New diarylmethylpiperazines as potent and selective nonpeptidic δ opioid receptor agonists with increased in vitro metabolic stability

3878

J . Med. Chem. 2000, 43, 3878-3894

New Dia r ylm eth ylp ip er a zin es a s P oten t a n d Selective Non p ep tid ic δ Op ioid

Recep tor Agon ists w ith In cr ea sed In Vitr o Meta bolic Sta bility

Niklas Plobeck,* Daniel Delorme,^§Zhong-Yong Wei, Hua Yang, Fei Zhou, Peter Schwarz, Lars Gawell,

He´le`ne Gagnon, Benjamin Pelcman, Ralf Schmidt, Shi Yi Yue, Christopher Walpole, William Brown,

Edward Zhou, Maryse Labarre,^#Kemal Payza,^#Stephane St-Onge,^#Augustus Kamassah,^#

Pierre-Emmanuel Morin,^#Denis Projean,^#J ulie Ducharme,^#and Edward Roberts^†

Departments of Chemistry and Pharmacology, AstraZeneca R&D Montreal, 7171 Frederick-Banting,

Saint-Laurent, Quebec, Canada H4S 1Z9

Received May 30, 2000

Nonpeptide δ opioid agonists are analgesics with a potentially improved side-effect and abuse

liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead

SNC-80 suggested the removal of substituents not predicted to contribute to binding. This

approach led to a simplified lead, N,N-diethyl-4-[phenyl(1-piperazinyl)methyl]benzamide (1),

which retained potent binding affinity and selectivity to the human δ receptor (IC₅₀) 11 nM,

µ/δ ) 740, κ/δ > 900) and potency as a full agonist (EC₅₀) 36 nM) but had a markedly reduced

molecular weight, only one chiral center, and increased in vitro metabolic stability. From this

lead, the key pharmacophore groups for δ receptor affinity and activation were more clearly

defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1

confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic

nitrogen for δ binding, in agreement with mutagenesis data. A number of piperazine N-alkyl

substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery

of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)-

methyl]benzamide (56) which had an improved in vitro binding profile (IC₅₀) 0.5 nM, µ/δ )

1239, EC₅₀) 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.

In tr od u ction

close analogues have also been associated with side

effects such as seizures⁶and poor distribution, metabo-

lism, and pharmacokinetics (DMPK) attributes⁷which

make them unsuitable as therapeutic agents.

It is now well-established that three different types

of opioid receptors exist in the central nervous system

and that agonists of all receptor subtypes are known to

produce antinociception. Morphine and morphine-like

compounds are widely used clinically as analgesics.

However, it is also known that they induce unwanted

side effects such as respiratory depression, dependence,

constipation, and euphoria. All of these side effects are

primarily due to the fact that they are agonists at the

µ receptor. Consequently the discovery of an opioid

analgesic that acts at different opioid receptor subtypes

may have the advantage of analgesia but without

unwanted side effects. Studies based on δ-selective

opioid peptide ligands have suggested potential advan-

tages over other opioid receptors.¹However the inherent

inability for systemically administered peptides to be

well-absorbed from the gastrointestinal tract and to

cross the blood-brain barrier has encouraged various

approaches to develop nonpeptide δ ligands.²

The purpose of this study was to explore further the

SAR around SNC-80 with the aim of finding new

structures with improved pharmacological properties by

eliminating sites of metabolism, removing centers of

chirality, and lowering molecular weight while retaining

high affinity and selectivity for the δ opioid receptor.⁸

Here we discuss how structural simplification of SNC-

80 first led to the lead compound 1 and was further

optimized to a number of new potent δ agonists by

modifications of the different parts of the molecule

(Figure 1).⁹We present binding data for the racemic

compounds against the cloned human δ, µ, and κ

receptors and agonist potency as measured by the GTP-

[γ-³⁵S] binding assay.

Ch em istr y

The synthetic pathways to the target compounds are

outlined in Schemes 1-13. Synthesis of substituted

piperazines 3 and 4 is described in Scheme 1. N-Boc-

2-aminoisobutyric acid was coupled with D,L-alanine

methyl ester using 1-(3-dimethylaminopropyl)-3-ethyl-

carbodiimide hydrochloride (EDC). N-Boc deprotection

with trifluoroacetic acid (TFA) followed by heating in

2-butanol gave the diketopiperazine 2. Reduction with

lithium aluminum hydride (LAH) in THF gave the

racemic piperazine 3, which was selectively N-Boc-

protected at the least sterically hindered nitrogen with

Boc₂O in THF to give 4. Compounds 1 and 10-16 where

The discoveries of the nonpeptidic δ opioid agonist (()-

BW373U86³((+)-isomer, SNC-86) and the more δ-selec-

tive methyl ether analogue SNC-80⁴were important

developments, and SAR data around SNC-80 has con-

tinued to be published,⁵but these compounds and their

* To whom correspondence should be addressed. Tel: 514-832-3200,

ext 2406. Fax: 514-832-3232. E-mail: niklas.plobeck@astrazeneca.com.

#

Department of Pharmacology.

^§Present address: Methylgene Inc., 7220 Frederick-Banting, Saint-

Laurent, Quebec, Canada H4S 2A1.

^†Present address: F. Hoffman-LaRoche Ltd., Pharmaceuticals

Division, PRBC, Bldg 015/203, CH-4070 Basel, Switzerland.

Published on Web 09/19/2000

δ Opioid Receptor Agonists: Metabolic Stability

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3879

F igu r e 1. SAR strategy from SNC-80 and compound 1.

Sch em e 1. Synthesis of Piperazines 3 and 4

Sch em e 2. Synthesis of Compounds 1 and 10-16

the piperazine ring has been replaced or altered were

prepared as described in Scheme 2. Reaction between

N,N-diethyl-4-formylbenzamide (5)¹⁰and phenylmag-

nesium bromide or reaction with m-methoxyphenyl-

lithium gave compounds 6 and 7, respectively. Com-

pounds 6 and 7 were subsequently treated with thionyl

chloride to give compounds 8 and 9, respectively, which

were directly treated with the corresponding amine in

acetonitrile to give compounds 1, 10-11, and 13-16.

Reaction with piperazine 4 followed by N-Boc deprotec-

tion with TFA gave the compound 12.

The carbon analogue 19 was obtained using the

synthetic pathway described in Scheme 3. N,N-Diethyl-

4-iodobenzamide (17)¹¹was subjected to lithium-

halogen exchange with t-BuLi in THF at low tempera-

ture followed by the addition of N-Boc-4-benzoylpiperidine

3880 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21

Sch em e 3. Synthesis of Compound 19

Plobeck et al.

Sch em e 4. Preparation of Compounds 20-31

to furnish compound 18 in 94% yield. Reduction of the

benzylic alcohol was effected using triethylsilane in

methylene chloride in the presence of TFA¹²giving

compound 19 in 82% yield.

HCl in AcOH. Esterification of 22 with iodomethane in

DMF in the presence of cesium carbonate gave the ester

23 and after N-Boc cleavage the methyl ester 24. The

tertiary alcohol 25 was prepared by addition of meth-

yllithium to the methyl ester 23 which at the same time

cleaved the N-Boc group. The methyl ketone 26 was

obtained from 22 by treatment with excess methyl-

lithium followed by trimethylsilyl chloride.¹³Different

amides were prepared by the mixed anhydride method¹⁴

by treatment with isobutyl chloroformate followed by

the addition of the corresponding amine. N-Boc depro-

tection gave amides 27-29. Conversion of 22 to the

primary amide as for 27 followed by treatment with

trifluoroacetic anhydride in THF in the presence of

Compounds where the N,N-diethylamide group had

been replaced were prepared using the synthetic path-

way described in Scheme 4. Reduction of the amide with

lithium aluminum hydride in toluene gave the N,N-

diethylaminomethyl compound 20. The N-Boc-protected

acid 22 was prepared from the N,N-diethylamide 1 by

hydrolysis in refluxing 6 N hydrochloric acid followed

by treatment with Boc₂O in THF and used as a general

starting material for the preparation of different deriva-

tives. The acid 21 was prepared by N-Boc cleavage with

δ Opioid Receptor Agonists: Metabolic Stability

Sch em e 5. Preparation of Compound 38

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3881

Sch em e 6. Preparation of Compound 41

Sch em e 7. Preparation of Compound 44

34, followed by O-demethylation with boron tribromide,

gave in 72% yield the phenol 35. The phenyl ring was

introduced using arylcarbonylation¹⁶on the triflate 36.

Thus, treatment of 36 with phenyltributyltin in the

presence of carbon monoxide and palladium acetate, bis-

diphenylphosphinoferrocene as catalyst, in warm DMF

gave after sodium borohydride reduction 93% yield of

the benzylic alcohol 37. Finally chlorination and reaction

with piperazine gave 38 in 64% yield over two steps.

Ketone 41 was prepared following the synthetic route

described in Scheme 6. (4-Bromophenyl)(phenyl)metha-

nol was used as the starting material. Chlorination and

substitution with N-Boc-piperazine in acetonitrile gave

compound 39 in 78% yield for two steps. The ketone

functionality was introduced by lithium-halogen ex-

change on 39 using n-BuLi in THF followed by addition

of 2-ethyl-N-methoxy-N-methylbutanamide¹⁷to give the

protected ketone 40 in 25% yield. N-Boc deprotection

using HCl in acetic acid gave compound 41 in 45% yield.

pyridine gave quantitatively the nitrile 30 where the

Boc protecting group has also been cleaved. The tetra-

zole 31 was prepared by treating 30 with trimethyltin

azide in refluxing toluene.¹⁵

The N-methyl-3,4-dihydroisoquinolone (38) was pre-

pared using the synthetic pathway described in Scheme

5. 3-Methoxyphenethylamine was treated with ethyl

chloroformate giving the corresponding carbamate 32

which was subsequently cyclized with polyphosphoric

acid at 120 °C to give 6-methoxy-3,4-dihydroisoqui-

nolone (33) in 76% yield. N-Methylation of 33 to give

The sulfonamide 44 was prepared using 4-bromoben-

zenesulfonyl chloride which upon treatment with di-

ethylamine in methylene chloride gave compound 42 in

91% yield (Scheme 7). Lithium-halogen exchange with

n-BuLi followed by addition of benzaldehyde furnished

3882 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21

Sch em e 8. Synthesis of Compounds 45-49

Plobeck et al.

tween 17 and n-BuLi in THF at -78 °C to different

quinolinecarboxaldehydes (Scheme 10). The 4-quinoli-

necarboxaldehyde was commercially available, and the

6- and 7-quinolinecarboxaldehydes were obtained from

the corresponding methylquinolines by oxidation with

selenium dioxide. Chlorination and reaction with pip-

erazine gave quinoline analogues 58-60 in good yields.

The 5-isoquinoline analogue 63 was obtained using

the protocol described in Scheme 11. DIBAL reduction

of 5-carbomethoxyisoquinoline in toluene at low tem-

perature gave the aldehyde 61 in 51% yield. The

aldehyde 61 was converted into the piperazine 63 via

the alcohol 62 by the standard procedures.

The synthesis of the indole analogue 67 was effected

using the protocol described in Scheme 12. 6-Formylin-

dole (64) was made from 6-bromoindole¹⁸by deproto-

nation of indole with potassium hydride followed by

lithium-halogen exchange with t-BuLi and quenching

with DMF to give 64.¹⁹Protection of the indole nitrogen

by sulfonylation with phase-transfer catalysis²⁰gave

compound 65 in 54% yield. The standard transforma-

tions via the alcohol 66 gave the 6-indolyl analogue 67

in 51% overall yield. The N-phenylsulfonyl group was

simultaneously cleaved during the reaction with pip-

erazine.

The 2,3-dihydro-2,2-dimethyl-7-benzofuranyl ana-

logue 72 was synthesized starting from 2,3-dihydro-2,2-

dimethyl-7-benzofuranol (Scheme 13). Preparation of

the triflate 68 followed by palladium-catalyzed carbo-

nylation²¹gave the methyl ester 69. The ester was

transformed to the aldehyde 70 by DIBAL reduction to

the alcohol followed by pyridinium dichromate (PDC)

oxidation. The standard transformations via the alcohol

71 led to 72 in 22% overall yield.

the benzylic alcohol 43 in 66% yield. Chlorination and

reaction with piperazine gave the sulfonamide 44 in 76%

yield.

Compounds 45-49 representing different N-alkyl

groups of compound 1 have been prepared as depicted

in Scheme 8. Compound 1 was treated with iodomethane

or with different alkyl bromides in the presence of

potassium carbonate or triethylamine in methylene

chloride or acetonitrile at room temperature to produce

compounds 45-48. Finally, the N-acetyl compound 49

was obtained quantitatively by reaction with acetyl

chloride in methylene chloride.

Resu lts a n d Discu ssion

The pharmacological profile of the compounds was

determined in radioligand binding studies. The binding

affinities (IC₅₀) of the compounds against cloned human

δ, µ, and κ receptors were determined. Agonist potency

(EC₅₀) was measured using the GTP[γ-³⁵S] binding

assay.

A calculation of the binding energy of SNC-80 by

Andrews analysis²²gave a significantly higher binding

energy (∆G_calc) 18.3 kcal/mol) compared to the experi-

mental value (∆G_obs) 12.5 kcal/mol). The large differ-

ence suggested that not all parts of SNC-80 were

Variations of the phenyl ring were made following

reaction sequences described in Scheme 9. Addition of

5 to either Grignard reagents or aryllithium compounds

from metal-halogen exchange between the aryl bromide

and BuLi at low temperature in THF furnished the

corresponding benzylic alcohols in 14-72% yield. The

standard transformations of chlorination and reaction

with piperazine then gave compounds 50-57.

Quinolyl analogues 58-60 were prepared by a similar

synthetic approach utilizing the addition of the lithium

compound derived from lithium-halogen exchange be-

Sch em e 9. Preparation of Compounds 50-57

δ Opioid Receptor Agonists: Metabolic Stability

Sch em e 10. Preparation of Compounds 58-60

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3883

Sch em e 11. Preparation of Compound 63

the number of chiral centers and investigate the effects

of steric bulkiness of the piperazine ring. It was found

that the simple analogue 10 in which the N-allyl group

and the piperazine methyl groups had been removed

had the same selectivity as SNC-80 and retained

significant binding affinity and agonist potency. On the

other hand, an additional methyl group was found to

be tolerated away from the benzylic carbon (11) with

decreased selectivity for δ receptors over µ and κ

receptors, but near the benzylic carbon (12) it led to

much decreased selectivity and also to decreased affinity

and lower δ agonist potency, indicating a less good fit

into the receptor or that inappropriate conformational

effects hinder proper alignment in the receptor.

Next, the structure was further simplified by replac-

ing the aryl methoxy group by hydrogen to give the

simplified piperazine 1 which retained strong δ binding

affinity (IC₅₀) 11 nM), had improved selectivity (µ/δ )

700, κ/δ > 900), and was a full agonist (ED₅₀) 36 nM)

at the human δ receptor. The approach of simplification

of the structure of SNC-80 was independently taken also

by others^5c,eleading to 1^5cand closely related structures.

Sch em e 12. Preparation of Compound 67

Compared with SNC-80, 1 had a reduced molecular

weight from 450 to 350, two of the three chiral centers

were removed, and several possible metabolic sites were

eliminated. Indeed, 1 was found to be considerably more

stable in rat liver microsomes. 60% of 1 remained after

1-h incubation at 10 µM compared to 1% for SNC-80.

The same trend was observed at 100 µM concentration

(Table 2). A radioactive analogue of SNC-80 has been

shown to undergo rapid metabolism in vivo, and the

main metabolite was identified as the O-demethylation

product.⁷In vitro metabolic profiling of SNC-80 and

SNC-86 (see separate section) showed that O-demeth-

ylation and N-deallylation were the major metabolic

reactions. The increased stability of 1 could be explained

by the absence of these two metabolic sites.

optimally involved in binding to the receptor (Figure 1).

This indicated the possibility for deletions and alter-

ations to the structure without a decrease in binding

affinity.

Variations to the piperazine ring are shown in Table

1. Initially, the structure of SNC-80 was altered by

changing the number of substituents in order to reduce

3884 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21

Sch em e 13. Preparation of Compound 72

Plobeck et al.

Using Andrews analysis,²²the difference between

calculated binding energy and observed binding energy

was found to be smaller for 1 (∆G_calc) 14.7 kcal/mol,

∆G_obs) 11.1 kcal/mol, ∆∆G ) -3.6 kcal/mol) than for

SNC-80 (∆G_calc) 18.3 kcal/mol, ∆G_obs) 12.5 kcal/mol,

∆∆G ) -5.7 kcal/mol), indicating that the binding of 1

to the receptor was more optimized, compared to that

for SNC-80 (Scheme 1). Compound 1, containing only

the most essential structural features for binding, was

therefore taken as a new lead compound for further

modifications to improve the pharmacological and DMPK

profile.

complement binding data reported by others for a large

number of substituted amides and amide replacements

in related series.^3,5b,5dRemoval of the carbonyl (20) or

replacement of the nitrogen (41) or one or two of the

ethyl groups (27, 28) all led to much decreased δ

receptor affinity compared with 1. The N,N-dimethyl-

amide (29) had 6 times lower δ binding. Replacement

of the amide with other functional groups such as the

carboxylic acid (21), tetrazole (31), methyl ester (24),

methyl ketone (26), tertiary alcohol (25), or nitrile (30)

all led to a significant drop in affinity (>30-fold). Of the

N,N-diethylamide replacements made, only the N,N-

diethylsulfonamide (44) had comparable binding affinity

and selectivity but was 20 times less potent as an

agonist (Table 3). Torsional constraint to rotation of the

amide bond as in 38 led to a large drop in affinity (>100-

fold), indicating that the alignment of the amide bond

out of the plane of the aromatic ring is necessary for

efficient binding. The X-ray crystal structures published

on two related compounds^5a,9both show the N,N-

diethylamide carbonyl group to be out of plane with the

aromatic ring.

The pharmacophore groups of 1 could be more clearly

identified in comparison with SNC-80, and a binding

model evolved with support from mutagenesis experi-

ments²³showing that amino acid residues of the third

extracellular loop of the δ receptor were important for

recognition and selectivity. The N,N-diethylamide car-

bonyl could interact by hydrogen bonding with a tryp-

tophan side chain (W284) at one side of the extracellular

loop, while at the other end the phenyl group could form

a hydrophobic interaction with a leucine (L300) or valine

(V296) side chain. Subsequently, the lower basic pip-

erazine nitrogen could form an ionic bond with an

aspartic acid (D128) within the transmembrane domain.

A series of lower alkyl substituents on the lower

piperazine nitrogen were made (Table 4), and our

results paralleled and complemented the results re-

ported earlier for this series.^5c,e,fThe methyl derivative

(45) had decreased agonist potency and was only a

partial δ agonist. The allyl derivative (46) was compa-

rable to 1 but showed slightly reduced selectivity,

whereas the cyclopropyl (47) and butyl (48) congeners

had much reduced selectivity (µ/δ ) 68 and 17, respec-

tively). On the other hand, the N-acetyl substituent (49)

led to almost complete loss of binding affinity, again

emphasizing the importance of the basicity of the lower

piperazine nitrogen.

The effect of further changes to the piperazine moiety

in 1 on biological activity was then investigated (Table

1). Similarly to the results by others in this and a closely

related series,^5c,ereplacement of the lower piperazine

ring nitrogen in 1 with carbon or oxygen (13 and 14)^5c

sharply reduced δ binding indicating the loss of an ionic

interaction, as would be expected from the receptor

model. The upper piperazine nitrogen could be replaced

with carbon (19) with marginal effect on binding affinity

compared to 1, which showed that the upper basic

piperazine nitrogen was not directly involved in ionic

bonding to the receptor. However, 19 had 3 times lower

potency as an agonist. The larger seven-membered ring

analogue homopiperazine 15 had comparable binding

affinity but was 10 times less potent as an agonist. The

ring-opened analogue 16 showed a 5-fold decrease in

binding affinity as would be predicted by the increase

in conformational freedom.

Significant improvements were made when modifica-

tions were done to the phenyl ring of 1. The phenyl ring

was replaced with a variety of substituted aryl and

heteroaryl groups (Table 5). First, substitutions on the

phenyl ring were explored. As discussed previously, the

replacement of the 3-methoxy group (10) with hydrogen

(1) was found to increase selectivity for δ over µ and to

retain strong δ binding. Both electron-withdrawing and

-donating groups were tolerated on the phenyl ring (10,

50-53), but substitution in the 4-position tended to

produce less potent agonists (51, 52). Replacement of

the phenyl ring with a cyclohexyl ring (57) gave a sharp

decrease in affinity and selectivity. Increasing the size

The importance of the N,N-diethylamide for binding,

selectivity, and agonist activity in this series of com-

pounds was confirmed by our attempts to find a re-

placement group. A number of N,N-diethylamide re-

placements and isosteres were made (Table 3) that

δ Opioid Receptor Agonists: Metabolic Stability

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3885

Ta ble 1. Binding Affinity and Agonist Activity for Derivatives with Piperazine Ring Substitutions and Piperazine Ring

Replacements^a

a

Average of n g 3 determinations; > signifies n ) 2 determinations.

3886 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21

Plobeck et al.

Ta ble 2. Metabolic Stability of Selected δ Agonists following a

presence of a heteroatom in other positions as in the

4-quinolyl (58) and 6-quinolyl (60) had a strong negative

effect on binding affinity. Other nitrogen heterocycle

derivatives made were the isoquinoline (63) and indole

(67) which also had higher binding affinity and were

comparable in agonist potency to 1. A heterocyclic

derivative with an oxygen hydrogen bond acceptor was

found to be the 2,2-dimethyl-2,3-dihydro-1-benzofuran-

7-yl derivative (72) which gave a 10-fold increase in

binding affinity and 5 times higher agonist potency

compared to 1. Compounds 56 and 72 showed in vitro

metabolic stability in rat liver microsomes comparable

to 1 and markedly superior to SNC-80 (Table 2 and

Metabolic Profiling section).

1-h Incubation in Rat Liver Microsomes

% compound remaining at

agonist

10 µM

100 µM

SNC-80

SNC-86

1

56

72

1 ( 1 (n ) 5)

4 (n ) 2)

60 ( 4 (n ) 4)

52 ( 2 (n ) 3)

43 ( 4 (n ) 4)

24 ( 6 (n ) 5)

59 (n ) 2)

89 ( 4 (n ) 4)

83 ( 5 (n ) 3)

93 ( 2 (n ) 3)

Ta ble 3. Binding Affinity and Agonist Activity for Derivatives

with N,N-Diethylamide Replacements

Meta bolic P r ofilin g of SNC-80, SNC-86, a n d 56.

The main metabolic pathways of SNC-80 in vitro, in rat

liver microsomes, appeared to be N-deallylation (M -

40) and O-demethylation (M - 14) into SNC-86. Both

routes of metabolism accounted for approximately 80%

of SNC-80’s microsomal metabolism in vitro. Under the

same experimental conditions, SNC-86 was slightly

more stable than SNC-80 (Table 2), being essentially

metabolized by N-deallylation (M - 40), which ac-

counted for approximately 85% of its in vitro metabo-

lism. In vitro, 56 was significantly more stable than

either SNC-80 or SNC-86. 56 was mostly metabolized

by N-deethylation (M - 28), which represented 70% of

its in vitro metabolism. Other metabolites included

hydroxylated derivatives (M + 16).

Con clu sion s

The results presented here complement and extend

the scope of SAR studies around diarylmethylpipera-

zines of the SNC-80 type. The initial simplification of

the structure of SNC-80 (Figure 1) by deletions of

substituents led to the lead compound 1 with only the

most essential pharmacophore groups remaining. In 1,

the number of chiral centers was decreased from three

to one, and it had substantially reduced molecular

weight. In addition, 1 had increased in vitro metabolic

stability as predicted by the removal of metabolically

labile sites such as the methyl ether. Further SAR

studies were made on the basis of the lead compound 1

by modifications of the piperazine ring, replacements

of the N,N-diethylamide group, introduction of pipera-

zine N-alkyl substituents, and replacements of the

phenyl ring. The result was the discovery of several new,

more potent and selective δ receptor agonists. In

particular, variations of the phenyl ring led to the more

potent 1-naphthyl (55), 8-quinolyl (56), and 2,2-di-

methyl-2,3-dihydro-1-benzofuran-7-yl (72) derivatives.

The new compounds presented here are potentially

useful as drugs and therefore represent a significant

advance with respect to SNC-80. They have an improved

in vitro profile, a simplified structure, and greater

metabolic stability which, in the case of 56, is manifest

in good oral bioavailability (F ) 33% in the rat) in

contrast to SNC-80.²⁴

of the aromatic group with the aim of increasing the

hydrophobic interactions led to the 1-naphthyl (54) and

2-naphthyl (55) derivatives. Compound 55 had both

improved binding affinity and agonist potency. Addition

of a heteroatom to allow for a hydrogen bond acceptor

atom as in SNC-80 led to the 8-quinolyl derivative (56)

which had significantly higher binding affinity, im-

proved selectivity, and 10-fold increased agonist potency

(IC₅₀) 0.5 nM, µ/δ ) 1239, ED₅₀) 3.6 nM). The

7-quinolyl isomer (59) was almost as potent, but the

Exp er im en ta l Section

Ma ter ia ls a n d Meth od s. Purification by flash chromatog-

raphy was done on silica gel 60 (70-230 mesh), eluting with

gradients of EtOAc in heptane or MeOH (with 1% NH₄OH) in

CH₂Cl₂. Revers-phase chromatography was done on LiChro-

prep RP-18 (40-63 µm) from EM Separations, eluting with

δ Opioid Receptor Agonists: Metabolic Stability

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3887

Ta ble 4. Binding Affinity and Agonist Activity for Derivatives with N-Alkyl Substituents

gradient of acetonitrile in water each containing 0.1% TFA,

followed by lyophilization. Melting points were recorded of the

corresponding salt if not noted otherwise, on a Βu¨chi 535

melting point apparatus and are uncorrected. ¹H and ¹³C NMR

spectra were recorded on a Varian Unity Plus 400 MHz

spectrometer. Spectra in CDCl₃are of the free base and

chemical shifts are given in ppm relative to TMS. In D₂O,

chemical shifts are given relative to DSS. IR spectra were

recorded of the corresponding salt if not noted otherwise, on a

Perkin-Elmer Paragon 1000 FT-IR spectrometer. MS spectra

were obtained on a Hewlett-Packard G1800A GCD system. Dry

solvents with molecular sieves were obtained from Fluka.

Elemental analyses were made by Canadian Microanalytical

Service Ltd., Delta, British Columbia, and were within (0.4%

of calculated values unless noted otherwise.

2,2,5-Tr im eth ylp ip er a zin e (3). N-(tert-Butoxycarbonyl)-

2-methylalanine (5.0 g, 25 mmol) and d,^L-alanine methyl ester

hydrochloride (3.5 g, 25 mmol) were dissolved in CH₂Cl₂(50

mL) and cooled to 0 °C. Et₃N (3.5 mL, 25 mmol) and then 1-(3-

dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)

(4.8 g, 25 mmol) were added and the mixture was stirred at 0

°C until dissolved. The reaction mixture was then left in the

freezer 4 days at -20 °C. The organic solution was washed

with water, 1 M citric acid (aq), water, dried (Na₂SO₄) and

evaporated in vacuo to give 6.0 g (83%) of coupling product.

Most of the coupling product (5 g) was dissolved in formic acid

(50 mL) and stirred 12 h at 25 °C. The acid was removed in

vacuo and the residue dissolved in 2-butanol and heated at

reflux for 4 h. The solution was cooled to 0 °C and the crystals

filtered off and dried in vacuo at 100 °C. Yield 2.6 g of pure

3,3,6-trimethyl-2,5-piperazinedione (2) (82%). The product (2.2

g, 14 mmol) was dissolved in dry THF (120 mL). LiAlH₄(42

mL, 1 M in THF) was added in portions. When addition

complete, the solution was heated at reflux overnight. The

solution was allowed to cool, then excess hydride was destroyed

by dropwise addition of water (1.6 mL), NaOH (1.6 mL, 15%

solution) and water (4.8 mL). The granular precipitate was

filtered off and solvent evaporated in vacuo. The residue was

dissolved in CH₂Cl₂, dried (K₂CO₃) and evaporation of solvent

in vacuo gave 1.5 g of 3 (84%). Treatment with excess HCl in

ether gave the dihydrochloride: mp >300 °C (MeOH/ether);

IR (KBr, ν_max) 2760, 1570 cm^-1; MS 128, 113; ¹H NMR (2xHCl,

D₂O+DSS) δ 0.94-1.00 (s+d, 6H), 1.14 (s, 3H), 2.50-2.70 (m,

5H). Anal. (C₇H₁₇ClN₂) C, H, N.

P r oced u r e A: Gr ign a r d Rea gen t Ad d ition to Ald e-

h yde. N,N-Dieth yl-4-[h ydr oxy(ph en yl)m eth yl]ben zam ide

(6). N,N-Diethyl-4-formylbenzamide (5)¹⁰(19.5 g, 95 mmol)

was dissolved in dry THF, cooled to -78 °C under nitrogen.

Phenylmagnesium bromide (104 mL, 1.0 M in THF) was added

dropwise at -78 °C. After 1 h, NH₄Cl (aq) was added. The

solvent was removed in vacuo, the residue dissolved in EtOAc/

heptane, 1:1, washed with brine and dried (MgSO₄). Evapora-

tion of solvent in vacuo gave 26.5 g of 6 (98%). Spectral data

were identical with those reported.^5a

P r oced u r e B: Or ga n olit h iu m R ea gen t Ad d it ion t o

Ald eh yd e. N,N-Diet h yl-4-[h yd r oxy(3-m et h oxyp h en yl)-

m eth yl]ben za m id e (7). 3-Bromophenyl methyl ether (1.1

mL, 8.5 mmol) was dissolved in THF (25 mL) and cooled to

-78 °C. n-BuLi (6.1 mL, 1.4 M in hexanes, 8.5 mmol) was

added dropwise. After 30 min N,N-diethyl-4-formylbenzamide

(1.7 g, 8.5 mmol) was added dissolved in THF (5 mL). The

solution was stirred 1 h, then NH₄Cl (aq) was added. After

aqueous workup and chromatography on silica (50-70%

EtOAc in heptane) 1.0 g (37%) of 7 was obtained. Spectral data

were identical with those reported.^5a

P r oced u r e C: Ch lor in a t ion of Ben zylic Alcoh ols.

4-[Ch lor o(ph en yl)m eth yl]-N,N-dieth ylben zam ide (8). Com-

pound 6 (24.5 g, 93 mmol) was dissolved in dry CH₂Cl₂(300

mL) and SOCl₂(7.5 mL, 103 mmol) was added. The solution

was stirred at 25 °C for 1 h and the solvent was evaporated in

vacuo. Compound 8 was obtained as an oil (∼100%) and used

in the next reaction without further purification. Spectral data

were identical with those reported.^5a

4-[Ch lor o(3-m eth oxyp h en yl)m eth yl]-N,N-d ieth ylben -

za m id e (9) was prepared analogously to 8 and spectral data

were identical with those reported.^5a

P r oced u r e D: R ea ct ion of Ben zylic Ch lor id es w it h

P ip er a zin es. N,N-Dieth yl-4-[p h en yl(1-p ip er a zin yl)m eth -

yl]ben za m id e (1). Compound 8 (28 g, 93 mmol) and pipera-

zine (40 g, 0.46 mol) were dissolved in dry MeCN (200 mL)

and heated at reflux 12 h. The solvent was removed in vacuo,

the residue dissolved in CH₂Cl₂and washed with 1 M NaOH

3888 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21

Plobeck et al.

Ta ble 5. Binding Affinity and Agonist Activity for Derivatives with Phenyl Ring Replacements

δ Opioid Receptor Agonists: Metabolic Stability

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3889

and the organic phase dried (K₂CO₃) and evaporated in vacuo.

The crude product was recrystallized from MeCN to give 26 g

of 1 (78%). The dihydrochloride salt was prepared with HCl

in ether or with HCl (aq) followed by lyophilization: mp 157-

69 °C; IR (KBr, ν_max) (free amine) 3690, 3630, 1613, 1435, 1265

cm^-1; MS 351, 306, 295, 266, 194, 165; ¹H NMR (CDCl₃) δ 1.1,

1.2 (2 brs, 6H), 1.94 (brs, 1H), 2.36 (brs, 4H), 2.89 (m, 4H),

3.2, 3.5 (2 brs, 4H), 4.24 (s, 1H), 7.16-7.46 (m, 9H). Anal.

(C₂₂H₃₁Cl₂N₃O) C, H, N.

(brs, 2H), 3.58 (brs, 4H), 3.88 (brs, 2H), 4.62 (brs, 1H), 4.82 (s,

1H), 7.45 (m, 5H), 7.96 (m, 4H). Anal. (C₂₂H₂₉ClN₂O₂) C, H,

N.

4-[1,4-Dia zep a n -1-yl(p h en yl)m eth yl]-N,N-d ieth ylben -

za m id e (15). Procedure D. Compound 8 was reacted with

homopiperazine. The product 15 was obtained as an oil (354

mg, 40%). The dihydrochloride salt made with HCl: mp 155-

65 °C (AcOEt-ether); IR (KBr, ν_max) 3418, 1628, 1591, 1074

cm^-1; MS 365, 322, 295, 281, 267, 236, 194, 165; ¹H NMR

(CDCl₃) δ 1.08 (brs, 3H), 1.18 (brs, 3H), 1.69 (m, 2H), 2.56 (s,

1H), 2.62 (m, 4H), 2.85 (m, 2H), 2.97 (m, 2H), 3.23 (brs, 2H),

3.50 (brs, 2H), 4.63 (s, 1H), 7.16 (m, 1H), 7.26 (m, 4H), 7.40

(d, J ) 8.0 Hz, 2H), 7.44 (d, J ) 8.0 Hz, 2H); ¹³C NMR (CDCl₃)

δ 12.6, 14.0, 30.7, 39.0, 43.1, 46.9, 49.6, 52.9, 56.1, 74.9, 126.4,

126.7, 127.6, 127.7, 128.3, 135.5, 142.9, 144.8, 171.0. Anal.

(C₂₃H₃₃Cl₂N₃O) C, H, N.

N ,N -Die t h yl-4-[(3-m e t h oxyp h e n yl)(1-p ip e r a zin yl)-

m eth yl]ben za m id e (10). Procedure D. Compound 9 was

reacted with piperazine to give 10. Dihydrochloride made with

HCl in ether: mp 165-82 °C; IR (KBr, ν_max) (free amine) 3688,

1611, 1458, 1436, 1285 cm^-1; MS 381, 336, 296, 224, 196, 165,

152, 112; ¹H NMR (CDCl₃) δ 1.05, 1.15 (2 brs, 6H), 2.51, 3.02

(2 brs, 8H), 3.2, 3.45 (2 brs, 4H), 3.72, 3.73 (2s, 3H), 4.21 (s,

1H), 4.5 (brs, 1H), 6.60-7.40 (m, 8H). Anal. (C₂₃H₃₃Cl₂N₃O)

C, H, N.

N,N-Dieth yl-4-[{m eth yl[2-(m eth yla m in o)eth yl]a m in o}-

(p h en yl)m eth yl]ben za m id e (16). Procedure D. Compound

8 (0.11 g, 0.36 mmol) was reacted with N¹,N²-dimethyl-1,2-

ethanediamine (0.32 mL, 3.0 mmol). Purification with reverse

phase chromatography (TFA in mobile phase) gave 16 (0.20

g, 97%) as the ditrifluoroacetate: mp 40-50 °C (H₂O); IR (KBr,

N,N-Diet h yl-4-[(3-m et h oxyp h en yl)(2,5,5-t r im et h yl-1-

p ip er a zin yl)m eth yl]ben za m id e (11). Compound 9 (0.61 g,

2.0 mmol) and 3 (0.50 g, 3.9 mmol) were dissolved in dry MeCN

(5 mL). K₂CO₃(0.26 g, 2.0 mmol) was added and the mixture

heated at reflux for 48 h. The solvent was removed in vacuo

and the residue purified by chromatography on silica (CH₂-

Cl₂/MeOH/NH₃(aq), 98:1:1 to 95:5:1) to yield 0.65 g of 11 (79%).

Treatment with excess of HCl in ether, filtering and drying

crystals in vacuo over KOH gave the dihydrochloride: mp

ν

_max) 3029, 2487, 2788, 2282, 1705, 1667, 1596 cm^-1; ¹H NMR

(CD₃OD) δ 1.04-1.16 (br, 3 H), 1.16-1.28 (br, 3 H), 2.52 (s, 3

H), 2.68 (s,3 H), 2.96-3.06 (br, 2 H), 3.20-3.35 (br, 4 H), 3.48-

3.58 (br, 2 H), 4.89 (s, 2 H), 4.97 (s, 1 H), 7.32-7.41 (m, 5 H),

7.57 (d, J ) 7.6 Hz, 2 H), 7.68 (d, J ) 7.6 Hz, 2 H). Anal.

(C₂₆H₃₃F₆N₃O₅) C, H, N.

134-6 °C; IR (KBr, ν_max) 3400, 2900, 1600, 1283, 1038 cm^-1

;

P r oced u r e E: Lith iu m -Ha logen Exch a n ge a n d Rea c-

tion w ith Electr op h ile. N,N-Diethyl-4-iodobenzamide (17)

(0.60 g, 2.0 mmol) was dissolved in THF (10 mL) and cooled

to -78 °C under nitrogen atmosphere. n-BuLi (1.2 mL, 1.6 M

solution in hexane, 2.0 mmol) was added dropwise. Stirring

was continued for 30 min at -78 °C. The electrophile (2.0

mmol) was added dropwise dissolved in THF (2 mL). The

temperature was allowed to reach room temperature and after

NH₄Cl (aq) addition, extraction with EtOAc, drying (MgSO₄)

and evaporation of the organic phase, the residue was purified

by chromatography on silica.

1

MS 423, 353, 325, 296, 127; H NMR (CDCl₃) δ 0.9-1.3 (m,

15H), 2.0-3.1 (m, 5H), 3.2, 3.4 (2 brs, 4H), 3.70 (s, 3H), 4.61,

5.25, 5.26 (3s, 1H), 6.60-7.40 (m, 8H). Anal. (C₂₆H₃₉Cl₂N₃O₂)

C, H, N.

N,N-Diet h yl-4-[(3-m et h oxyp h en yl)(2,2,5-t r im et h yl-1-

p ip er a zin yl)m eth yl]ben za m id e (12). Compound 3 (42 mg,

0.33 mmol) and K₂CO₃(46 mg, 0.33 mmol) were dissolved in

water (2 mL) and di-tert-butyl dicarbonate (79 mg, 0.36 mmol)

was added. After stirring 1 h the solvent was evaporated in

vacuo and the residue purified by chromatography on silica

(CH₂Cl₂/MeOH, 90:10) to give 43 mg of tert-butyl 2,5,5-

trimethyl-1-piperazinecarboxylate (4) which was dissolved in

dry MeCN together with K₂CO₃(26 mg, 0.19 mmol) and 9 (63

mg, 0.19 mmol). After heating 4 days at reflux, the solvent

was removed in vacuo and residue purified by chromatography

on silica (0-5% MeOH in CH₂Cl₂). Treatment with TFA (5 mL)

for 3 h, evaporation of solvent in vacuo and extraction of the

residue with CH₂Cl₂/1 M NaOH, drying of the organic phase

(K₂CO₃) and evaporation of solvent in vacuo gave 27 mg (33%)

of 12. Treatment with excess HCl in ether gave the dihydro-

chloride which was dissolved in water and lyophilized: mp

P r oced u r e F . Alternatively the lithium-halogen exchange

was done as for procedure E but with t-BuLi (2 equiv) instead

of n-BuLi (1 equiv).

ter t-Bu t yl

4-[{4-[(Diet h yla m in o)ca r bon yl]p h en yl}-

(h yd r oxyp h en yl)m eth yl]-1-p ip er id in eca r boxyla te (18). A

mixture of 4-benzoylpiperidine hydrochloride (6.77 g, 30.0

mmol), di-tert-butyl dicarbonate (7.2 g, 33.0 mmol) and KHCO₃

(6.0 g, 60 mmol) in H₂O-THF (50/20 mL) was refluxed for 1

h. The reaction mixture was extracted with EtOAc (2 × 100

mL). The combined organic layers were washed with brine and

dried (MgSO₄). Removal of solvents gave tert-butyl 4-benzoyl-

1-piperidinecarboxylate (8.54 g, 98%): ¹H NMR (CDCl₃) δ 1.47

(s, 9H), 1.70 (m, 2H), 1.83 (m, 2H), 2.91 (m, 2H), 3.42 (m, 1H),

4.18 (brs, 2H), 7.46 (m, 2H), 7.56 (m, 1H), 7.93 (m, 2H).

Following procedure F, 17 (6.67 g, 22.0 mmol) in dry THF (70

mL) and t-BuLi (18.0 mL, 2.5 M, 45.0 mmol) and tert-butyl

4-benzoyl-1-piperidinecarboxylate (4.34 g, 15.0 mmol) gave a

crude product, which was purified by silica gel column (0-5%

MeOH in CH₂Cl₂) to provide 18 (6.56 g, 94%): mp 100-3 °C

(CH₂Cl₂); IR (KBr, ν_max) 3426, 2973, 1687, 1618, 1428, 1289,

145-50 °C; IR (KBr, ν_max) 3500-3400, 1601, 1442, 1285 cm^-1

;

1

MS 423, 296, 325, 127; H NMR (CDCl₃) δ 0.85 (s, 3H), 0.90

(d, 3H), 1.15 (s, 3H), 1.0-1.25 (brm, 6 H), 1.5 (brs, 1H), 2.05,

2.50, 2.80 (3m, 5H), 3.25, 3.5 (2 brs, 4H), 3.75 (s, 3H), 5.36,

5.39 (2s, 1H), 6.6-7.4 (m, 8H). Accurate mass determination

of 12 with the calculated monoisotopic mass of 424.2964 Da

was detected as 424.2973 Da (error 2.12 ppm).

N,N-Diet h yl-4-[p h en yl(1-p ip er id in yl)m et h yl]b en za -

m id e (13). Procedure D. Compound 8 was reacted with

piperidine. Compound 13 was obtained in 68% yield (0.18 g).

The hydrochloride was made with HCl in ether: mp (free base)

124-5 °C (EtOAc-petroleum ether); IR (KBr, ν_max) 2925, 2793,

1620, 1447, 1281, 1095 cm^-1; ¹H NMR (CDCl₃) δ 1.07 (brs, 3H),

1.17 (brs, 3H), 1.39 (d, 2H), 1.52 (m, 4H), 2,29 (brs, 4H), 3.21

(brs, 2H), 3.48 (brs, 2H), 4.20 (s, 1H), 7.16-7.42 (m, 9H). Anal.

(C₂₃H₃₀N₂O) C, H, N.

1

1168 cm^-1; H NMR (CDCl₃) δ 1.08 (brs, 3H), 1.20 (brs, 3H),

1.30 (m, 4H), 1.41 (s, 9H), 2.50 (t, J ) 11.2 Hz, 1H), 2.66 (m,

2H), 2.86 (s, 1H), 3.22 (brs, 2H), 3.50 (brs, 2H), 4.09 (brs, 2H),

7.18 (m, 1H), 7.26 (m, 4H), 7.45 (m, 4H); ¹³C NMR (CDCl₃) δ

12.8, 14.1, 26.2, 28.3, 39.1, 43.2, 44.3, 53.3, 79.2, 79.4, 125.75,

125.79, 126.2, 126.6, 128.1, 135.1, 145.3, 146.8, 154.6, 171.0.

N,N-Diet h yl-4-[p h en yl(4-p ip er id in yl)m et h yl]b en za -

m id e (19). To a solution of 18 (3.26 g, 7.0 mmol) and

triethylsilane (2.44 g, 21.0 mmol) in dry CH₂Cl₂(20 mL) was

added trifluoroacetic acid (30.0 mL) at 25 °C. The reaction

mixture was stirred for 3 days at 25 °C and then concentrated

in vacuo. The residue was dissolved in AcOEt (100 mL). The

resulting solution was washed with 1 M NaOH solution,

aqueous NH₄Cl solution and brine, dried over MgSO₄. Removal

of solvents gave a crude product, which was purified by silica

N,N-Diet h yl-4-[4-m or p h olin yl(p h en yl)m et h yl]b en za -

m id e (14). Procedure D. Compound 8 was reacted with

morpholine. Compound 14 was obtained in 78% yield (0.15 g).

The hydrochloride was made with HCl in ether: mp (free base)

143.5-6 °C (EtOAc-ether); IR (KBr, ν_max) 3488, 2973, 2362,

1

1622, 1438, 1288, 1128, 1076 cm^-1; H NMR (CDCl₃) δ 1.11

(brs, 3H), 1.20 (brs, 3H), 1.67 (brs, 2H), 2.27 (brs, 2H), 3.23

3890 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21

Plobeck et al.

gel column eluting with NH₄OH (1 N)-MeOH-CH₂Cl₂(2.5:

15:82.5) to provide 19 (2.0 g, 82%): mp 160-2 °C (CH₂Cl₂); IR

(KBr, ν_max) 3325, 2937, 1613, 1461, 1283, 1095 cm^-1; ¹H NMR

(CDCl₃) δ 1.05 (brs, 3H), 1.07 (m, 2H), 1.19 (brs, 3H), 1.53 (m,

2H), 2.04 (brs, 1H), 2.20 (m, 1H), 2.55 (t, J ) 11.6 Hz, 2H),

3.01 (m, 2H), 3.23 (brs, 2H), 3.51 (d, J ) 10.4 Hz, 1H), 3.52

(brs, 2H), 7.15 (m, 1H), 7.27 (m, 8H); ¹³C NMR (CDCl₃) δ 12.8,

14.1, 32.2, 39.0, 39.9, 43.1, 46.5, 59.0, 126.1, 126.5, 127.9, 128.0,

128.3, 134.8, 143.0, 144.7, 171.0. Anal. (C₂₃H₃₁ClN₂O) C, H,

N.

(aq) was added and the organic phase decanted off and

evaporated in vacuo. Chromatography on silica, (0 to 5%

methanol in CH₂Cl₂with 1% NH₄OH) gave 0.11 g (76%) of

26. Dihydrochloride salt made with HCl (ether): mp 175-85

°C (ether); IR (KBr, ν_max) 3400, 2700, 1680, 1607, 1424, 1269

cm^-1; MS 294, 249, 209, 165; ¹H NMR (CDCl₃) δ 2.40 (m, 4H),

2.43 (s, 3H), 2.92 (m, 4H), 4.22 (s, 1H), 7.04-7.77 (m, 9H).

Anal. (C₁₉H₂₄Cl₂N₂O) C, H, N.

4-[P h en yl(1-p ip er a zin yl)m eth yl]ben za m id e (27). Pre-

pared analogously to 28. Reaction with excess NH₃(1 M

solution in CH₂Cl₂). Compound 27 obtained in 62% yield (70

mg). Dihydrochloride made with HCl in ether: mp 192-200

°C (ether); IR (KBr, ν_max) 3939, 3184, 2700, 1665, 1610, 1565,

N-Eth yl-N-{4-[p h en yl(1-p ip er a zin yl)m eth yl]ben zyl}-1-

eth a n a m in e (20). Compound 1 (0.10 g, 0.28 mmol) was

dissolved in toluene (2 mL) and treated with LiAlH₄(0.56 mL,

1 M in THF, 0.56 mmol) at 25 °C for 12 h. After adding silica

gel, concentration in vacuo and chromatography on silica (0-

20% MeOH in CH₂Cl₂(1% NH₄OH), 83 mg (88%) of 20 was

obtained. Treatment with HCl in ether gave trihydrochloride

salt: mp 185-95 °C (ether); IR (KBr, ν_max) 3661, 2650, 1590,

1426 cm^-^{1 1}H NMR (amine, CD₃OD) δ 2.46, 2.94 (2m, 8H),

;

4.40 (s, 1H), 4.93 (s, 2H), 7.22-7.96 (m, 9H). Anal. (C₁₈H₂₃

Cl₂N₃O) C, H, N.

-

4-((1-P ip er a zin yl)ben zyl)-N-eth ylben za m id e (28). Com-

pound 22 (0.12 g, 0.31 mmol) was dissolved in dry THF (5 mL)

under nitrogen atmosphere and cooled to -20 °C. Et₃N (87

µL, 0.62 mmol) and isobutyl chloroformate (40 µL, 0.31 mmol)

were added. Stirring was continued for 10 min, then ethyl-

amine (0.31 mL, 0.62 mmol) was added and temperature was

allowed to rise to 25 °C. After 3 h, the solvent was evaporated

and the residue treated with excess TFA for 30 min. Evapora-

tion of solvent in vacuo and chromatography on silica, 0 to

20% methanol (with 10% NH₄OH), in CH₂Cl₂gave 69 mg (69%)

of 28.The dihydrochloride salt was made by treatment with

excess HCl in ether, filtering and drying in vacuo over

NaOH: mp 180-5 °C; IR (KBr, ν_max) 3331, 2700, 1640, 1545,

1437, 1325 cm^-^{1 1}H NMR (CDCl₃) δ 0.98 (m, 6H), 2.45 (m,

;

4H), 2.33, 2.85 (2 brs, 8H), 3.0 (s, 1H), 3.45, 3.50 (2s, 2H), 4.17

(s, 1H), 7.40-7.09 (m, 9H). Anal. (C₂₂H₃₄Cl₃N₃) C, H, N.

4-[P h en yl(1-p ip er a zin yl)m eth yl]ben zoic Acid Dih y-

d r och lor id e (21) a n d 4-[[4-(ter t-Bu toxyca r bon yl)-1-p ip -

er a zin yl](p h en yl)m eth yl]ben zoic Acid (22). Compound 1

(6.0 g, 17 mmol) was heated at reflux in 6 N HCl (50 mL) for

72 h. The solution was made basic with NaOH, then di-tert-

butyl dicarbonate (3.7 g, 17 mmol) was added in THF (100

mL). After 1 h the solution was acidified with 1 M citric acid

and extracted with EtOAc. The organic phase was dried

(MgSO₄) and evaporated in vacuo and the residue purified by

chromatography on silica (EtOAc/heptane/AcOH, 10:90:0 to

66: 33:1) which gave 22 (3.85 g, 57%). Treatment with HCl

in AcOH (4 equiv, 1 M solution) for 1 h, then evaporation of

solvent in vacuo, dissolving in water and freeze-drying gave

21 as a white powder: mp 172-80 °C; IR (KBr, ν_max) 3000,

1

1440, 1308 cm^-1; MS 323, 278, 267, 238, 195, 165; H NMR

(CD₃OD) δ 1.20 (m, 3H), 2.65, 3.25 (2m, 8H), 3.40 (m, 2H),

4.45 (s, 1H), 4.9 (brs, 1H), 7.14-7.84 (m, 9H). Anal. (C₂₀H₂₇

Cl₂N₃O) C, H, N.

-

N,N-Dim eth yl-4-[p h en yl(1-p ip er a zin yl)m eth yl]ben za -

m id e (29). Prepared analogously to 28. Reaction with excess

dimethylamine (2 M solution in THF). Compound 29 obtained

in 97% yield (0.40 g). Dihydrochloride made with HCl in

ether: mp 182-90 °C; IR (KBr, ν_max) 3372, 2953, 2698, 2480,

1620, 1492, 1448, 1405, 1266, 1084 cm^-1; MS 323, 278, 267,

1

1700, 1606, 1454 cm^-1; H NMR (DMSO-d₆) δ 12.85 (s, 1H),

8.95 (s, 2H), 7.92-7.20 (m, 9H), 4.56 (s, 1H), 3.33 (s, 8H). Anal.

(C₁₈H₂₁ClN₂O₂) C, H, N.

Meth yl 4-[P h en yl(1-p ip er a zin yl)m eth yl]ben zoa te (24).

Compound 22 (0.87 g, 2.2 mmol) was dissolved in dry DMF (5

mL) and potassium carbonate (0.33 g, 2.4 mmol) and methyl

iodide (0.22 mL, 3.5 mmol) were added. After stirring 12 h

the methyl ester was isolated by extraction with EtOAc and

washing with water and brine followed by evaporation in

vacuo. The methyl ester 23 (0.13 g, 0.31 mmol) was treated

with excess HCl in MeOH for 30 min, the solvent was

evaporated and the residue purified by chromatography on

silica, 0 to 10% methanol in CH₂Cl₂(with 10% NH₄OH), to

give 24 (35 mg, 38%). Treatment with HCl in ether gave the

dihydrochloride: mp 185-95 °C (ether); IR (KBr, ν_max) 3400,

2700, 1720, 1612, 1430, 1285, 1190, 1112 cm^-1; ¹H NMR (D₂O/

CD₃OD +DSS) δ 3.08 (m, 4H), 3.42 (m, 4H), 3.89 (s, 3H), 5.03

(s, 1H), 7.34-8.20 (m, 9H). Anal. (C₁₉H₂₄Cl₂N₂O₂) C, H, N.

1

238, 194, 165; H NMR (CDCl₃) δ 1.8 (s, 1H), 2.32, 2.85 (2m,

8H), 2.9, 3.0 (2 brs, 6H), 4.20 (s, 1H), 7.10-7.44 (m, 9H). Anal.

(C₂₀H₂₇Cl₂N₃O) C, H, N.

4-[P h en yl(1-piper azin yl)m eth yl]ben zon itr ile (30). Com-

pound 22 (0.11 g, 0.28 mmol) was converted to the amide as

for 27 but without TFA treatment. The amide (45 mg, 0.11

mol) was dissolved in dry THF (2 mL) and cooled to 0 °C.

Pyridine (36 µL, 0.44 mmol) and trifluoroacetic anhydride (31

µL, 0.22 mmol) were added and stirring was continued for 1 h

at 25 °C. Water was added and the solution was extracted with

EtOAc. The organic phase was washed with dilute NaHCO₃

(aq), dried (K₂CO₃) and evaporated in vacuo. The residue was

treated with HCl in MeOH 3 h at 50 °C. Removal of solvent

in vacuo and chromatograpy on silica (CH₂Cl₂/MeOH/NH₃, 90:

10:1) of residue gave 15 mg (49%) of 30. Treatment with excess

HCl in ether/MeOH gave the dihydrochloride: mp 141-5 °C;

IR (KBr, ν_max) 3400, 2700, 2230, 1434 cm^-1; MS 277, 232, 192,

165; ¹H NMR (CDCl₃) δ 1.70 (s, 1H), 2.35, 2.89 (2m, 8H), 4.27

(s, 1H), 7.18-7.58 (m, 9H). Anal. (C₁₈H₂₁Cl₂N₃) C, H, N.

1-{P h en yl[4-(1H-1,2,3,4-tetr a a zol-5-yl)p h en yl]m eth yl}-

p ip er a zin e (31). Trimethylsilyltin azide (0.21 g, 1.0 mmol)

was added to 30 (0.25 g, 0.9 mmol) in toluene (10 mL) and

heated at 110 °C under inert atmosphere. After 24 h, another

portion of azide was added and heating continued for 48 h.

The solution was cooled to 0 °C and filtered. The beige solid

was dissolved in MeOH (5 mL) and stirred with concentrated

HCl (1 mL) at 60 °C for 15 min. Solvent was removed in vacuo

and chromatography on silica, 0 to 50% methanol (with 10%

NH₄OH) in CH₂Cl₂gave 65 mg 31 (22%). Dihydrochloride salt

with HCl (ether): mp >240 °C dec; IR (KBr, ν_max) 3405, 2912,

2663, 1567, 1496, 1442, 1302, 1067 cm^-1; ¹H NMR (amine, CD₃-

OD) δ 2.74, 3.34 (2s, 8H), 4.55 (s, 1H), 7.28-8.08 (m, 9H). Anal.

(C₁₈H₂₂Cl₂N₆) C, H, N.

2-{4-[P h e n yl(1-p ip e r a zin yl)m e t h yl]p h e n yl}-2-p r o-

p a n ol (25). Compound 23 (0.13 g, 0.31 mmol) was dissolved

in dry THF (5 mL) under nitrogen atmosphere and cooled to

-78 °C. Methyllithium (3.8 mL, 0.9 M in ether, 3.4 mmol) was

added and the temperature was allowed to reach 0 °C before

NH₄Cl (aq) was added and the reaction was worked up by

extraction with CH₂Cl₂. The organic phase was evaporated in

vacuo and chromatography on silica, 0 to 10% methanol (with

10% NH₄OH), in CH₂Cl₂gave 26 mg (25%) of 25. Dihydro-

chloride salt made with HCl (ether): mp 180-90 °C (ether);

IR (KBr, ν_max) (free amine) 3308, 2650, 1588, 1431, 1379 cm^-1

MS 310, 265, 254, 225, 206, 165; H NMR (CDCl₃) δ 1.52 (s,

6H), 2.34 (s, 4H), 2.47 (s, 2H), 2.85 (m, 4H), 4.19 (s, 1H), 7.14-

7.42 (m, 9H). Anal. (C₂₀H₂₈Cl₂N₂O) C, H, N.

;

1

1-{4-[P h e n yl(1-p ip e r a zin yl)m e t h yl]p h e n yl}-1-e t h a -

n on e (26). Compound 22 (0.20 g, 0.50 mmol) was dissolved

in dry THF (5 mL) under nitrogen atmosphere and cooled to

0 °C. MeLi (3.1 mL, 0.8 M in ether, 2.5 mmol) was added over

1 min. The reaction was stirred for 2 h, then trimethylsilyl

chloride (0.63 mL, 5.0 mmol) was added in one portion and

the temperature allowed to reach 25 °C. A solution of NH₄Cl

Eth yl 3-Meth oxyp h en eth ylca r ba m a te (32), 6-Meth oxy-

3,4-dih ydr o-1(2H)-isoqu in olin on e (33), 6-Meth oxy-2-m eth -

δ Opioid Receptor Agonists: Metabolic Stability

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3891

yl-3,4-d ih yd r o-1(2H)-isoqu in olin on e (34), 6-Hyd r oxy-2-

m eth yl-3,4-d ih yd r o-1(2H)-isoqu in olin on e (35), 2-Meth -

yl-1-oxo-1,2,3,4-tetrahydro-6-isoquinolinyl Trifluoromethane-

su lfon a te (36), 6-[Hyd r oxy(p h en yl)m eth yl]-2-m eth yl-3,4-

dih ydr o-1(2H)-isoqu in olin on e (37), an d 2-Meth yl-6-[ph en -

yl(1-p ip er a zin yl)m et h yl]-3,4-d ih yd r o-1(2H )-isoq u in oli-

n on e (38). 2-(3-Methoxyphenyl)-1-ethanamine (5 g, 33 mmol)

was dissolved in CH₂Cl₂(100 mL) with Et₃N (5.1 mL, 36 mmol)

at 0 °C. Ethyl chloroformate (3.5 mL, 36 mmol) was added and

stirring was continued 1.5 h. After aqueous workup, 7.6 g

(100%) of ethyl 3-methoxyphenethylcarbamate (32) was ob-

tained. Compound 32 was treated with polyphosphoric acid

(PPA) (30 g) at 120 °C under nitrogen atmosphere for 1.5 h.

After addition of water and repeated extraction with EtOAc,

a total of 6.4 g (76%) of 6-methoxy-3,4-dihydro-1(2H)-isoquino-

linone (33) was obtained. Compound 33 (3.1 g, 17 mmol) was

dissolved in THF/toluene 1:1 (80 mL) and NaH (60% in oil,

7.0 g, 175 mmol) was added in portions. Methyl iodide (5.5

mL, 87 mmol) was added and stirring was continued for 2 h.

The reaction mixture was slowly added to 1 N HCl (aq). After

extractive workup with EtOAc, crude 34 (1.6 g, 8.8 mmol, 77%)

was obtained. Compound 34 was dissolved in CH₂Cl₂(45 mL)

and BBr₃(18 mL, 1 M in CH₂Cl₂, 18 mmol) was added at -78

°C and solution was stirred at 25 °C overnight. MeOH was

added at 0 °C until all was dissolved and the solvent was

removed in vacuo. Extractive workup with EtOAc and 1 N HCl

(aq) gave 35 (0.80 g, 4.5 mmol, 94%). Compound 35 (0.40 g,

2.2 mmol) and pyridine (0.36 mL, 4.5 mmol) were dissolved

in CH₂Cl₂(10 mL), then trifluoromethanesulfonic anhydride

(0.45 mL, 2.7 mmol) was added dropwise at 0 °C and the

reaction mixture was allowed to reach 25 °C. Aqueous workup

with EtOAc and 1 N HCl followed by chromatography on silica

(20% EtOAc in hexane) gave 36 (0.30 g, 0.97 mmol) and

recovered 35 (0.12 g). Compound 36 (0.20 g, 0.65 mmol) was

dissolved in DMF (4 mL) and tributyl(phenyl)stannane (0.26

g, 0.71 mmol) was added. Carbon monoxide was passed

through the solution 2-3 min, then palladium acetate (15 mg,

67 µmol) and diphenylphosphinoferrocene (dppf) (72 mg, 0.13

mmol) were added and the mixture heated at 70 °C under a

CO atmosphere. After 12 h, Aqueous workup with EtOAc and

1 N HCl followed by chromatography on silica (EtOAc) gave

the crude coupling product (0.12 g, 0.45 mmol). Reduction with

NaBH₄(25 mg, 0.66 mmol) in MeOH (3 mL) gave 37 (72 mg,

0.27 mmol, 93%). Treatment of 37 following procedures C and

D gave 38 (58 mg, 65%): IR (KBr, ν_max) (free amine) 2943,

7.53 (d, J ) 8.4 Hz, 2H), 7.87 (d, J ) 8.4 Hz, 2 H). Anal.

(C₂₇H₃₂F₆N₂O₄) C, H, N.

4-Br om o-N,N-d iet h ylb en zen esu lfon a m id e (42), N,N-

D ie t h y l-4-[h y d r o x y (p h e n y l)m e t h y l]b e n ze n e s u lfo n -

a m id e (43), a n d N,N-Dieth yl-4-[p h en yl(1-p ip er a zin yl)-

m eth yl]ben zen esu lfon a m id e (44). 4-Bromobenzenesulfonyl

chloride (0.50 g, 2.0 mmol) was treated with diethylamine (0.61

mL, 5.9 mmol) in CH₂Cl₂(20 mL) at 0 °C and stirred 12 h at

25 °C. After aqueous workup with 1 N HCl (aq) and chroma-

tography on silica (EtOAc in hexane), 42 (0.52 g, 1.8 mmol)

was obtained. Compound 42 was treated with n-BuLi and

benzaldehyde following procedure B to give 43 (0.18 g, 0.57

mmol). Treatment of 43 following procedures C and D gave

44 (0.15 g, 71%): mp >220 °C; IR (NaCl, ν_max) 3055, 2986,

1

1423, 1265 cm^-1; H NMR (CDCl₃) δ 1.11 (t, J ) 7.2 Hz, 6H),

2.64 (m, 4H), 3.18 (m, 8H), 4.37 (s, 1H), 7.27 (m, 5H), 7.51 (d,

J ) 8.4 Hz, 2H), 7.71 (d, J ) 8.4 Hz, 2H). Anal. (C₂₁H₂₉N₃O₂S)

C, H, N.

P r oced u r e G: N-Alk yla tion of P ip er a zin e Com p ou n d s.

4-[(4-Allyl-1-p ip er a zin yl)(p h en yl)m et h yl]-N,N-d iet h yl-

ben za m id e (46). Compound 1 (0.30 g, 0.85 mmol) was

dissolved in MeCN (5 mL). K₂CO₃(0.17 g, 1.3 mmol) and allyl

bromide (110 µL, 1.3 mmol) were added. After 3 h at 25 °C

the solvent was evaporated and the residue purified by

chromatography on silica (0-5% MeOH in CH₂Cl₂), to give a

total of 0.26 g 46 (79%). Treatment with HCl in ether gave

the dihydrochloride salt: mp 175-205 °C; IR (KBr, ν_max) (free

amine) 3689, 1613, 1455, 1434, 1290, 1143 cm^-1; MS 391, 165,

125; ¹H NMR (CDCl₃) δ 1.1 (2 brs, 6H), 2.4-2.6 (brs, 8H), 3.00

(m, 2H), 3.2, 3.5 (2 brs, 4H), 4.23 (s, 1H), 5.10 (m, 2H), 5.81

(m, 1H), 7.12-7.42 (m, 9H). Anal. (C₂₅H₃₇Cl₂N₃O) C, H, N.

N,N-Dieth yl-4-[(4-m eth yl-1-p ip er a zin yl)(p h en yl)m eth -

yl]ben za m id e (45). Procedure G. Alkylation with methyl

iodide gave 60 mg (29%) of 45: mp 180-5 °C (ether); IR (KBr,

ν

_max) 3328, 2978, 2485, 1603, 1449, 1361, 1292, 1180, 1100

cm^-1; ¹H NMR (CDCl₃) δ 1.1, 1.2 (2 m, 6H), 2.27 (s, 3H), 2.3-

2.6 (m, 8H), 3.2, 3.5 (2 m, 4H), 3.50 (s, 2H), 4.24 (s, 1H), 7.10-

7.50 (m, 14H). Anal. (C₂₃H₃₃Cl₂N₃O) C, H, N.

4-[[4-(Cyclop r op ylm e t h yl)-1-p ip e r a zin yl](p h e n yl)-

m eth yl]-N,N-d ieth ylben za m id e (47). Procedure G. Alkyla-

tion with cyclopropyl chloride (0.18 g, 2 mmol), KI (0.30 g, 2

mmol) and K₂CO₃(0.28 g, 2 mmol) gave 0.21 g of 47 (52%).

Dihydrochloride made with HCl in ether: IR (KBr, ν_max) 3679,

3431, 3050, 2977, 2389, 1624, 1433, 1275 cm^-^{1 1}H NMR

;

(CDCl₃) δ 0.08 (m, 2H), 0.48 (m, 2H), 0.85 (m, 1H), 1.10 (brs.,

6H), 2.25 (d, J ) 6.8 Hz, 2H), 2.50 (m, 8H), 3.24 (br d, 2H),

3.50 (brs, 2H), 4.26 (s, 1H), 7.18 (m, 1 H), 7.28 (m, 4H), 7.41

(m, 4H). Anal. (C₂₆H₃₇Cl₂N₃O) C, H, N.

1

2818, 1643, 1491, 1446, 1335, 1265 cm^-1; H NMR (CDCl₃) δ

2.42 (bs, 4H), 2.94 (m, 6H), 3.08 (s, 3H,), 3.48 (t, J ) 6.8 Hz,

2H), 4.21 (s, 1H), 7.15-7.39 (m, 7H), 7.94 (d, J ) 8 Hz, 1H).

Anal. (C₂₁H₂₇Cl₂N₃O) C, H, N.

4-[(4-Bu tyl-1-p ip er a zin yl)(p h en yl)m eth yl]-N,N-d ieth -

ylben za m id e (48). Procedure G. Compound 1 (0.20 g, 0.57

mmol) and Et₃N (0.80 mmol) were dissolved in dry CH₂Cl₂(15

mL), followed by the addition of the 1-iodobutane (0.52 g, 2.8

mmol); the reaction mixture was stirred at room temperature

for 48 h. Compound 48 (0.20 g, 84%) was obtained. The

dihydrochloride salt was made with HCl in ether: mp 212-4

°C dec; IR (amine, NaCl, ν_max) 3439, 2967, 2414, 1621, 1439,

1288 cm^-1; ¹H NMR (CDCl₃) δ 0.91 (t, J ) 7.2 Hz, 3H), 1.10-

1.26 (br, 6H), 1.32 (m, 2H), 1.53 (m, 2H), 2.42 (m, 2H), 2.46-

2.70 (br, 8H), 3.16-3.60 (br, 4H), 4.27 (s, 1H), 7.19-7.45 (m,

9H). Anal. (C₂₆H₃₉Cl₂N₃O) C, H, N.

ter t-Bu tyl 4-[(4-Br om op h en yl)(p h en yl)m eth yl]-1-p ip -

er a zin eca r boxyla te (39). (4-Bromophenyl)(phenyl)methanol

was treated according to procedure C and then according to

procedure D with tert-butyl 1-piperazinecarboxylate, diisopro-

pylethylamine, and a catalytic amount of potassium iodide to

give 39 in 80% yield: mp 136-9 °C (EtOAc/hexane); ¹H NMR

(CDCl₃) δ 1.43 (s, 9H), 2.27-2.37 (m, 4H), 3.37-3.46 (m, 4 H),

4.19 (s, 1H), 7.16-7.22 (m, 1H), 7.24-7.32 (m, 4H), 7.33-7.42

(m, 4 H).

ter t-Bu t yl

4-[[4-(2-E t h ylb u t a n oyl)p h en yl](p h en yl)-

m eth yl]-1-p ip er a zin eca r boxyla te (40) a n d 2-Eth yl-1-{4-

[p h en yl(1-p ip er a zin yl)m eth yl]p h en yl}-1-bu ta n on e (41).

Compound 39 (0.62 g, 1.4 mmol) was converted following

procedure E to the aryllithium and then quenched with

2-ethyl-N-methoxy-N-methylbutanamide¹⁶(0.23 g, 1.4 mmol).

Aqueous workup and chromatography on silica (10% EtOAc

in heptane) gave 40 (0.15 g, 25%). Treatment with 1 M HCl

in AcOH and extraction with K₂CO₃(aq)/CH₂Cl₂gave 41 (52

mg, 45%). Further purification with reverse-phase chroma-

tography (mobile phase with TFA) and lyophilization gave the

4-[(4-Acetyl-1-p ip er a zin yl)(p h en yl)m eth yl]-N,N-d ieth -

ylben za m id e (49). 1 (0.10 g, 0.28 mmol) and Et₃N (43 µL,

0.31 mmol) were dissolved in CH₂Cl₂(5 mL) and acetyl chloride

(22 µL, 0.31 mmol) was added at 0 °C. After aqueous workup

and chromatography on silica (0-5% MeOH in CH₂Cl₂), 49

(0.11 g, quant.) was obtained. Treatment with HCl gave the

hydrochloride salt: mp 140-50 °C (ether); IR (KBr, ν_max) 3480,

1

2987, 2500, 1623, 1429, 1285,1245 cm^-1; H NMR (CDCl₃) δ

1.15 (brm, 6H), 2.05 (s, 3H), 2.36 (m, 4H), 3.15-3.70 (m, 8H),

4.25 (s, 1H), 7.18-7.46 (m, 9H). Anal. (C₂₄H₃₂ClN₃O₂) C, H,

N.

ditrifluoroacetate salt: mp 37-45 °C (H₂O); IR (NaCl, ν_max

)

3777-3004, 2962, 1675 cm^-^{1 1}H NMR (CDCl₃) δ 0.78-1.00

;

(t, J ) 7.2 Hz, 6H), 1.46-1.63 (m, 2H), 1.63-1.86 (m, 3H),

2.24-2.49 (m, 4H), 2.81-3.02 (t, J ) 4.8 Hz, 4H), 3.19-3.30

(m, 1H), 4.28 (s,1H), 7.19 (m, 1H), 7.29 (m, 2H), 7.40 (m, 2H),

Com p ou n d s 50-57 were made following procedure A using

the corresponding grignard reagent or procedure B using the

corresponding bromide. Treatment by procedures C and D gave

3892 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21

Plobeck et al.

the target compounds. Intermediate alcohols were purified by

chromatography on silica (EtOAc in heptane) and final com-

pounds purified as bases by chromatography on silica (0-10%

MeOH in CH₂Cl₂(1% NH₄OH)). Dihydrochlorides were made

with HCl in ether.

7-methylquinoline: mp 180-3 °C; IR (KBr, ν_max) 3406, 2660,

1614, 1439, 1372, 1287, 1175, 1124 cm^-1; MS 383, 363, 335,

266, 165; ¹H NMR (CDCl₃) δ 1.1, 1.2 (2s, 6H), 1.8 (s, 1H), 2.3,

2.9 (2m, 8H), 3.24, 3.52 (2s, 4H), 4.35 (s, 1H), 8.09-6.56 (m,

10H). Accurate mass determination of 59 with the calculated

monoisotopic mass of 403.2498 Da was detected as 403.2486

Da (error 2.98 ppm).

N ,N -Die t h yl-4-[(4-m e t h oxyp h e n yl)(1-p ip e r a zin yl)-

m eth yl]ben za m id e (50). Procedure B (0.12 g of 50 obtained,

39%): mp (free base) 142-4 °C (MeCN); IR (KBr, ν_max) 3318,

2965, 2813, 1611, 1511, 1465, 1286, 1250, 1100, 1032, 833

N,N-Dieth yl-4-[1-p ip er a zin yl(6-qu in olin yl)m eth yl]ben -

za m id e (60). 6-Methylquinoline (1.0 g, 6.9 mmol) was heated

to 160 °C and selenium dioxide (0.5 g, 4.6 mmol) was added.

After 12 h the mixture was cooled and diluted with heptane

and the solution was decanted off and evaporated onto silica

gel. Chromatography on silica, 0 to 30% ethyl acetate in

heptane, gave 0.45 g 6-formylquinoline (41%). Procedure E

gave 0.15 g (0.43 mmol) of the benzylic alcohol. Following

procedures C and D, the alcohol was converted into 60 (0.12

g, 0.31 mmol, 72%). The dihydrochloride salt was prepared by

treatment with excess HCl in ether, filtering and drying the

crystals in a vacuum over NaOH: mp 185-95 °C; IR (KBr,

1

cm^-1; H NMR (CDCl₃) δ 1.1, 1.2 (2 brs, 6H), 1.63 (brs, 1H),

2.33 (brs, 4H), 2.46 (brs, 2H), 2.85-2.89 (m, 4H), 3.25 (brs,

2H), 3.51 (brs, 2H), 3.76 (s, 3H), 4.19 (s, 1H), 6.78-6.84 (m,

2H), 7.25-7.32 (m, 4H), 7.40-7.44 (m, 2H). Anal. (C₂₃H₃₁N₃O₂)

C, H, N.

4-[(4-Ch lor op h en yl)(1-p ip er a zin yl)m eth yl]-N,N-d ieth -

ylben za m id e (51). Procedure A (0.45 g of 51 obtained, 39%):

mp (free base) 112-3 °C (MeCN); IR (KBr, ν_max) 3347, 2947,

2809, 1615, 1451, 1318, 1284, 1094, 836 cm^-1; ¹H NMR (CDCl₃)

δ 1.10 (brs, 3H), 1.21 (brs, 3H), 1.69 (brs, 1H), 2.33 (brs, 4H),

2.86-2.89 (m, 4H), 3.24 (brs, 2H), 3.51 (brs, 2H), 4.22 (s, 1H),

7.23-7.41 (m, 8H). Anal. (C₂₂H₂₈ClN₃O) C, H, N.

N,N-Dieth yl-4-[(4-m eth ylp h en yl)(1-p ip er a zin yl)m eth -

yl]ben za m id e (52). Procedure A (0.50 g of 52 obtained,

40%): mp (free base) 129-32 °C (MeCN); IR (KBr, ν_max) 3320,

2957, 2811, 1610, 1437, 1285, 1128, 1010, 838 cm^-1; ¹H NMR

(CDCl₃) δ 1.10 (brs, 3H), 1.20 (brs, 3H), 1.83 (brs, 1H), 2.30 (s,

3H), 2.34 (brs, 4H), 2.86-2.89 (m, 4H), 3.24 (brs, 2H), 3.51

(brs, 2H), 4.20 (s, 1H), 7.06-7.46 (3m, 8H). Anal. (C₂₃H₃₁N₃O)

C, H, N.

ν

_max) (free amine) 3358, 2648, 1615, 1439, 1310 cm^-1; MS 350,

196, 173, 146, 91; ¹H NMR (CDCl₃) δ 1.07, 1.20 (2s, 6H), 2.60,

3.09 (2s, 8H), 3.20, 3.50 (2s, 4H), 4.5 (s, 1H), 5.7 (s, 1H), 7.26-

8.86 (m, 10H). Anal. (C₂₅H₃₀N₄O) C, H, N.

5-Isoqu in olin eca r ba ld eh yd e (61). A solution of DIBAL

(1.5 M, 7.3 mL, 10.95 mmol) in 15 mL of toluene which was

precooled to -78 °C and added dropwise to a solution of methyl

5-isoquinolinecarboxylate (1.7 g, 9.09 mmol) in 90 mL of

toluene at -78 °C, under

a nitrogen atmosphere. After

addition, the resulting mixture was stirred at -78 °C for 4 h.

1 mL of methanol was added to quench the reaction at -78

°C and gradually warmed to 25 °C. The mixture was filtered

through Celite and the filtrate extracted with ethyl acetate

several times. The combined organic phases were washed with

water and brine, and dried over sodium sulfate. Concentration

and chromatography on silica (ethyl acetate) afforded 61 (725

mg, 51% yield): IR (NaCl, ν_max) 3031, 2859, 2753, 1683, 1619,

1569 cm^-1; ¹H NMR (CDCl₃) δ 7.75 (m, 1H), 8.2 (m, 2H), 8.65

(d, J ) 6.1 Hz,1H), 8.95 (d, J ) 6.1 Hz, 1H), 9.3 (s, 1H), 10.4

(s, 1H); ¹³C NMR (CDCl₃) δ 116.6, 122.8, 125.4, 129.6, 132.2,

133.6, 138.7, 145.3, 151.8, 191.4.

N,N-Dieth yl-4-[(3-flu or op h en yl)(1-p ip er a zin yl)m eth yl]-

ben za m id e (53). Procedure B (85 mg of 53 obtained, 88%):

mp 155-65 °C (ether); IR (KBr, ν_max) 3408, 2926, 2461, 1612,

1437, 1290, 1097 cm^-1; ¹H NMR (CDCl₃) δ 1.1 (m, 6H), 1.6 (s,

1H), 2.38, 2.85 (2m, 8H), 3.4 (m, 4H), 4.23 (s, 1H), 6.85-7.45

(m, 8H). Anal. (C₂₂H₃₀Cl₂FN₃O) C, H, N.

N,N-Dieth yl-4-[2-n a p h th yl(1-p ip er a zin yl)m eth yl]ben -

za m id e (54). Procedure B (0.50 g, of 54 obtained, 40%): mp

(free base) 106-8 °C (MeCN); IR (KBr, ν_max) 3324, 3052, 2964,

2810, 2774, 1613, 1465, 1287, 1130, 1098 cm^-^{1 1}H NMR

;

(CDCl₃) δ 1.07 (brs, 3H), 1.19 (brs, 3H), 1.89 (brs, 1H), 2.40

(brs, 4H), 2.89-2.92 (m, 4H), 3.21 (brs, 2H), 3.50 (brs, 2H),

4.41 (s,1H), 7.24-7.84 (3m, 11H). Anal. (C₂₆H₃₁N₃O) C, H, N.

N,N-Dieth yl-4-[1-n a p h th yl(1-p ip er a zin yl)m eth yl]ben -

za m id e (55). Procedure B (0.30 g of 55 obtained, 57%): IR

(KBr, ν_max) 3307, 3050, 2966, 2814, 1625, 1431, 1287, 1098,

N,N-Diethyl-4-[hydroxy(5-isoquinolinyl)methyl]benzamide

(62) and N,N-Diethyl-4-[5-isoquinolinyl(1-piperazinyl)methyl]-

benzamide (63). Following procedure E, 61 (400 mg, 2.545

mmol) was converted to 62 (110 mg, 12% yield). Following

procedures C and D, 62 was converted into 63 (40 mg, 31%

yield) after chromatography on silica (0-10% MeOH in CH₂-

Cl₂with 1% NH₄OH). Trihydrochloride salt made with HCl:

843, 797 cm^-^{1 1}H NMR (CDCl₃) δ 1.04 (brs, 3H), 1.17 (brs,

;

3H), 2.14 (brs, 1H), 2.40 (brs, 2H), 2.46 (brs, 2H), 2.83-2.95

(m, 4H), 3.17 (brs, 2H), 3.48 (brs, 2H), 5.05 (s, 1H), 7.22-7.28

(m, 2H), 7.40-7.54 (m, 5H), 7.70-7.94 (m, 3H), 8.40-8.43 (m,

1H). Anal. (C₂₆H₃₁N₃O) C, H, N.

IR (NaCl, ν_max) 3383, 1669, 1617 cm^{-1 1}H NMR (CDCl₃) δ

;

0.90-1.25 (m, 6H), 2.40 (m, 4H), 2.90 (m, 4H), 3.15 (m, 2H),

3.50 (m, 2H), 4.95 (s, 1H), 7.25 (d, J ) 8.6 Hz, 2H), 7.50 (d, J

) 8.6 Hz, 2H), 7.60 (t, J ) 7.3 Hz, 1H), 7.85 (d, J ) 8.5 Hz,

1H), 8.05 (d, J ) 7.3 Hz, 1H), 8.15 (d, J ) 6 Hz, 1H), 8.50 (d,

J ) 6 Hz, 1H), 9.20 (s, 1H); ¹³C NMR (CDCl₃) δ 12.7, 14.1,

39.1, 43.1, 46.1, 53.3, 71.3, 116.3, 126.6, 127.0, 127.2, 128.3,

129.1, 129.5, 131.1, 134.0, 136.0, 137.2, 142.9, 153.3, 170.7.

Anal. (C₂₅H₃₃Cl₃N₄O) C, H, N.

N,N-Dieth yl-4-[1-p ip er a zin yl(8-qu in olin yl)m eth yl]ben -

za m id e (56). Procedure B. 8-Quinolyllithium made from

8-Bromoquinoline with s-BuLi²⁵(0.22 g of 56 obtained, 64%):

mp 180-90 °C (ether); IR (KBr, ν_max) 3297, 2982, 2716, 2474,

1611, 1434, 1380, 1288, 1098 cm^-1; MS 402, 318, 246, 217, 109;

¹H NMR (CDCl₃) δ 1.2, 1.1 (2s, 6H), 2.94, 2.51 (2m, 8H), 3.5-

3.1 (m, 5H), 6.05 (s, 1H), 8.94-7.20 (m, 10H). Anal. (C₂₅H₃₂

Cl₂N₄O) C, H, N.

-

1-(P h en ylsu lfon yl)-1H-in d ole-6-ca r ba ld eh yd e (65). 1H-

Indole-6-carbaldehyde (64)¹⁷(0.14 g, 1.0 mmol) was dissolved

in CH₂Cl₂(5 mL). Ground NaOH (0.8 g) and phenylsulfonyl

chloride (1.3 mL, 1.0 mmol) were added, then tetrabutylam-

monium hydrogen sulfate (50 mg) was added, and the reaction

stirred at 25 °C for 1 h. The organic solution was filtered in a

glass filter, washed with water and brine, dried (MgSO₄) and

evaporated. Chromatography on silica (0-50% EtOAc in

heptane) gave 65 (0.15 g, 0.54 mmol): ¹H NMR (CDCl₃) δ 6.74

(m, 1H), 7.42-7.94 (m, 10H), 8.50 (m, 1H), 10.08 (s, 1H); ¹³C

NMR (CDCl₃) δ 109.1, 116.1, 122.0, 123.9, 126.7 (2), 129.5 (2),

130.0, 133.2, 134.2, 134.5, 135.6, 137.8, 191.7.

N,N-Dieth yl-4-{h yd r oxy[1-(p h en ylsu lfon yl)-1H-in d ol-

6-yl]m eth yl}ben za m id e (66) a n d N,N-Dieth yl-4-[1H-in -

d ol-6-yl(1-p ip er a zin yl)m eth yl]ben za m id e (67). Compound

65 was converted to 66 in 66% yield according to procedure

E. Compound 66 was converted to 67 by treatment first with

SOCl₂and then with piperazine with concomitant loss of the

4-[Cycloh exyl(1-p ip er a zin yl)m eth yl]-N,N-d ieth ylben -

za m id e (57). Procedure A (60 mg of 57 obtained, 17%): mp

(free base) 113-6 °C (MeCN); IR (KBr, ν_max) 3330, 2936, 2845,

1

1623, 1431, 1286, 1096, 823 cm^-1; H NMR (CDCl₃) δ 0.64-

2.02 (m, 18H), 2.18-2.40 (m, 4H), 2.75-2.87 (m, 4H), 3.06 (d,

J ) 9 Hz, 1H), 3.27 (brs, 2H), 3.52 (brs, 2H), 7.11 (d, J ) 8.5

Hz, 2H), 7.29 (d, J ) 8.5 Hz, 2H). Anal. (C₂₂H₃₅N₃O) C, H, N.

N,N-Dieth yl-4-[1-p ip er a zin yl(4-qu in olin yl)m eth yl]ben -

za m id e (58). Preparation as for 60, starting from 4-quinoli-

necarboxaldehyde, gave 0.21 g of 58 (41%): mp 180-5 °C; IR

(KBr, ν_max) 3345, 2698, 1600, 1434, 1382, 1289 cm^-1; ¹H NMR

(CDCl₃) δ 1.03, 1.18 (2s, 6H), 2.45 (m, 4H), 2.94 (m, 5H), 3.15,

3.47 (2s, 4H), 5.06 (s, 1H), 7.26-8.94 (m, 10H). Anal.

(C₂₅H₃₀N₄O) C, H, N.

N,N-Dieth yl-4-[1-p ip er a zin yl(7-qu in olin yl)m eth yl]ben -

za m id e (59). Preparation as for 60 gave 0.11 g of 59 (7%) from

δ Opioid Receptor Agonists: Metabolic Stability

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3893

phenylsulfonyl protecting group, according to procedures C and

D. The desired product 67 (0.1 g, 81%) was obtained after

chromatography on silica. Treatment with HCl in ether gave

the dihydrochloride salt: mp 180-5 °C; IR (KBr, ν_max) 3439,

2694, 1607, 1400, 1385, 1293 cm^-1; MS 266, 207, 195, 165; ¹H

NMR (CDCl₃) δ 1.1, 1.2 (2s, 6H), 1.8 (s, 1H), 2.42, 2.91 (2m,

8H), 3.2, 3.5 (2s, 4H), 4.48 (s, 1H), 7.26-8.90 (m, 10H). Anal.

(C₂₄H₃₀N₄O) C, H, N.

2,2-Dim et h yl-2,3-d ih yd r o-1-b en zofu r a n -7-yl Tr iflu o-

r om eth a n esu lfon a te (68). 2,2-Dimethyl-2,3-dihydro-1-ben-

zofuran-7-ol (19 g, 0.11 mol) and pyridine (18 mL, 0.23 mol)

were dissolved in CH₂Cl₂at 0 °C. Triflic anhydride (23 mL,

0.14 mol) was added dropwise. After strirring 1 h at 25 °C the

mixture was diluted with CH₂Cl₂and washed with HCl (aq),

dried (MgSO₄) and evaporated in vacuo. Compound 68 (32 g,

96%) was obtained, which did not need purification and was

used directly in the following step: ¹H NMR (CDCl₃) δ 1.50

(s, 6H), 3.09 (s, 2H), 6.81 (m, 1H), 7.03 (m, 1H), 7.11 (m, 1H);

MS (EI) m/e 296, 163, 135, 107.

Meth yl 2,2-Dim eth yl-2,3-d ih yd r o-1-ben zofu r a n -7-ca r -

boxyla te (69). Compound 68 (32 g, 0.11 mol) was dissolved

in DMSO (200 mL), MeOH (100 mL) and Et₃N (34 mL, 0.25

mol). Carbon monoxide was passed through the solution 2-3

min, then palladium acetate (0.24 g) and dppf (1.1 g) were

added and the mixture heated at 70 °C under a CO atmo-

sphere. After 4 h, more palladium acetate (0.10 g) and dppf

(0.50 g) were added. After 12 h, EtOAc and water were added

and the organic phase was washed with HCl (aq), brine, dried

(MgSO₄) and evaporated. Chromatography on silica (0-20%

EtOAc in heptane) gave 12 g (52%) of 69: ¹H NMR (CDCl₃) δ

1.52 (s, 6H), 3.00 (s, 2H), 3.88 (s, 3H), 6.82 (m, 1H), 7.27 (m,

1H), 7.70 (m, 1H); MS (EI) m/e 206, 174, 159, 146, 131.

2,2-Dim e t h yl-2,3-d ih yd r o-1-b e n zofu r a n -7-ca r b a ld e -

h yd e (70). Compound 69 (5.0 g, 24 mmol) was dissolved in

toluene (100 mL) and DIBAL in toluene (33 mL, 1.5 M, 50

mmol) was added at -78 °C under a nitrogen atmosphere.

After 30 min, the reaction was worked up by addition of HCl

(aq), the organic phase was dried (MgSO₄) and evaporated in

vacuo. The residue was dissolved in CH₂Cl₂(50 mL) and finely

ground pyridinium dichromate (PDC) (11 g, 29 mmol) was

added in portions. The mixture was heated to 40 °C and

portions of PDC (1 g) were added until reaction was complete.

Dilution with heptane, filtering through silica and evaporation

gave a crude product which was purified by chromatography

on silica (0-20% EtOAc in heptane) to give 70 (3.3 g, 19 mmol,

79% from 69): ¹H NMR (CDCl₃) δ 1.54 (s, 6H), 3.03 (s, 2H),

6.88 (m, 1H), 7.34 (m, 1H), 7.58 (m, 1H), 10.22 (s, 1H); MS

(EI) m/e 176, 161, 147, 130.

each at 0.5 µg/µL. One microliter of the sample solution was

injected into the LCT. The mass calibration was performed

with poly(ethylene glycol) (PEG) according to the LCT opera-

tor’s manual.

P h a r m a cology. 1. Test Com p ou n d s. The compounds

were tested as their corresponding hydrochloride or trifluoro-

acetate salts.

2. Cell Cu ltu r e a n d Mem br a n e P r ep a r a tion s. Human

HEK-293S cells were subject to stable transfection with cDNA

encoding the human µ, δ and κ receptors. Clones were chosen

for high receptor expression and grown in suspension culture.

Cells were harvested and P2 membrane preparations were

produced.

3. Recep tor Bin d in g Assa ys. Membranes were combined

with test compounds and approximately 0.07 nM of the

appropriate radioligand: [¹²⁵I][D-Ala²]deltorphin II (K_d) 0.93

nM at δ), [¹²⁵I]FK33824 (K_d) 1.1 nM at µ), and [¹²⁵I]-D-Pro¹⁰-

dynorphin A[1-11] (K_d) 0.16 nM at κ) in 50 mM Tris, 3 mM

MgCl₂, 1 mg/mL BSA, pH 7.4. The amounts of bound radio-

activity were determined at equilibrium by filtration. The

nonspecific (NS) binding was defined in the presence of 10 µM

naloxone. The IC₅₀values of test compounds were determined

from 2-parameter logistic curve fits of percent specific binding

vs log(molar ligand), solving for IC₅₀and Hill slope.

4. GTP [γ-³⁵S] Bin d in g Assa ys. Membranes expressing

human δ receptors (9.7 pmol/mg protein) were combined with

test compounds and approximately 0.2 nM GTP[γ-³⁵S] in 50

mM Hepes, 20 mM NaOH, pH 7.4, 5 mM MgCl₂, 100 mM

NaCl, 1 mM EDTA, 1 mM DTT, 0.1% BSA, 15 µM GDP. The

bound radioactivity was determined after 1 h by filtration.

Control and stimulated binding were determined in the

absence and presence of 3 µM SNC-80, respectively. Values of

EC₅₀and E_maxfor ligands were obtained from 3-parameter

logistic curve fits of percent stimulated GTP[γ-³⁵S] binding vs

log(molar ligand), solving for EC₅₀, Hill slope and %E_max

.

5. In Vitr o Meta bolism . In cu ba tion con d ition s: All

incubations [rat liver microsomes (0.4 mg/mL proteins; Xeno-

tech LLC, Kansas City, KS), substrate at 10 or 100 µmol/L, 1

mM NADPH, 100 mM phosphate buffer at pH 7.4] were

performed in duplicate in disposable 96-well plates on a gently

shaking platform maintained at 37 °C. Control incubations

were carried out by incubating the same substrate concentra-

tions in phosphate buffer without rat liver microsomes or

NADPH. The final assay volume was 500 µL, containing 1%

of DMSO (test article stock solutions were prepared at 10 mM

in DMSO).

Incubations were started by the addition of NADPH (or

buffer for NADPH-free controls) and were stopped after 0 and

60 min by the addition of 500 µL of ice-cold acetonitrile.

Precipitated proteins were removed following a 10-min cen-

trifugation at 8500g and supernatants were directly injected

into the LC-MS system (Hewlett-Packard, Kirkland, Quebec,

Canada) using a micro plate sampler (HP220, Hewlett-

Packard).

4-[(2,2-Dim et h yl-2,3-d ih yd r o-1-b en zofu r a n -7-yl)(h y-

d r oxy)m eth yl]-N,N-d ieth ylben za m id e (71) a n d 4-[(2,2-

Dim eth yl-2,3-d ih yd r o-1-ben zofu r a n -7-yl)(1-p ip er a zin yl)-

m eth yl]-N,N-d ieth ylben za m id e (72). Compound 70 (3.0 g,

17 mmol) was reacted with 17 (10 g, 34 mmol) according to

procedure E to give alcohol 71 (4.0 g, 67%) followed by

procedures C and D to give 72 (3.2 g, 67%). Dihydrochloride

made with HCl: mp 130-40 °C (water); IR (KBr, ν_max) 2982,

2722, 2481, 1628, 1450, 1371, 1292, 1140 cm^-1; ¹H NMR (CD₃-

OD) δ 1.1,1.2 (2m, 6H), 1.36, 1.43 (2s, 6H), 2.72 (m, 4H), 2.95

(m, 2H), 3.25 (m, 6H), 3.5 (m, 2H), 4.8 (s, 1H), 6.74-7.60 (m,

7H). Anal. (C₂₆H₃₅N₃O₂) C, H, N.

HP LC con d ition s (m eta bolic sta bility): Aliquots (5 µL)

of the supernatants were directly injected onto a Zorbax

Eclipse XDB C18 column (4.6 × 30 mm, 3.5-µm particles). The

mobile phase consisted of a mixture of acetonitrile, methanol

and 0.04% formic acid in water (60-80:0-15:15-30, v/v). The

flow rate was 1.0 mL/min.

Accu r a te Ma ss Deter m in a tion by Tim e-of-F ligh t Ma ss

Sp ectr om etr y. Time-of-flight mass spectrometer (LCT, Mi-

cromass Inc. England) and HPLC (HP1100, Hewlett-Packard)

were used for the accurate mass determination with instru-

ment parameters of: ion mode, electrospray; desolvation temp,

350 °C; source temp, 130 °C; sample cone voltage, 30 V.

Acquisition was carried out in the mass range 100-1000 Da,

1 spectrum/s at 5000 resolution. The sample was introduced

into LCT mass spectrometer in loop injection mode with a

HPLC flow of 0.4 mL/min. The mobile phase consists of 50%

water and 50% acetonitrile. Leucine-enkephalin (lock mass

556.2771 Da) was used as the reference standard (Sigma Ref.L-

9133; 1 mg/mL in water). The sample was prepared with the

analyte compound and the reference standard in methanol

HP LC con d ition s (m eta bolic p r ofilin g): Supernatants

(30-µL aliquots) were directly injected onto a Phenomenex

Luna column (4.6 × 75 mm, 3-µm particles). Metabolites and

parent compounds were separated using a linear gradient of

acetonitrile (from 0% to 95% over 15 min) in 0.04% formic acid

in water. The flow rate was kept at 1.0 mL/min.

MS con d ition s: The LC system (HP1100, Hewlett-Pack-

ard) was interfaced with a MS detector (MSD) equipped with

an electrospray source. The MSD was operated in selected ion

monitoring mode for the metabolic stability studies (m/z )

MH⁺, M being the mass of the parent compound) and in scan

mode for the metabolic profiling studies (m/z from 85 to 650).

Nebulizer pressure was 60 psi while the drying gas (nitrogen)

3894 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21

Plobeck et al.

(6) Hong, E. J .; Rice, K. C.; Calderon, S. N.; Woods, J . H.; Traynor,

J . R. Convulsive Behavior of Nonpeptide δ-Opioid Ligands:

Comparison of SNC80 and BW373U86 in Mice. Analgesia 1998,

3, 269-276.

(7) Schetz, J . E.; Calderon, S. N.; Bertha, C. M.; Rice, K.; Porreca,

F. Rapid In Vivo Metabolism of a Methylether Derivative of (()-

BW373U86: The Metabolic Fate of [³H]SNC121 in Rats. J .

Pharmacol. Exp. Ther. 1996, 279, 1069-1076.

(8) Roberts, E.; Plobeck, N.; Wahlestedt, C. Novel Compounds with

Analgesic Effect. International Patent Application WO9723466,

Astra Pharma Inc., 1997.

(9) In the companion article, replacement of the chiral benzylic

carbon and upper piperazine nitrogen with a carbon-carbon

double bond is discussed.

(10) Amide 5 was prepared from the acid by heating in SOCl₂followed

by treatment with diethylamine: Bishop, M. J .; McNutt, R. W.

An Efficient Synthesis of the Benzhydrylpiperazine Delta Opioid

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(12) Carey, F. A.; Tremper, H. S. Carbonium Ion - Silane Hydride

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was delivered at 13 L/min. The capillary voltage was 3500 V

and the fragmentor (collision-induced dissociation cell) was set

at 70 eV.

6. Da ta An a lysis. For metabolic stability determinations,

chromatograms were analyzed for parent drug disappearance

from the incubation medium. The parent drug peak area in

the 0-min incubation sample was considered to be the 100%

value and parent drug levels were expressed as percent (%)

parent remaining. For metabolic profiling studies, chromato-

grams were analyzed for both the disappearance of parent drug

and the appearance of metabolites. For each metabolite, the

metabolite peak area in the 60-min incubation sample was

compared to the sum of all peak areas corresponding to

metabolites and expressed as percent (%) contribution to total

microsomal metabolism.

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J M000228X

Article Doi

New diarylmethylpiperazines as potent and selective nonpeptidic δ opioid receptor agonists with increased in vitro metabolic stability

DOI: 10.1021/jm000228x

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Article abstract of DOI:10.1021/jm000228x

Full text of DOI:10.1021/jm000228x

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