo function at the 2positron and of the amide group at the 1 -positron were then systematically

mveshgated

As can be seen

(entries 43 to 48). replaclng the pyrrokdino group wrth any amine other than 3-pyrrokne (entry 46) led to

P. RAJAGOPALANet al.

724

reduced kappa selectivity and complete loss of in viva activity. Even with the 3pyrrolino

substitution, reduced

kappa selectivity was evident.

With regard to the amide group at the l-position, even changing the methyl group on the nitrogen to an ethyl abolished both kappa selectivity and in viva activity (entry 50). Removal of the methylene group between the amide carbonyl

function

and the benzene

ring or addition of a methylene

respectively) reduced both kappa selectivrty and analgesrc potency.

thereto (entries 48 and 49,

Introduction of an oxygen between the

methylene and the benzene ring (entry 51) retained both kappa selectivity and analgesic activity whereas a sulfur in the place of oxygen (entry 52) reduced kappa selectivity and eliminated in wvo activity. exceptions,

the benzene

ring of the amide function

tolerated

donating groups as well as mono-, di- and trisubstitutions selectivity and parenteral activity.

both electron withdrawing

With a few

and electron

(entries 53 to 71) without much loss of kappa

Replacing the benzene ring of the amide function with 4thianaphthyl

group

retained both kappa selectivity and analgesic potency (entry 76), while replacing it either with 1-naphthyl group or with some heteroaromatic 77).

rings generally resulted in a decrease of both properties (entries 72 to

Decreasing the aliphatic ring size of the tetralin unit by one carbon led to retention of both kappa

selectrvity

and analgesic

selectivity

but a decrease

potency

(entry 14), while increasing It by one carbon resulted in retention of

in potency (entry 15)

However, almost all of these analogues

elicited only

moderate to poor activity when administered orally.

The kappa affinity and analgesic activity of DuP 747 (1) resides exclusively in the (+)-S,S-diastereomer

(the

fourth entry in Table 2).

Acknowledgement:

We thank Mana Marynowski, Kimberly Cornwell, William Keim, Carla Maciag, Anne

Marshall, Carol Morgan, and Eionni Rule for biological evaluations and the members of the Analytrcal Service Unit for spectral and optical rotation determinations

REFERENCES

AND

NOTES

1

Part of two posters presented at the 200th Meeting of the American Chemical Society, Washington,

2

Deceased.

3

Paris, D.E.; Fanta, P.E ; J.Amer Chem.Soc 1951, 74,3007

DC, August 1990; Division of Medicrnal Chemistry, Abstracts No. 58 and 59.

4.

Newman, MS.; Blum, S.; J AmerChemSoc

5.

Jerina, D.M., Yagi, H. J.Amer.Chem.Soc.

6.

Blumberg. H ; Wolf, P S.; Dayton, f-i.8 Proc.Soc.ExpBrol.Med

1964, 86,5598.

1975, 97, 3185 1965, 118, 763.

7.

Szmuszkovicz,

8

This compound has also been described by Freeman et a/ (Ref.13, preceding letter).

9.

Satisfactory analytical and spectral data were obtained for all the new compounds described in this tetter.

J.; VonVoigtlander,

P F. J. Med. Chem., 1982, 25, 1125.

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TABLE 2 Receptor binding (niilf

ErLltY U-50488H Morphine DuP 747 (1) (+)-s,s-DuP747 (_).R,R-5P747 10 11 12 13 14 16 16 17

do5 6

3570 10 2760 20 1000 56 7 87 857 190 70 5 : 9: 3 5 19 4

32 33

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59 60 t: ::

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70 71 33 74 76 :5

764 15 32 9 1 3%

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3E 750 260 463

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400 18 49

6400 975 >lO,Oca

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662 545 2310 2300 9100 330 >10,000

1:: 12 15 20 14 6 120 12 7 14 230 15,263 144 15 6 13

>lcm E 4930 1345 1640 2500 1600 2200 640 3600 510 1200 >lO,aGQ 1200 z 775 775 2660 460 1465 360 10,KQ 33.460 21‘7W 245 285 207

Mouse PQW antagonjsm ED50 (mg/kg) s&a 1.2 E6 0:15 281 2.7 0.16 46.8 a61 3.6 1.5 24.2 Pm >8? 6.1 0.33 2.2 15 003 3 0.46 0 71 4.5 0.24 0.71 2Bl 5.2 8.1 0.69 0 19 8.1 >81 4.2 16 45 A31 3.4 1.5 E6 z-681 z.81 0.24 zB1 47 36 47 0.46 zl 12 10 1.2 3.4 8.3 19 0.89 0.72 47 4.2 z-81 Z:if 2.3 F* YS 38 Z-61 16 >6t 0.46 27

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