Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity

J . Med. Chem. 2002, 45, 3143-3160

3143

Syn th esis, SAR, a n d Biologica l Eva lu a tion of Oxim in o-P ip er id in o-P ip er id in e

Am id es. 1. Or a lly Bioa va ila ble CCR5 Recep tor An ta gon ists w ith P oten t

An ti-HIV Activity

Anandan Palani,*^,†Sherry Shapiro,^†Hubert J osien,^†Thomas Bara,^†J ohn W. Clader,^†William J . Greenlee,^†

Kathleen Cox,^‡J ulie M. Strizki,^§and Bahige M. Baroudy^§

Chemical Research, Drug Safety and Metabolism, and Antiviral Research, Schering-Plough Research Institute,

2015 Galloping Hill Road, Kenilworth, New J ersey 07033

Received February 19, 2002

We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1′-[(2,4-

dimethyl-3-pyridinyl)carbonyl]-4′-methyl-1,4′-bipiperidine N-oxide 1 (SCH 351125) as an orally

bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe

in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR

studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side

amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF₃, 4-OCF₃,

4-SO₂Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me,

n

i

Et, Pr, Pr, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism.

The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side.

Several compounds in this series, including compound 1, exhibited excellent antiviral activity

in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates,

excellent oral bioavailability, and potent antiviral activity against a wide range of primary

HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.

In tr od u ction

compelling evidence that functional inhibition of the

CCR5 receptor can be highly protective against HIV-1

infection. Therefore, it is hoped that the blockade of viral

entry by a small molecule CCR5 receptor antagonist

would represent a new class of anti-HIV therapeutics.

Various academic institutions^6aand pharmaceutical

companies, including ours, have reported structurally

diverse small molecule CCR5 antagonists as shown in

Figure 1.^6bResearchers at Takeda Chemical Industries

published their work on the discovery of the potent and

selective small molecule CCR5 antagonist TAK-779.⁷In

addition, the Takeda group disclosed patents claiming

that derivatives of TAK-779 were potential orally bio-

available CCR5 antagonists.⁸Recently, research groups

at Merck have published patents and papers highlight-

ing the synthesis, SAR, and biological activity of struc-

turally diverse antagonists.⁹Scientists at Glaxo Smith-

kline and Pfizer have also published patents covering

potential CCR5 antagonists.¹⁰We have previously dis-

cussed our efforts in the optimization of our initial hits

from our privileged piperazine- and piperidine-based

structures. These efforts led to the discovery of the

potent and orally bioavailable CCR5 antagonist SCH

350634, from the piperazino-piperidine series, and a

clinical candidate SCH 351125 (1), from the piperidino-

piperidine series.¹¹In this paper, we describe in detail

the identification of 1 as well as the design, synthesis,

and biological activity of various analogues of 1, with

studies directed toward optimizing the left-hand side

(LHS) phenyl, oxime, and right-hand side (RHS) amide

regions of compound 1, as shown in Figure 1.¹²

The current therapies now approved for human

immunodeficiency virus type I (HIV-1) include combina-

tions of reverse transcriptase and protease inhibitors

which are highly successful in reducing morbidity and

mortality in HIV-1-infected individuals.¹Although the

use of combination therapy can be highly effective in

suppressing viral replication, the emergence of drug

resistant viruses and intolerance to available agents can

lead to treatment failure. Hence, there remains a need

for novel agents with better potency and less toxicity.

It has been established that HIV-1 enters macro-

phages and T-cells by attaching to the CD4 receptor and

subsequent interactions with CCR5 chemokine recep-

tors which serve as a viral coreceptor for the entry

process.²The CCR5 receptor is a member of the G-

protein-coupled receptor (GPCR) superfamily, for which

small molecule inhibitors have been developed. The

endogenous ligands which bind to the CCR5 receptor

are the chemokines RANTES, MIP-1R, and MIP-1â

which have been reported to inhibit HIV-1 infection.³

The absence of CCR5 in humans who are homozygous

for a defective CCR5-∆32 allele has little impact on

health, while being strongly protective against HIV-1

infection.⁴Furthermore, individuals who have reduced

expression of CCR5 due to heterozygosity for the ∆32

allele advance more slowly to the disease than those

with wild-type CCR5.⁵These observations provided

* To whom correspondence should be addressed: Schering-Plough

Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033.

Tel: (908) 740-7158. Fax: (908) 740-7152. E-mail: anandan.palani@

spcorp.com.

Ch em istr y

^†Chemical Research.

The general synthetic method for the preparation of

aryl piperidino-piperidine amide analogues is shown in

^‡Drug Safety and Metabolism.

^§Antiviral Research.

Published on Web 06/12/2002

3144 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14

Palani et al.

F igu r e 1. CCR5 antagonists.

Sch em e 1. General Synthetic Scheme of Aryl

the resulting free amine with the desired aromatic acids

proceeded under standard conditions to afford the

desired products 5.

Piperidino-Piperidine Amides^a

Oximino-piperidino-piperidine analogues containing

a p-bromo aryl substituent were prepared according to

Scheme 2. Protection of commercially available isonipe-

cotic acid as the trifluoroacetamide followed by treat-

ment with thionyl chloride afforded N-trifluoroacetyl-

isonipecotyl chloride 6. Friedel-Crafts condensation of

acid chloride 6 and bromobenzene afforded ketone 7,

which was then converted to ketal 9. Ketal 9 was

allowed to react with N-Boc-piperidine-4-one in the

presence of titanium isopropoxide. Subsequent treat-

ment of the resulting intermediate with diethylalumi-

num cyanide gave aminonitrile 10. This aminonitrile

was treated with an excess of methylmagnesium bro-

mide to afford the alkylated product 11, which was then

processed to ketone 12 in 2 steps. The ketone was then

converted to the desired oximino-piperidino-piperidine

analogue 13 by treatment with either alkyl or aryl

hydroxylamine hydrochloride in the presence of sodium

acetate. Boc removal and coupling of the resulting free

amine with the desired aromatic acids proceeded under

standard conditions. The oxime formation step afforded

a mixture of E and Z oxime isomers in a ratio of 1.5:1

which was readily separated by silica gel chromatogra-

phy. For subsequent large-scale preparation, the E/Z

mixture was first equilibrated with 1 M hydrochloric

acid in ether to provide a 1:2.5 mixture favoring the Z

a

Reagents and conditions: (a) CH₃P⁺Ph₃Br^-, BuLi, -78 °C to

rt, 24 h, 91%; (b) HCl, EtOAc, rt, 1.5 h; (c) N-Boc-piperidine-4-

one, Ti(OⁱPr)₄, 1,2-dichloroethane, rt, 12 h, and then Et₂AlCN, rt,

3 h, 96%; (d) MeMgBr, THF, rt, 2 h, 99%; (e) 9-BBN, THF, 70 °C,

3 h, cooled to rt, added aqueous K₃PO₄, R¹-substituted bromoben-

zene or iodobenzene, PdCl₂(dppf)₂, 70 °C, 24 h; (f) TFA, DCM, rt,

2 h; (g) Ar¹CO₂H, EDCI, DIPEA, HOBT, DCM, rt, 12 h.

Scheme 1. Wittig olefination of commercially available

N-Boc-piperidine-4-one followed by Boc removal afforded

the free amine. The amine was then treated with a

second equivalent of N-Boc-piperidine-4-one under modi-

fied Strecker conditions to afford olefin 3 bearing a

methyl group at the 4-position of the piperidine.¹³

Hydroboration of the olefin with 9-BBN followed by

palladium-catalyzed cross-coupling with a substituted

bromobenzene gave the aryl-bipiperidine product 4.¹⁴

Boc removal with trifluoroacetic acid and coupling of

Oximino-Piperidinio-Piperidine Amides

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3145

Sch em e 2. General Synthetic Scheme of 4-Bromophenyl Oximino-Piperidino-Piperidine Amides^a

a

Reagents and conditions: (a) TFAA (excess), reflux, 4 h; (b) SOCl₂(excess), 12 h, 30% in two steps; (c) AlCl₃, bromobenzene (excess),

reflux; (d) ethylene glycol, p-TSA, toluene, reflux (azeotropically remove water), 90% in two steps; (e) MeOH, H₂O, K₂CO₃, rt, 12 h, 99%;

(f) N-Boc-piperidine-4-one, Ti(OⁱPr)₄, 1,2-dichloroethane, rt, 12 h, and then Et₂AlCN, rt, 3 h, 63%; (g) MeMgBr, THF, rt, 2 h, 98%; (h) 6

N HCl, EtOAc, rt, 12 h; (i) Boc₂O, 10% NaOH, ether, rt, 12 h, 77%; (j) NH₂OR²‚HCl, NaOAc, MeOH, rt, 24 h, 94% when R²) Et, followed

by 1 M HCl in ether (3 equiv), DCM, rt, 48 h, followed by chromatographic separation; (k) NH₂OH‚HCl, NaOAc, MeOH, rt, 24 h, followed

by chromatographic separation, and then KHMDS, THF, 0 °C, 30 min, followed by R²I or R²Br, rt, 5 h, 35-80%; (l) TFA, DCM, rt, 2 h;

(m) Ar₁CO₂H, EDCI, DIPEA, HOBT, DCM, rt, 12 h, 45% for compound 1.

isomer, which was then separated as above following

reprotection of the secondary amine with Boc anhydride.

Alternatively, the preparation of oximes wherein the

alkyl hydroxylamine is not commercially available can

be carried out via O-alkylation of the oxime. The ketone

12 was converted to the oxime 13, where R²) H, by

treatment with hydroxylamine hydrochloride in the

presence of sodium acetate. Separation of E and Z oxime

isomers could be readily carried out at this stage via

silica gel chromatography. The Z isomer was then

deprotonated with potassium bis(trimethylsilyl)amide

followed by alkylation with alkyl halide to yield the

desired oximino-piperidino-piperidine analogue 13 with

retention of stereochemistry.

To investigate structure-activity relationships of the

4-aryl substituent in the oxime series, we developed a

synthetic route, shown in Scheme 3, in which the

desired left-hand aryl group was introduced via nucleo-

philic addition of 4-substituted aryllithium or arylmag-

nesium reagents to piperidino-piperidine carboxalde-

hyde. Hydroboration of olefin 3 followed by tetrapro-

pylammonium perruthenate (TPAP) oxidation provided

aldehyde 15. It is important to note that in the hydrobo-

ration reaction, the oxidative workup in the presence

of a pH ) 7 buffer is necessary to prevent N-oxidation

of piperidine. Addition of the arylmagnesium bromide

or aryllithium reagent to the aldehyde gave alcohol 16

which was oxidized to the ketone 17 using TPAP,

4-methylmorpholine N-oxide (NMO), and molecular

sieves. The ketone was then converted to the desired

oximino-piperidino-piperidine analogue 19 by treatment

with either methyl or ethyl hydroxylamine hydrochlo-

ride in the presence of sodium acetate. Boc removal and

coupling of the resulting free amine with the desired

aromatic acids proceeded under standard conditions.

In Vitr o a n d in Vivo Stu d ies. The in vitro activity

of these CCR5 receptor antagonists was determined

using a membrane binding assay, and the antiviral

activity was evaluated using viral entry and replication

assays.¹⁵Rat plasma levels after oral administration

were evaluated using a rapid rat pharmacokinetic

screen.¹⁶All the preliminary in vitro and in vivo studies

on compounds were conducted using the amorphous

tartrate or hydrochloride salts.

Resu lts a n d Discu ssion s

Screening of in-house compound collections using a

high-throughput ¹²⁵I-labeled RANTES binding assay led

to the identification of several structurally diverse

compounds, including compound 20 with CCR5 receptor

affinity (K_i) 1 µM). In addition to its CCR5 receptor

activity, compound 20 was a potent antagonist of the

muscarinic M2 receptor (M2, K_i) 1.3 nM); therefore,

our goals at the beginning of the program were to

improve the CCR5 binding affinity and increase selec-

tivity versus the M2 receptor. In efforts parallel to those

3146 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14

Palani et al.

Sch em e 3. General Synthetic Scheme of 4-Phenyl Oximino-Piperidino-Piperidine Amides^a

a

Reagents and conditions: (a) BH₃‚THF complex, THF, 0 °C to rt, 24 h, followed by workup with H₂O₂, pH ) 7 buffer, THF, EtOH,

41%; (b) TPAP, NMO, molecular sieves, 0 °C to rt, 1 h, 64%; (c) R¹-substituted 4-bromobenzene, BuLi, -78 °C to rt, 2 h, 41%, R¹) CF₃

or OCF₃; (d) 4-chlorophenylmagnesium bromide, THF, 0 °C to rt, 5 h, 47%; (e) TPAP, NMO, molecular sieves, 0 °C to rt, 1 h, 63%; (f)

NH₂OR²‚HCl, NaOAc, MeOH, rt, 24 h, 94% when R²) Et; (g) TFA, DCM, rt, 2 h; (h) Ar¹CO₂H, EDCI, DIPEA, HOBT, DCM, rt, 12 h.

Ta ble 1. 4-Aryl Substitution

compound

R¹

K_i(nM)^a,b

IC₅₀(nM)^c

5a

5e

5f

Br

Cl

I

58

68

33

10

23

9

5g

5h

5i

5j

5k

5l

CF₃

OCF₃

CH₃

OCH₃

SCH₃

SO₂CH₃

COCH₃

Ph

25

55

113

155

86

33

596

363

1

5

38

26

7

5m

5n

F igu r e 2. Piperidino-piperidine analogues.

a

The standard error was 10%, and variability was 2- to 3-fold

carried out in a related piperazino-piperidine series, we

studied structure-activity relationships at both ends of

molecule 20.^11c,17Left-hand side truncation, along with

replacement of 4-fluoronaphthamide with 2,6-dimeth-

ylbenzamide and the introduction of a methyl group at

the 4-position of the piperidine, resulted in the identi-

fication of piperidino-piperidine compound 5a which

showed improvement in CCR5 activity and selectivity

versus the M2 muscarinic receptor (CCR5, K_i) 58 nM;

M2, K_i) 1323 nM). Antagonist 5a provided an excellent

starting point for further optimization. As described in

Figure 2, the des-halo compound 5d and the ortho-

substituted derivative 5c were significantly less active

than 5a. The meta-substituted derivative 5b was slightly

less active than 5a , suggesting the requirement of a

para substituent.

Optimization of the 4-phenyl substituent led to the

discovery that other halogens and small polar groups

are tolerated at this position, as shown in Table 1. The

p-chloro and p-iodo substituents, as in 5e and 5f, as well

as the medium-size halogenated and nonhalogenated

groups, as in 5g, 5h , and 5l, gave binding potency

similar to that of antagonist 5a .

b

from assay to assay. Data for inhibition of RANTES binding.

^cConcentration required to inhibit the entry of HIV-1 reporter

virus (ADA) into U-87 cells by 50%. For IC₅₀values, the 95%

confidence limit was within 1 log and intra-assay variation was

less than 0.5 log.

possibly due to metabolism at the benzylic site. Thus,

subsequent SAR efforts were first focused at the ben-

zylic site by introducing substituents that would either

block or reduce metabolism (Table 2). Branching of the

sp³benzylic carbon, as in 23, had no effect on binding

potency. However, rigidifying it in the form of an sp²

center, as in 24, provided an 8-fold improvement in

binding at CCR5. Replacement with other linkers such

as oxygen, alcohol, or carbonyl as in compound 25, 22,

or 21, respectively, offered no advantage in terms of

CCR5 potency. The introduction of the oxime linker in

14a not only improved the CCR5 binding affinity 6-fold

but also substantially improved plasma levels in the rat

after oral administration. Separation of the oxime

geometric isomers led to the discovery that the Z isomer

14c was 10-fold more potent than the E isomer 14b. To

determine the stability of compound 14c, the compound

was treated with 0.1 N HCl (pH ) 1) at 37 °C for 12 h.

No evidence of hydrolysis or oxime equilibration was

observed.

Although the CCR5 antagonist potency of these

compounds was promising, oral bioavailability was poor,

Oximino-Piperidinio-Piperidine Amides

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3147

Ta ble 2. Linker Modifications

or oral drug exposure in rats. Metabolite identification

studies of these nicotinamides indicated less metabolism

at the methyl and aryl groups but indicated the forma-

tion of a new major (M + 16) metabolite. We suspected

that this was due to oxidation of the pyridine nitrogen,

so the corresponding nicotinamide N-oxide 1 was pre-

pared. Again, the necessity for 2,6-disubstitution was

determined by compounds 36-38, all of which resulted

in a decrease in CCR5 binding potency.

K_i

IC₅₀rat PK (10 mg/kg‚po)^d

compound

X

(nM)^a,b(nM)^c

AUC_{0-6 h}(h‚µg/mL)

5a

CH₂

CdO

66

54

190

62

8

10

12

76

0.04

At this point, it was clear that the presence of either

the methyl or ethyl oxime moiety in addition to the 2,6-

dimethylnicotinamide N-oxide moiety was optimal for

binding affinity and oral absorption. Analogues of 1

were prepared by varying the left-hand side aryl sub-

stituent as shown in Table 5. In general, the ethyl oxime

derivatives (1, 39f, 39g, and 39i) exhibited greater

CCR5 binding affinity (K_i) and antiviral potency (IC₅₀)

than the equivalent methyl derivatives (39a , 39b, 39c,

and 39e). The 4-fluoro derivative 39j and methylsulfone

derivatives 39h and 39d were significantly less active.

Although the p-trifluoromethyl- and trifluoromethoxy-

containing compounds (39f and 39g) as well as the

chloro compound (39i) compared well with compound 1

in terms of both inhibition of RANTES binding and

inhibition of viral entry, these modifications resulted in

lower oral blood levels of compound 1 in rats.

21

22

23

24

25

14a

CH-OH

CH-CH₃

CdCH₂

O

CdNOMe

(mix)

1.0

0.59

2.1

29

11

1.4

2.8

1.2

14b

14c

CdNOMe

(E)

CdNOMe

(Z)

25

2

1.2

1.4

a

The standard error was 10%, and variability was 2- to 3-fold

b

from assay to assay. Data for inhibition of RANTES binding.

^cConcentration required to inhibit the entry of HIV-1 reporter

virus (ADA) into U-87 cells by 50%. For IC₅₀values, the 95%

confidence limit was within 1 log and intra-assay variation was

d

less than 0.5 log. See ref 16 for procedure.

With Z methoxime 14c in hand (K_i) 2 nM), the next

step was to study the significance of the oxime substitu-

tion and other substituted oximes. Table 3 displays the

results for the inhibition of RANTES binding and viral

entry for antagonists with the modifications of oxime.

The oxime 14f exhibited considerable loss in potency,

indicating that alkyl substitution is required. Introduc-

tion of aromatic and other bulkier groups (14k , 14l,

14m , and 14n ) resulted in a loss of potency. It is clear

from this study that the small alkyl-substituted oximes

(14c, 14e, 14g, and 14h ) are the most potent. The

ethoxime and methoxime are optimal for CCR5 activity.

The introduction of a more polar substituent, such as

14i and 14j, onto the oxime alkyl side chain resulted in

a moderate loss of activity.

Having optimized the oxime geometry and alkyl

substitution, we turned our attention to address the key

metabolic issues associated with compounds 14c and

14e. We observed extensive oxidative metabolism (mono-

hydroxylation) of the 2,6-dimethylbenzamide moiety in

the rat, along with minor amounts of dihydroxylation

and a carboxylic acid metabolite resulting from oxida-

tion of one of the methyl groups. Therefore, our subse-

quent medicinal chemistry efforts were focused on

replacements for the metabolically labile 2,6-dimethyl-

benzamide moiety (Table 4). Because 2,6-disubstitution

is necessary for high binding potency, our initial ap-

proach was to replace the methyl groups with hetero-

atoms. This resulted in compounds 26-29, which all

showed a slight decrease in CCR5 binding potency or

oral drug exposure in the rat. However, changing the

benzamide to a nicotinamide while leaving the 2-methyl

groups intact provided potent CCR5 antagonists with

significantly improved rat plasma levels after oral

administration (30a and 30b). Compounds containing

various nicotinamides (31-35) emphasized the fact that,

like the benzamides, the 2,6-disubstitution is necessary

for high binding potency. Substitution at the 4-position,

as in 33 and 34, provided no advantage in CCR5 binding

Compound 1 exhibited 2- to 3-fold higher oral plasma

levels in the rat pharmacokinetic screen, in addition to

satisfying our preliminary criteria of antiviral potency.

Therefore, we selected compound 1 for detailed phar-

macokinetic investigations in rats and monkeys (Table

6). Compound 1 was absorbed well in both species,

providing oral bioavailability of 63% in rats and 52% in

monkeys. More importantly, the plasma levels exceeding

the mean in vitro IC₉₀inhibitory concentrations (IC₉₀

values range from 3 to 78 nM) can be obtained and

sustained at least 12-24 h after oral administration.

The plasma concentrations of compound 1 at 12 and 24

h after the oral administrations were 330 and 16 nM in

the rat and 300 and 40 nM in the monkey, respectively.

In addition, compound 1 exhibited minimal or modest

protein binding in human (16% free) and rat (11% free)

plasma.

For the more potent compounds incorporating phenyl

or oxime variations, CCR5 binding affinity correlated

well with the inhibition of viral entry. It is important

to note that IC₅₀values obtained from the viral entry

assay were generally lower than the K_ivalues deter-

mined from the RANTES binding assay. This is prob-

ably due to differences in both the ligand (RANTES vs

HIV) and the target (whole cells vs membrane) used in

these assays. In addition, compounds with good activity

against the ADA strain (1, 5a , 5f-h , 5l, 14a -h , 14l,

24, 26-31, 33, 34, 38, 39a -c, 39f, 39g, and 39i)

inhibited the entry of other HIV-1 isolates as well as

YU-2 or J RFL in U-87 cells with IC₅₀values less than

10 nM. Several compounds in this series, including 1,

were shown to be functional antagonists of the CCR5

receptor by their ability to block the effects of RANTES-

induced calcium flux in cells.^11a,bAlso, antagonist 1

showed no appreciable affinity (less than 15% inhibition

at concentrations of 2-20 µM ) for muscarinic receptors

or the closely related chemokine receptors, including

CCR1, CCR2, CCR3, and CCR7.^11a,bThe cytotoxicity

3148 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14

Ta ble 3. Oxime Substitutions

Palani et al.

(CC₅₀) of antagonist 1 is 92 µM in PBMC cultures using

the MTS cell titer 96 protocol which is well above its

therapeutic concentration.

Cl, CF₃, OCF₃, and MeSO₂at the 4-phenyl group; small

n

i

alkyl groups Me, Et, Pr, and Pr; and 2,6-dimethylni-

cotinamide are optimal for antiviral activity. On the

basis of extensive structure-activity studies, we have

chosen compound 1 for human clinical trials for the

treatment of HIV-1 infection because of its potent

antiviral activity and favorable in vivo pharmacokinetic

profile. Compound 1 exists as a mixture of 4 rotational

isomers due to hindered bond rotation caused by the

steric and unsymmetrical nature of the tertiary amide.

Our ongoing studies on rotational isomers of 1 and

subsequent amide SAR investigations on this promising

oximino-piperidino-piperidine series will be reported in

due course.

Compound 1 has been advanced to clinical studies due

to its superior antiviral potency, receptor specificity, and

pharmacokinetic profile. Compound 1 inhibits the rep-

lication of a wide range of genetically diverse HIV-1

isolates with geometric mean IC₅₀values ranging from

0.40 to 8.9 nM and IC₉₀values from 3 to 78 nM.^11a,b

More importantly, compound 1, when dosed orally (30

mg/kg/day) for 28 days after inoculation with HIV-1,

showed a 3.6 log reduction in viral RNA levels compared

to those of the untreated mice in the SCID-hu Thy/Liv

mouse infection model.^11b

Con clu sion

Exp er im en ta l Section

In summary, the identification of compound 1 as well

as complete SAR investigations of the phenyl, oxime,

and right-hand side amide groups of oximino-piperidino-

piperidine series were described. The substituents Br,

Elemental analyses were performed by the Physical-

Analytical Chemistry Department, Schering-Plough Research

Institute, either on a Leeman CE 440 or on a FISONS EA 1108

elemental analyzer. Mass spectra were recorded using an

Oximino-Piperidinio-Piperidine Amides

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3149

Ta ble 4. Right-Hand Side Amide Substitution

a

b

The standard error was 10%, and variability was 2- to 3-fold from assay to assay. Data for inhibition of RANTES binding.

^cConcentration required to inhibit the entry of HIV-1 reporter virus (ADA) into U-87 cells by 50%. For IC₅₀values, 95% confidence limit

d

was within 1 log and intra-assay variation was less than 0.5 log. See ref 16 for procedure.

3150 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14

Ta ble 5. 4-Aryl Modifications of Compound 1

Palani et al.

h. The reaction mixture layers were separated, and the

aqueous layer was concentrated to afford 12.8 g (95%) of crude

amine. To a stirred solution of this amine (12.8 g, 97.0 mmol),

1,8-diazabicyclo[5.4.0]undec-7-ene (14.6 mL, 97.0 mmol), and

4-Boc-piperidinone (27.8 g, 145.4 mmol) in 1,2-dichloroethane

(200 mL) was added titanium isopropoxide (30.4 mL, 145.4

mmol), and the mixture was stirred for 18 h at room temper-

ature. The mixture was concentrated, and a 1.0 M solution of

diethylaluminum cyanide (145.4 mL, 145.4 mmol) was added

at room temperature. The mixture was stirred for 3 h, and

then diluted with EtOAc. The reaction was quenched with

water (20 mL), and the mixture was stirred a further 2 h. The

mixture was then filtered through Celite, and the resulting

filtrate was concentrated and chromatographed to afford 20.0

g (67%) of cyano compound: ¹H NMR CDCl₃δ 4.74 (s, 2 H),

4.00 (m, 2 H), 3.20 (m, 2 H), 2.69 (m, 4 H), 2.32 (m, 4 H), 2.17

(m, 2 H), 1.76 (m, 2 H), 1.51 (s, 9 H).

P r ep a r a tion of 4-Meth ylen e-1′-(ter t-bu toxyca r bon yl)-

4′-m eth yl-1,4′-bip ip er id in e (3). To a stirred solution of

cyanide 2 (20.0 g, 71.4 mmol) in THF (200 mL) was added a

3.0 M solution of MeMgBr in ether (71.4 mL, 214.3 mmol),

and the mixture was stirred for 2 h at room temperature. The

reaction was then quenched with saturated aqueous am-

monium chloride, and the mixture was extracted twice with

methylene chloride. The extracts were concentrated to afford

20.0 g (90%) of the desired methylated compound 3: R_f0.68

(20% EtOAc/hexanes); ¹H NMR CDCl₃δ 4.58 (s, 2 H), 3.34

(m, 2 H), 3.33 (m, 2 H), 2.47 (m, 4 H), 2.17 (m, 4 H), 1.78 (m,

2 H), 1.42 (s, 9 H), 1.32 (m, 2 H), 0.85 (s, 3 H).

K_i

R²(nM)^a,b(nM)^c

IC₅₀rat PK (10 mg/kg‚po)^d

compound

R¹

AUC_{0-6 h}(h‚µg/mL)

39a

39b

39c

39d

39e

1

39f

39g

39h

39i

39j

Br

CF₃

OCF₃

MeSO₂Me

Cl

Br

CF₃

OCF₃

MeSO₂Et

Cl

F

Me

19

5.3

7.6

30

24

2.1

3.8

4.4

20

5.6

30

5.6

1.1

5.1

2.4

0.35

3.3

Me

Et

0.6

1.3

1.8

6.5

2.2

3.0

0

Et

1.4

1.7

a

The standard error was 10%, and variability was 2- to 3-fold

b

from assay to assay. Data for inhibition of RANTES binding.

^cConcentration required to inhibit the entry of HIV-1 reporter

virus (ADA) into U-87 cells by 50%. For IC₅₀values, the 95%

confidence limit was within 1 log and intra-assay variation was

d

less than 0.5 log. See ref 16 for procedure.

Gen er a l P r oced u r e for P r ep a r a tion of Su bstitu ted

Ben zyl Bip ip er id in es 5a -j, 5m , a n d 5n . (1) To a stirred

solution of the olefin 3 (1.56 g, 5.33 mmol) in THF (5 mL) was

added a 0.5 M 9-BBN solution in THF (10.66 mL, 5.33 mmol),

and the mixture was heated to 70 °C for 3 h. The reaction

mixture was cooled to room temperature, and a 3.0 M aqueous

K₃PO₄(3 mL) solution was added followed by the substituted

bromo- or iodobenzene (4.44 mmol) in DMF and PdCl₂(dppf)₂

(0.18 g, 0.22 mmol). The solution was reheated to 70 °C for 18

h. The mixture was cooled to room temperature. The reaction

was quenched with water, and the mixture was extracted with

EtOAc (3 times). The combined organic layers were washed

with brine, dried, concentrated, and chromatographed to yield

EXTREL 401 (CI), J EOL or MAT-90 (FAB), VG ZAB-SE

(SIMS), or Finnigan MAT-CH-5 (EI) spectrometer. In general,

NMR structure determinations of the compounds were made

using chemical shifts, coupling constants, coupling information

from COSY spectra, and 1D NOE experiments. The ¹H and

¹³C NMR spectra were obtained on a Varian VXR-200 (200

MHz, H), Varian Gemini-300 (300 MHz, H; 75.5 MHz, ¹³C),

or XL-400 (400 MHz, ¹H; 100 MHz, ¹³C) spectrometer and are

reported as parts per million downfield from Me₄Si with the

number of protons, multiplicities, and coupling constants in

hertz (Hz) indicated parenthetically. For ¹³C NMR, a Nalorac

Quad nuclei probe was used. Compound purity was checked

by TLC and LC/MS analysis using an Applied Biosystems API-

100 mass spectrometer and Shimadzu SCL-10A LC column

(Altech platinum C18, 3 µm, 33 × 7 mm i.d.). A gradient flow

was used as follows: 0 min, 10% CH₃CN; 5 min, 95% CH₃CN;

7 min, 95% CH₃CN; 7.5 min, 10% CH₃CN; 9 min, stop;

retention times are reported (t_R) for the final targets.

In vitro and in vivo data given throughout the text for

compounds 1, 14a -n , and 26-39j were collected for the

amorphous tartrate salts. The tartrate salts were prepared by

mixing the final compound with 1 equiv of a 1.0 M tartaric

acid solution in methylene chloride followed by evaporation

of the solvent. In vitro and in vivo data given throughout the

text for final compounds 5a -n and 21-25 were collected for

the amorphous hydrochloride salts. The hydrochloride salts

were prepared by mixing the final compound with an excess

of a 3.0 M hydrogen chloride solution in diethyl ether followed

by evaporation of the solvent.

P r ep a r a tion of 4-Meth ylen e-1′-(ter t-bu toxyca r bon yl)-

4′-cya n o-1,4′-bip ip er id in e (2). To a solution of methyl tri-

phenylphosphonium bromide (60.8 g, 168.8 mmol) in THF (400

mL) was slowly added 2.5 M n-butyllithium in THF (65.2 mL,

163.2 mmol) at -78 °C, and the mixture was stirred for 1 h.

4-Boc-piperidinone (22.4 g, 112.8 mmol) in THF (80 mL) was

added dropwise to the mixture, and then the reaction mixture

was warmed to ambient temperature and stirred overnight.

The reaction was then quenched with water, and the mixture

was extracted with hexanes (3 times). The combined extracts

were concentrated and filtered through silica gel to give 20.2

g (91%) of the crude olefin. To a stirred solution of this crude

olefin (20.0 g, 101.5 mmol) in ethyl acetate (100 mL) were

added water (100 mL) and concentrated hydrochloric acid (30

mL), and the mixture was stirred at room temperature for 1.5

1

1.4 g of (60% for R¹) 4-CF₃) compound 4. For R¹) 4-CF₃

1

compound: R_f0.38 (20% EtOAc/hexanes); H NMR CDCl₃

δ

7.50 (d, 2 H), 7.21 (d, J ) 7.8 Hz, 2 H), 3.39-3.43 (m, 4 H),

2.85 (m, 2 H), 2.54 (m, 2 H), 1.99 (m, 2 H), 1.75 (m, 2 H), 1.60

(m, 2 H), 1.43 (s, 9 H), 1.13-1.39 (m, 5 H), 0.87 (s, 3 H).

(2) To a stirred solution of 4 (R¹) 4-CF₃, 1.4 g, 3.16 mmol)

in methylene chloride (20 mL) was added trifluoroacetic acid

(TFA) (2.5 mL), and the mixture was stirred at room temper-

ature for 2 h. The mixture was concentrated, poured into 10%

NaOH, and extracted twice with methylene chloride. The

combined extracts were dried and concentrated to afford 1.05

g (97%) of crude amine. To a stirred solution of this crude

amine (0.10 g, 0.29 mmol) in methylene chloride (1 mL) were

added 2,6-dimethylbenzoic acid (0.066 g, 0.44 mmol), 1-(3-

dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)

(0.084 g, 0.44 mmol), diisopropylethylamine (DIPEA) (0.5 mL),

and 1-hydroxybenzotriazole hydrate (HOBT) (0.060 g, 0.44

mmol), and the mixture was stirred for 18 h at room temper-

ature. The reaction was quenched with 10% NaOH, and the

mixture was extracted twice with methylene chloride. The

combined extracts were dried, concentrated, and chromato-

graphed to give amide (67% for 4-CF₃compound) 5. Purity was

checked by LC/MS analysis.

4-[(4-Br om op h en yl)m eth yl]-1′-(2,6-d im eth ylben zoyl)-

4′-m eth yl-1,4′-bip ip er id in e (5a ). The compound was pre-

pared from 1-bromo-4-iodobenzene by following the general

procedure described above to afford 4 where R¹) 4-Br, which

was then converted to compound 5a in the subsequent steps

by removal of the Boc and treatment of the resulting amine

with 2,6-dimethylbenzoic acid: R_f0.60 (96:4:1 ratio of CH₂-

1

Cl₂:MeOH:NH₄OH); HPLC t_R) 4.50 min; H NMR CDCl₃

δ

7.35 (d, J ) 7.6 Hz, 2 H), 7.09 (m, 1 H), 6.98 (m, 4 H), 4.09 (m,

Oximino-Piperidinio-Piperidine Amides

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3151

Ta ble 6. Pharmacokinetic Parameters of Compound 1

iv administration

oral administration

C_maxAUC_{(0-24 h)}

dose (iv/po)

(mg/kg)

A

CL

t_1/2

T_max

BA

(%)

(%)^a

(mL/min/kg)

(h)

(µM)

(µM‚h)

rat

monkey

10/10

2/2

57

80

12.8

4.28

5.4

6.0

0.5

2.0

2.5

0.76

15

6.9

63

52

a

A ) absorption.

1 H), 3.48 (m, 1 H), 3.26 (m, 1 H), 2.97 (m, 1 H), 2.87 (m, 1 H),

2.72 (m, 1 H), 2.44 (d, J ) 3.3 Hz, 2 H), 2.23 (s, 3 H), 2.21 (s,

3 H), 1.86-2.06 (m, 3 H), 1.34-1.76 (m, 4 H), 1.05-1.28 (m, 4

H), 0.87 (s, 3 H); mass spectrum FAB+ observed ) 483.2006,

estimated ) 483.2011.

4-[(3-Br om op h en yl)m eth yl]-1′-(2,6-d im eth ylben zoyl)-

4′-m eth yl-1,4′-bip ip er id in e (5b). The compound was pre-

pared from 1-bromo-3-iodobenzene by following the general

procedure described above to afford 4, where R¹) 3-Br, which

was then converted to compound 5b in the subsequent steps

by removal of the Boc and treatment of the resulting amine

with 2,6-dimethylbenzoic acid: HPLC t_R) 5.31 min; ¹H NMR

CDCl₃δ 7.57 (d, J ) 7.7 Hz, 2 H), 7.14 (m, 1 H), 7.01 (d, J )

7.8 Hz, 2 H), 6.88 (d, J ) 7.8 Hz, 2 H), 4.12 (m, 1 H), 3.52 (m,

1 H), 3.29 (m, 1 H), 3.01 (m, 1 H), 2.90 (m, 1 H), 2.75 (m, 1 H),

2.47 (d, J ) 3.9 Hz, 2 H), 2.28 (s, 3 H), 2.24 (s, 3 H), 1.90-2.08

(m, 3 H), 1.36-1.79 (m, 4 H), 1.08-1.30 (m, 4 H), 0.90 (s, 3

H); mass spectrum FAB+ observed ) 531.1878, estimated )

531.1872.

1′-(2,6-Dim e t h ylb e n zoyl)-4′-m e t h yl-4-[[4-(t r iflu or o-

m eth yl)p h en yl]m eth yl]-1,4′-bip ip er id in e (5g). The com-

pound was prepared from 4-bromobenzotrifluoride by following

the general procedure described above to afford 4 where R¹)

4-CF₃, which was then converted to compound 5g in subse-

quent steps by removal of the Boc and treatment of the

resulting amine with 2,6-dimethylbenzoic acid: R_f0.58 (50%

EtOAc/hexanes); HPLC t_R) 5.16 min; ¹H NMR CDCl₃δ 7.52

(d, J ) 7.8 Hz, 2 H), 7.24 (d, J ) 7.7 Hz, 2 H), 7.12 (m, 1 H),

7.00 (d, J ) 7.8 Hz, 2 H), 4.11 (m, 1 H), 3.51 (m, 1 H), 3.29 (m,

1 H), 3.00 (m, 1 H), 2.91 (m, 1 H), 2.75 (m, 1 H), 2.58 (d, J )

3.9 Hz, 2 H), 2.26 (s, 3 H), 2.24 (s, 3 H), 1.99-2.09 (m, 3 H),

1.38-1.78 (m, 4 H), 1.16-1.32 (m, 4 H), 0.90 (s, 3 H); mass

spectrum FAB+ observed ) 473.2788, estimated ) 473.2780.

1′-(2,6-Dim e t h ylb e n zoyl)-4′-m e t h yl-4-[[4-(t r iflu or o-

m eth oxy)p h en yl]m eth yl]-1,4′-bip ip er id in e (5h ). The com-

pound was prepared from 1-bromo-4-(trifluoromethoxy)ben-

zene by following the general procedure described above to

afford 4 where R¹) 4-OCF₃, which was then converted to

compound 5h in the subsequent steps by removal of the Boc

and treatment of the resulting amine with 2,6-dimethylbenzoic

acid: HPLC t_R) 5.00 min; ¹H NMR CDCl₃δ 7.05-7.15 (m, 5

H), 6.98 (d, J ) 7.7 Hz, 2 H), 4.09 (m, 1 H), 3.49 (m, 1 H), 3.27

(m, 1 H), 2.83-3.03 (m, 2 H), 2.73 (m, 1 H), 2.49 (d, 2 H), 2.23

(s, 3 H), 2.21 (s, 3 H), 1.85-2.07 (m, 3 H), 1.34-1.75 (m, 4 H),

1.07-1.30 (m, 4 H), 0.86 (s, 3 H); mass spectrum FAB+

observed ) 489.2741, estimated ) 489.2729.

1′-(2,6-Dim eth ylben zoyl)-4′-m eth yl-4-[(4-m eth ylph en yl)-

m eth yl]-1,4′-bip ip er id in e (5i). The compound was prepared

from 4-iodotoluene by following the general procedure de-

scribed above to afford 4 where R¹) 4-CH₃, which was then

converted to compound 5i in the subsequent steps by removal

of the Boc and treatment of the resulting amine with 2,6-

dimethylbenzoic acid: HPLC t_R) 4.96 min; ¹H NMR CDCl₃δ

6.98-7.14 (m, 7 H), 4.12 (m, 1 H), 3.53 (m, 1 H), 3.30 (m, 1

H), 2.99 (m, 1 H), 2.89 (m, 1 H), 2.75 (m, 1 H), 2.48 (d, J ) 3.9

Hz, 2 H), 2.31 (s, 3 H), 2.23 (s, 3 H), 1.87-2.08 (m, 3 H), 1.73

(m, 2 H), 1.61 (s, 3 H), 1.37-1.51 (m, 2 H), 1.08-1.31 (m, 4

H), 0.89 (s, 3 H); mass spectrum FAB+ observed ) 419.3064,

estimated ) 419.3062.

with 2,6-dimethylbenzoic acid: R_f0.60 (96:4:1 ratio of CH₂-

1

Cl₂:MeOH:NH₄OH); HPLC t_R) 5.21 min; H NMR CDCl₃

δ

7.25-7.31 (m, 2 H), 6.96-7.14 (m, 5 H), 4.09 (m, 1 H), 3.49

(m, 1 H), 3.26 (m, 1 H), 2.97 (m, 1 H), 2.88 (m, 1 H), 2.73 (m,

1 H), 2.47 (d, 2 H), 2.24 (s, 3 H), 2.22 (s, 3 H), 1.87-2.08 (m,

3 H), 1.10-1.76 (m, 8 H), 0.87 (s, 3 H); mass spectrum FAB+

observed ) 483.2014, estimated ) 483.2011.

4-[(2-Br om op h en yl)m eth yl]-1′-(2,6-d im eth ylben zoyl)-

4′-m eth yl-1,4′-bip ip er id in e (5c). The compound was pre-

pared from 1-bromo-2-iodobenzene by following the general

procedure described above to afford 4 where R¹) 2-Br, which

was then converted to compound 5c in the subsequent steps

by removal of the Boc and treatment of the resulting amine

with 2,6-dimethylbenzoic acid: R_f0.60 (96:4:1 ratio of CH₂-

1

Cl₂:MeOH:NH₄OH); HPLC t_R) 5.06 min; H NMR CDCl₃

δ

7.53 (d, J ) 7.8 Hz, 2 H), 6.98-7.24 (m, 5 H), 4.13 (m, 1 H),

3.54 (m, 1 H), 3.31 (m, 1 H), 2.37-3.06 (m, 7 H), 2.29 (s, 3 H),

2.27 (s, 3 H), 1.90-2.22 (m, 5 H), 1.20-1.66 (m, 4 H), 0.90 (s,

3 H); mass spectrum FAB+ observed ) 483.2002, estimated

) 483.2011.

1′-(2,6-Dim eth ylben zoyl)-4-(p h en ylm eth yl)-4′-m eth yl-

1,4′-bip ip er id in e (5d ). The compound was prepared from

bromobenzene by following the general procedure described

above to afford 4 where R¹) H, which was then converted to

compound 5d in the subsequent steps by removal of the Boc

and treatment of the resulting amine with 2,6-dimethylbenzoic

acid: HPLC t_R) 4.86 min; ¹H NMR CDCl₃δ 7.07-7.28 (m, 6

H), 6.97 (m, 2 H), 4.10 (m, 1 H), 3.49 (m, 1 H), 3.27 (m, 1 H),

2.97 (m, 1 H), 2.87 (m, 1 H), 2.72 (m, 1 H), 2.50 (d, J ) 3.9 Hz,

2 H), 2.23 (s, 3 H), 2.21 (s, 3 H), 1.87-2.07 (m, 3 H), 1.08-

1.79 (m, 8 H), 0.89 (s, 3 H); mass spectrum FAB+ observed )

405.2918, estimated ) 405.2906.

4-[(4-Ch lor op h en yl)m eth yl]-1′-(2,6-d im eth ylben zoyl)-

4′-m eth yl-1,4′-bip ip er id in e (5e). The compound was pre-

pared from 1-chloro-4-iodobenzene by following the general

procedure described above to afford 4 where R¹) 4-Cl, which

was then converted to compound 5e in the subsequent steps

by removal of the Boc and treatment of the resulting amine

with 2,6-dimethylbenzoic acid: HPLC t_R) 5.06 min; ¹H NMR

CDCl₃δ 7.18-7.25 (m, 3 H), 6.95-7.12 (m, 4 H), 4.08 (m, 1

H), 3.49 (m, 1 H), 3.27 (m, 1 H), 2.67-3.03 (m, 3 H), 2.46 (d,

J ) 3.9 Hz, 2 H), 2.23 (s, 3 H), 2.21 (s, 3 H), 1.85-2.05 (m, 3

H), 1.33-1.75 (m, 4 H), 1.08-1.28 (m, 4 H), 0.87 (s, 3 H); mass

spectrum FAB+ observed ) 439.2511, estimated ) 439.2516.

4-[(4-Iod op h en yl)m eth yl]-1′-(2,6-d im eth ylben zoyl)-4′-

m eth yl-1,4′-bip ip er id in e (5f). The compound was prepared

from 1-bromo-4-iodobenzene by following the general proce-

dure described above to afford 4 where R¹) 4-Br. To this

compound in THF at -78 °C was added nBuLi (1.1 equiv),

and the mixture was stirred for 10 min followed by the

dropwise addition of a solution of I₂(1.2 equiv) in THF. The

mixture was stirred for 1 h to afford 4 where R¹) 4-I, which

was then converted to compound 5f in the subsequent steps

by removal of the Boc and treatment of the resulting amine

1′-(2,6-Dim e t h ylb e n zoyl)-4′-m e t h yl-4-[(4-m e t h oxy-

p h en yl)m eth yl]-1,4′-bip ip er id in e (5j). The compound was

prepared from 4-iodoanisole by following the general procedure

described above to afford 4 where R¹) 4-OCH₃, which was

then converted to compound 5j in the subsequent steps by

removal of the Boc and treatment of the resulting amine with

2,6-dimethylbenzoic acid: R_f0.49 (97:3:1 ratio of CH₂Cl₂:

MeOH:NH₄OH); HPLC t_R) 4.66 min; ¹H NMR CDCl₃δ 6.96-

7.13 (m, 5 H), 6.79 (d, J ) 7.7 Hz, 2 H), 4.09 (m, 1 H), 3.76 (s,

3 H), 3.49 (m, 1 H), 3.28 (m, 1 H), 2.97 (m, 1 H), 2.87 (m, 1 H),

2.71 (m, 1 H), 2.44 (d, 2 H), 2.23 (s, 3 H), 2.21 (s, 3 H), 1.86-

2.07 (m, 3 H), 1.33-1.76 (m, 4 H), 1.05-1.29 (m, 4 H), 0.86 (s,

3 H); mass spectrum FAB+ observed ) 435.3004, estimated

) 435.3012.

4-[(4-Acetylp h en yl)m eth yl]-1′-(2,6-d im eth ylben zoyl)-4′-

m eth yl-1,4′-bip ip er id in e (5m ). The compound was prepared

from 4-iodoacetophenone by following the general procedure

3152 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14

Palani et al.

described above to afford 4 where R¹) 4-COCH₃, which was

then converted to compound 5m in subsequent steps by

removal of the Boc and treatment of the resulting amine with

2,6-dimethylbenzoic acid: ¹H NMR CDCl₃δ 7.83 (d, J ) 7.8

Hz, 2 H), 7.19 (m, 2 H), 7.09 (m, 1 H), 6.97 (d, J ) 7.7 Hz, 2

H), 4.08 (m, 1 H), 3.50 (m, 1 H), 3.27 (m, 1 H), 2.97 (m, 1 H),

2.89 (m, 1 H), 2.74 (m, 1 H), 2.55 (d, 2 H), 2.54 (s, 3 H), 2.24

(s, 3 H), 2.23 (s, 3 H), 1.87-2.08 (m, 3 H), 1.33-1.78 (m, 4 H),

1.08-1.31 (m, 4 H), 0.87 (s, 3 H); mass spectrum FAB+

observed ) 447.3016, estimated ) 447.3012.

4-[[(1,1′-Biph en yl)-4-yl]m eth yl]-1′-(2,6-dim eth ylben zoyl)-

4′-m eth yl-1,4′-bip ip er id in e (5n ). The compound was pre-

pared from 4-bromobiphenyl by following the general proce-

dure described above to afford 4 where R¹) 4-Ph, which was

then converted to compound 5n in the subsequent steps by

removal of the Boc and treatment of the resulting amine with

2,6-dimethylbenzoic acid: R_f0.45 (96:4:1 ratio of CH₂Cl₂:

MeOH:NH₄OH); HPLC t_R) 5.33 min; ¹H NMR CDCl₃δ 7.29-

7.57 (m, 7 H), 7.17 (d, J ) 7.8 Hz, 2 H), 7.09 (m, 1 H), 6.99 (m,

2 H), 4.09 (m, 1 H), 3.22-3.71 (m, 2 H), 2.63-3.05 (m, 3 H),

2.54 (d, J ) 3.9 Hz, 2 H), 2.36 (m, 1 H), 2.23 (s, 6 H), 1.86-

2.06 (m, 3 H), 1.10-1.77 (m, 7 H), 0.87 (s, 3 H); mass spectrum

FAB+ observed ) 481.3221, estimated ) 481.3219.

P r ep a r a tion of N-Tr iflu or oa cetylison ip ecotyl Ch lo-

r id e (6). Trifluoroacetic anhydride (TFAA) (300 mL, 210

mmol) was added to isonipecotic acid (96 g, 740 mmol) at 0

°C. Afterward, the mixture was heated at reflux for 4 h. Excess

TFAA was removed, and the reaction mixture was taken up

in EtOAc, washed with water, and concentrated to give 160 g

of the amide. The crude amide (50 g) was treated with 300

mL of thionyl chloride, and the mixture was heated at reflux

overnight. Excess thionyl chloride was then removed in vacuo

to give 54 g (32%) of the acid chloride 6 which was used in the

next step without further purification.

P r ep a r a tion of 4-(4-Br om oben zoyl)tr iflu or oa cetylp i-

p er id in e (7). Aluminum chloride (11.0 g, 82.5 mmol) was

added slowly to a solution of acid chloride 6 (10.0 g, 41.0 mmol)

in bromobenzene (40 mL, 380 mmol) at ambient temperature,

after which the reaction mixture was heated at reflux for 4 h.

It was then cooled and poured into a mixture of concentrated

HCl and ice, and the product was extracted with EtOAc. The

organic layer was separated, washed with water and half-

saturated sodium bicarbonate solution, and concentrated to

give 16.2 g of the crude ketone 7: ¹H NMR CDCl₃δ 7.75 (d, J

) 7.8 Hz, 2 H), 7.60 (d, J ) 7.7 Hz, 2 H), 4.41(m, 1 H), 4.00

(m, 1 H), 3.50 (m, 1 H), 3.30 (m, 1 H), 3.07 (m, 1 H), 1.70-

2.05 (m, 4 H).

P r ep a r a t ion of 4-[2-(4-Br om op h en yl)-1,3-d ioxola n -2-

yl]-1-tr iflou r oa cetylp ip er id in e (8). The crude ketone 7 (16.2

g, 44.5 mmol) was dissolved in toluene (200 mL) containing

ethylene glycol (25 mL) and p-toluenesulfonic acid (0.5 g). The

mixture was heated at reflux with azeotropic removal of water

until no further water was collected. The mixture was con-

centrated to give 17.4 g of the crude ketal 8: ¹H NMR CDCl₃

δ 7.75 (d, J ) 7.8 Hz, 2 H), 7.60 (d, J ) 7.7 Hz, 2 H), 4.51 (m,

1 H), 3.90-4.00 (m, 3 H), 3.70 (m, 2 H), 2.90 (m, 1 H), 2.55

(m, 1 H), 2.01 (m, 1 H), 1.30-1.80 (m, 4 H).

P r ep a r a t ion of 4-[2-(4-Br om op h en yl)-1,3-d ioxola n -2-

yl]-p ip er id in e (9). The crude ketal 8 (17.4 g, 42 mmol) was

dissolved in methanol (100 mL), and to this were added 25

mL of water and 12 g of potassium carbonate. Themixture was

stirred at ambient temperature overnight. The mixture was

diluted with water and extracted with EtOAc. The organic

layer was separated, washed with water and brine, and

concentrated to give 12.55 g (95%) of amine 9: ¹H NMR CDCl₃

δ 7.45 (d, J ) 7.8 Hz, 2 H), 7.25 (d, J ) 7.7 Hz, 2 H), 3.98 (m,

2 H), 3.70 (m, 2 H), 3.09 (m, 2 H), 2.40-2.55 (m, 3 H), 1.85

(m, 1 H), 1.70 (m, 1 H), 1.20-1.35 (m, 2 H).

temperature. The mixture was concentrated, and a 1.0 M

solution of diethylaluminum cyanide (35 mL) was added at

room temperature. The mixture was stirred for 3 h and then

diluted with EtOAc. The reaction was quenched with water

(5 mL), and the mixture was stirred a further 2 h. The mixture

was then filtered through Celite, and the resulting filtrate was

concentrated and chromatographed to afford 7.3 g (63%) of

compound 10: R_f0.25 (20% EtOAc/hexanes); ¹H NMR CDCl₃

δ 7.45 (d, J ) 7.8 Hz, 2 H), 7.25 (d, J ) 7.7 Hz, 2 H), 3.90-

4.00 (m, 4 H), 3.70 (m, 2 H), 3.00-3.25 (m, 4 H), 2.00-2.15

(m, 3 H), 1.60-1.85 (m, 4 H), 1.45 (s, 9 H), 1.30-1.45 (m, 4

H).

P r ep a r a t ion of 4-[2-(4-Br om op h en yl)-1,3-d ioxola n -2-

yl]-1′-(ter t-b u t oxyca r b on yl)-4′-m et h yl-1,4′-b ip ip er id in e

(11). To a stirred solution of cyanide 10 (7.3 g, 14.03 mmol) in

THF (100 mL) was added a 3.0 M solution of MeMgBr in ether

(14.0 mL, 42 mmol) at room temperature, and the mixture was

stirred for 2 h. The reaction was then quenched with saturated

aqueous ammonium chloride, and the mixture was extracted

twice with methylene chloride. The extracts were concentrated

to afford 7.0 g (98%) of the desired methylated compound 11:

1

R_f0.36 (35% EtOAc/hexanes); H NMR CDCl₃δ 7.45 (d, J )

7.8 Hz, 2 H), 7.25 (d, J ) 7.7 Hz, 2 H), 3.95 (m, 2 H), 3.73 (m,

2 H), 3.25 (m, 2 H), 2.85 (m, 2 H), 1.75-2.00 (m, 3 H), 1.45 (s,

9 H), 1.20-1.75 (m, 10 H), 0.95 (s, 3 H).

P r ep a r a tion of 4-(4-Br om oben zoyl)-1′-(ter t-bu toxyca r -

bon yl)-4′-m eth yl-1,4′-bip ip er id in e (12). The crude ketal 11

was dissolved in EtOAc (100 mL) and 6 N HCl (40 mL), and

the mixture was stirred at room temperature for 24 h. The

mixture was then neutralized with 20% NaOH and extracted

with EtOAc. The organic layer was dried and concentrated to

yield 5.0 g (98%) of crude amine. To a stirred solution of this

crude amine (5.0 g, 13.6 mmol) in ether (200 mL) were added

10% NaOH (50 mL) and di-tert-butylcarbonate (BOC₂O) (2.97

g, 13.6 mmol), and the mixture was stirred at room temper-

ature overnight. The layers were separated, and the organic

layer was washed with brine, dried, concentrated, and chro-

matographed to yield 5.1 g (79%) of Boc-protected amine 12:

1

R_f0.50 (35% EtOAc/hexanes); H NMR CDCl₃δ 7.80 (d, J )

7.8 Hz, 2 H), 7.60 (d, J ) 7.7 Hz, 2 H), 3.50 (m, 2 H), 3.10-

3.25 (m, 3 H), 2.95 (m, 2 H), 2.20 (m, 2 H), 1.75-1.90 (m, 6

H), 1.45 (s, 9 H), 1.20-1.40 (m, 2 H), 0.90 (m, 3 H).

Gen er a l P r oced u r e for P r ep a r a tion of Oxim es 1, 14a -

g, 14l-n , 26-42, 43a , 43d , a n d 43h . (1) To a stirred solution

of ketone 12 (1.5 g, 3.22 mmol) in MeOH (50 mL) were added

sodium acetate (5.0 g, 47 mmol) and O-alkyl or O-aryl

hydroxylamine hydrochloride, and the mixture was stirred at

room temperature for 24 h. The resulting mixture was then

poured into aqueous NaOH (10%) and extracted twice with

methylene chloride. The combined extracts were then dried

and chromatographed to yield 1.5 g of oxime 13 (94% for ethyl

oxime) as a mixture of E and Z isomers. The isomers could be

separated at this point by chromatography. For the ethyl

compound: E isomer, R_f0.70 (35% EtOAc/hexanes); Z isomer,

1

R_f0.61 (35% EtOAc/hexanes); H NMR CDCl₃δ 7.50 (d, J )

7.7 Hz, 2 H), 7.09 (d, J ) 7.8 Hz, 2 H), 4.05 (q, 2 H), 3.24-

3.49 (m, 4 H), 2.94 (m, 2 H), 2.40 (m, 1 H), 2.10 (m, 2 H), 1.76

(m, 4 H), 1.54 (m, 2 H), 1.44 (s, 9 H), 1.33 (m, 2 H), 1.18 (t, 3

H), 0.89 (s, 3 H).

(2) To a stirred solution of 13 (1.5 g, 3.0 mmol) in methylene

chloride (10 mL) was added trifluoroacetic acid (3 mL), and

the mixture was stirred at room temperature for 2 h. The

reaction mixture was concentrated, poured into 10% NaOH,

and extracted twice with methylene chloride. The combined

extracts were dried and concentrated to afford 1.2 g (100%) of

amine. To a stirred solution of this crude amine (1.3 g, 3.2

mmol) in methylene chloride (50 mL) were added substituted

benzoic, nicotinic, or nicotinic N-oxide acid (4.94 mmol), EDCI

(0.94 g, 4.94 mmol), DIPEA (0.84 g, 6.58 mmol), and HOBT

(0.66 g, 4.94 mmol), and the mixture was stirred for 12 h at

room temperature. The reaction was quenched with saturated

NaHCO₃, and the mixture was extracted twice with methylene

chloride. The combined extracts were dried and concentrated

to yield 1.6 g of oxime 14. The isomers can also be separated

P r ep a r a t ion of 4-[2-(4-Br om op h en yl)-1,3-d ioxola n -2-

yl]-1′-(ter t-bu toxycar bon yl)-4′-cyan o-1,4′-bipiper idin e (10).

To a stirred solution of amine 9 (7.2 g, 23 mmol) and N-tert-

butoxycarbonyl-4-piperidinone (4.8 g, 24 mmol) in 1,2-dichlo-

roethane (20 mL) was added titanium isopropoxide (6.7 mL,

32.3 mmol), and the mixture was stirred for 12 h at room

Oximino-Piperidinio-Piperidine Amides

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3153

at this point by chromatography. Purity was checked by LC/

MS analysis.

(50% EtOAc/hexanes); HPLC t_R) 5.08 min; ¹H NMR CDCl₃δ

7.49 (d, J ) 7.8 Hz, 2 H), 7.25 (m, 2 H), 7.21 (m, 1 H), 7.00 (d,

J ) 7.7 Hz, 2 H), 4.17 (q, 2 H), 4.08 (m, 1 H), 3.54 (m, 1 H),

3.20-3.33 (m, 3 H), 2.98 (m, 2 H), 2.81 (m, 2 H), 2.26 (s, 3 H),

2.23 (s, 3 H), 2.16 (m, 2 H), 1.93 (m, 1 H), 1.56-1.80 (m, 4 H),

1.44 (m, 1 H), 1.29 (t, 3 H), 0.93 (s, 3 H); mass spectrum FAB+

observed ) 540.2222, estimated ) 540.2226.

4-[(Z)-(4-Br om op h en yl)(et h oxyim in o)m et h yl]-1′-(2,6-

d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (14e). The

compound was prepared from ethyl hydroxylamine hydrochlo-

ride by following the general procedure described above to

afford the ethoxime, which was then converted to compound

14e in subsequent steps by removal of the Boc and treatment

of the resulting amine with 2,6-dimethylbenzoic acid: R_f0.36

(50% EtOAc/hexanes); HPLC t_R) 4.91 min; ¹H NMR CDCl₃δ

7.50 (d, J ) 7.7 Hz, 2 H), 7.15-6.95 (m, 5 H), 4.15 (m, 1 H),

4.05 (q, J ) 7.1 Hz, 2 H), 3.20-3.55 (m, 2 H), 2.90-3.05 (m, 2

H), 2.80 (m, 1 H), 2.35 (m, 1 H), 2.24 (m, 3 H), 2.25 (s, 3 H),

2.10 (m, 2 H), 1.40-2.00 (m, 7 H), 1.25 (m, 1 H), 1.28 (t, J )

7.1 Hz, 3 H), 0.92 (s, 3 H); mass spectrum FAB+ observed )

540.5210, estimated ) 540.5269.

4-[(Z)-(4-Br om op h en yl)(h yd r oxyim in o)m eth yl]-1′-(2,6-

d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (14f). The

compound was prepared from hydroxylamine hydrochloride by

following the general procedure described above to afford the

hydroxyoxime, which was then converted to compound 14f in

subsequent steps by removal of the Boc and treatment of the

resulting amine with 2,6-dimethylbenzoic acid: R_f0.20 (75%

EtOAc/hexanes); HPLC t_R) 4.66 min; ¹H NMR CDCl₃δ 7.49

(d, J ) 7.8 Hz, 2 H), 7.24 (m, 2 H), 7.08-7.17 (m, 1 H), 6.99

(d, J ) 7.8 Hz, 2 H), 3.98 (m, 1 H), 3.65 (m, 1 H), 3.25 (m, 2

H), 3.02 (m, 2 H), 2.86 (m, 1 H), 2.26 (s, 3 H), 2.24 (s, 3 H),

2.15 (m, 2 H), 1.93 (m, 1 H), 1.60-1.84 (m, 4 H), 1.49 (m, 1

H), 1.22-1.38 (m, 2 H), 0.96 (s, 3 H); mass spectrum FAB+

observed ) 514.1896, estimated ) 514.1892.

4-[(Z)-(4-Br om op h en yl)[(1,1-d im et h ylet h oxy)im in o]-

methyl]-1′-(2,6-dimethylbenzoyl)-4′-methyl-1,4′-bipiperidine

(14g). The compound was prepared from O-(tert-butyl)hy-

droxylamine hydrochloride by following the general procedure

described above to afford the tert-butyloxime, which was then

converted to compound 14g in subsequent steps by removal

of the Boc and treatment of the resulting amine with 2,6-

dimethylbenzoic acid: R_f0.40 (35% EtOAc/hexanes); HPLC

t_R) 5.26 min; ¹H NMR CDCl₃δ 7.48 (d, J ) 7.8 Hz, 2 H),

7.08-7.18 (m, 3 H), 7.00 (d, J ) 7.7 Hz, 2 H), 4.10 (m, 1 H),

3.54 (m, 1 H), 3.29 (m, 1 H), 2.98 (m, 2 H), 2.82 (m, 1 H), 2.43

(m, 1 H), 2.29 (s, 3 H), 2.25 (s, 3 H), 1.65-2.20 (m, 8 H), 1.31-

1.58 (m, 2 H), 1.26 (s, 9 H), 0.92 (s, 3 H); mass spectrum FAB+

observed ) 568.2554, estimated ) 568.2539.

4-[(4-Br om op h en yl)[(Z)-(1-m eth yleth yl)im in o]m eth yl]-

1′-(2,6-dim eth ylben zoyl)-4′-m eth yl-1,4′-bipiper idin e (14h ).

The compound was prepared from 2-iodopropane by following

the general procedure described above to afford the isopro-

pyloxime, which was then converted to compound 14h in

subsequent steps by removal of the Boc and treatment of the

resulting amine with 2,6-dimethylbenzoic acid: R_f0.51 (35%

EtOAc/hexanes); HPLC t_R) 5.56 min; ¹H NMR CDCl₃δ 7.50

(d, J ) 7.7 Hz, 2 H), 7.09-7.16 (m, 3 H), 7.00 (d, J ) 7.8 Hz,

2 H), 4.28 (m, 1 H), 4.12 (m, 1 H), 3.47 (m, 1 H), 3.28 (m, 1 H),

2.97 (m, 2 H), 2.82 (m, 1 H), 2.40 (m, 1 H), 2.27 (s, 3 H), 2.24

(s, 3 H), 2.10 (m, 2 H), 1.96 (m, 1 H), 1.22-1.82 (m, 7 H), 1.17

(s, 3 H), 1.15 (s, 3 H), 0.91 (s, 3 H); mass spectrum FAB+

observed ) 554.2387, estimated ) 554.2382.

4-[(Z)-(4-Br om op h e n yl)[(2-h yd r oxye t h oxy)im in o]-

methyl]-1′-(2,6-dimethylbenzoyl)-4′-methyl-1,4′-bipiperidine

(14i). The compound was prepared from (2-bromoethoxy)-tert-

butyldimethylsilane by following the general procedure de-

scribed above to afford the TBS-protected ethoxyoxime. The

protected alcohol was then treated with tetrabutylammonium

fluoride (3 equiv) in THF for 1.5 h to afford the hydroxyethoxy-

oxime, which was then converted to compound 14i in subse-

quent steps by removal of the Boc and treatment of the

resulting amine with 2,6-dimethylbenzoic acid: R_f0.51 (100%

EtOAc); HPLC t_R) 4.40 min; ¹H NMR CDCl₃δ 7.54 (d, 2 H),

Gen er a l P r oced u r e for P r ep a r a tion of Oxim es 14h -

k . (1) To a stirred solution of ketone 12 (2.0 g, 4.30 mmol) in

MeOH (50 mL) and THF (50 mL) were added sodium acetate

(7.1 g, 86 mmol) and hydroxylamine hydrochloride (5.98 g, 86

mmol), and the mixture was stirred at room temperature for

24 h. The resulting mixture was then poured into aqueous

NaOH (10%) and extracted twice with methylene chloride. The

combined extracts were then dried and concentrated to give

2.27 g of oxime 13, where R ) H, as a mixture of E and Z

isomers. Oxime isomers could be separated at this point by

chromatography: Z isomer, R_f0.25 (35% EtOAc/hexanes); ¹H

NMR CDCl₃δ 7.55 (d, J ) 7.8 Hz, 2 H), 7.14 (d, J ) 7.7 Hz,

2 H), 3.22-3.50 (m, 4 H), 2.94 (m, 2 H), 2.41 (m, 1 H), 2.10

(m, 2 H), 1.78 (m, 4 H), 1.45 (s, 9 H), 1.24-1.60 (m, 4 H), 0.90

(s, 3 H).

(2) To a stirred solution of 13 (0.25 g, 0.52 mmol), where R

) H, in THF (3 mL) was added a 0.5 M solution KHMDS (3

equiv) in toluene at 0 °C, and the mixture was stirred at 0 °C

for 1 h. Then the alkyl halide (3 equiv) was added, and the

mixture was stirred at room temperature for 6 h. The reaction

was quenched with water. The resulting mixture was then

poured into aqueous NaOH (10%) and extracted twice with

methylene chloride. The combined extracts were then dried,

concentrated, and chromatographed to yield 0.24 g of oxime

13 (84% for methoxy ethyl). Oxime isomers could be separated

at this point by chromatography if not done previously. For

the methoxy ethyl compound: R_f0.47 (35% EtOAc/hexanes);

¹H NMR CDCl₃δ 7.48 (d, J ) 7.8 Hz, 2 H), 7.11 (d, J ) 7.9

Hz, 2 H), 4.11 (m, 2 H), 3.57 (m, 2 H), 3.25-3.50 (m, 4 H),

3.31 (s, 3 H), 2.91 (m, 2 H), 2.40 (m, 1 H), 2.08 (m, 2 H), 1.75

(m, 4 H), 1.53 (m, 2 H), 1.45 (s, 9 H), 1.31 (m, 2 H), 0.87 (s, 3

H).

(3) Compound 13 was then converted to compound 14 via

the procedure described above in the general procedure for

oxime 1. Purity was checked by LC/MS analysis.

4-[(E)-(4-Br om op h en yl)(m eth oxyim in o)m eth yl]-1′-(2,6-

d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (14b). The

compound was prepared from methyl hydroxylamine hydro-

chloride by following the general procedure described above

to afford the methoxime, which was then converted to com-

pound 14b in subsequent steps by removal of the Boc and

treatment of the resulting amine with 2,6-dimethylbenzoic

1

acid: HPLC t_R) 4.71 min; H NMR CDCl₃δ 7.50 (d, J ) 7.7

Hz, 2 H), 7.23 (m, 2 H), 7.10 (m, 1 H), 6.90 (d, J ) 7.7 Hz, 2

H), 4.03 (m, 1 H), 3.90 (s, 3 H), 3.55 (m, 1 H), 3.20 (m, 3 H),

3.00 (m, 3 H), 2.82 (m, 1 H), 2.24 (s, 3 H), 2.23 (s, 3 H), 2.15

(m, 3 H), 1.80-1.20 (m, 5 H), 0.92 (s, 3 H); mass spectrum

FAB+ observed ) 526.2070, estimated ) 526.2069.

4-[(Z)-(4-Br om op h en yl)(m eth oxyim in o)m eth yl]-1′-(2,6-

d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (14c). The

compound was prepared from methyl hydroxylamine hydro-

chloride by following the general procedure described above

to afford the methoxime, which was then converted to com-

pound 14c in subsequent steps by removal of the Boc and

treatment of the resulting amine with 2,6-dimethylbenzoic

1

acid: HPLC t_R) 4.51 min; H NMR CDCl₃δ 7.50 (d, J ) 7.7

Hz, 2 H), 7.15-6.95 (m, 5 H), 4.15 (m, 1 H), 3.80 (s, 3 H), 3.45

(m, 1 H), 3.25 (m, 1 H), 3.00 (m, 3 H), 2.83 (m, 2 H), 2.24 (s, 3

H), 2.25 (s, 3 H), 2.10 (m, 2 H), 1.80-1.50 (m, 7 H), 0.92 (s, 3

H); ¹³C NMR (75.5 MHz, CDCl₃) δ 169.3, 159.9, 136.7, 133.7,

133.5, 132.9, 131.4, 129.2, 128.0, 127.4, 122.5, 61.7, 53.9, 44.8,

42.6, 41.7, 36.5, 36.4, 35.6, 32.5, 30.6, 30.5, 19.1, 17.8; mass

spectrum FAB+ observed ) 526.2072, estimated ) 526.2069.

Anal. Calcd for C₂₈H₃₆BrN₃O₂: C, 63.87; H, 6.89; N, 7.98.

Found: C, 63.62; H, 6.91; N, 8.03.

4-[(E)-(4-Br om op h en yl)(et h oxyim in o)m et h yl]-1′-(2,6-

d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (14d ). The

compound was prepared from ethyl hydroxylamine hydrochlo-

ride by following the general procedure described above to

afford the ethoxime, which was then converted to compound

14d in subsequent steps by removal of the Boc and treatment

of the resulting amine with 2,6-dimethylbenzoic acid: R_f0.43

3154 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14

Palani et al.

7.10-7.16 (m, 3 H), 7.00 (d, 2 H), 4.13 (br t, 2 H), 3.85 (br t, 2

H), 3.45 (m, 1 H), 3.27 (m, 1 H), 2.99 (m, 2 H), 2.85 (m, 1 H),

2.65 (m, 1 H), 2.40 (m, 1 H), 2.26 (s, 3 H), 2.23 (s, 3 H), 2.20

(m, 2 H), 1.95 (m, 1 H), 1.18-1.83 (m, 7 H), 0.91 (s, 3 H); mass

spectrum FAB+ observed ) 558.2166, estimated ) 558.2154.

t_R) 5.43 min; ¹H NMR CDCl₃δ 7.50 (d, J ) 7.7 Hz, 2 H),

7.24-7.39 (m, 5 H), 7.00-7.17 (m, 5 H), 5.05 (s, 2 H), 4.13 (m,

1 H), 3.47 (m, 1 H), 3.28 (m, 1 H), 2.97 (m, 2 H), 2.80 (m, 1 H),

2.40 (m, 1 H), 2.27 (s, 3 H), 2.23 (s, 3 H), 1.89-2.17 (m, 3 H),

1.69-1.82 (m, 3 H), 1.19-1.65 (m, 4 H), 0.91 (s, 3 H); mass

spectrum FAB+ observed ) 602.2388, estimated ) 602.2382.

4-[(4-Br om op h en yl)[(2-m eth oxyeth oxy)im in o]m eth yl]-

1′-(2,6-d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (14j).

The compound was prepared from 2-bromoethyl methyl ether

by following the general procedure described above to afford

the methoxyethoxyoxime, which was then converted to com-

pound 14j in subsequent steps by removal of the Boc and

treatment of the resulting amine with 2,6-dimethylbenzoic

1′-(2-Am in o-6-ch lor oben zoyl)-4-[(Z)-(4-br om op h en yl)-

(m eth oxyim in o)m eth yl]-4′-m eth yl-1,4′-bip ip er id in e (26).

The compound was prepared from methyl hydroxylamine

hydrochloride by following the general procedure described

above to afford the methoxime, which was then converted to

compound 26 in subsequent steps by removal of the Boc and

treatment of the resulting amine with 2-amino-6-chlorobenzoic

acid. Compound 26 exists as a mixture of nonseparable

1

acid: R_f0.43 (50% EtOAc/hexanes); HPLC t_R) 4.91 min; H

NMR CDCl₃δ (mix of isomers) 7.50 (m, 2 H), 7.25 (m, 2 H),

7.12 (m, 1 H), 7.01 (d, J ) 7.8 Hz, 2 H), 4.15 and 4.27 (m, 2

H), 3.58 and 3.68 (m, 2 H), 3.35 and 3.42 (s, 3 H), 3.25 (m, 1

H), 2.77-3.06 (m, 3 H), 2.40 (m, 1 H), 2.28 (s, 3 H), 2.24 (s, 3

H), 1.14-2.19 (m, 12 H), 0.93 and 0.91 (s, 3 H); mass spectrum

FAB+ observed ) 570.2325, estimated ) 570.2331.

rotational isomers: HPLC t_R) 4.56 min; ¹H NMR CDCl₃

δ

7.55 (m, 2 H), 7.30 (m, 2 H), 7.15 (t, J ) 7.7 Hz, 1 H), 6.75 (d,

J ) 7.8 Hz, 1 H), 6.60 (d, J ) 7.8 Hz, 1 H), 4.25 (m, 2 H), 3.80

(s, 2 H), 3.40 (m, 2 H), 2.80-3.20 (m, 4 H), 2.40 (m, 2 H), 1.40-

2.20 (m, 8 H), 0.90 (s, 3 H); mass spectrum FAB+ observed )

549.2133, estimated ) 526.2130.

E t h yl[(4-b r om op h e n yl)[1′-(2,6-d im e t h ylb e n zoyl)-4′-

m eth yl-[1,4′-bip ip er id in ]-4-yl]m eth ylen e]a m in ooxya ce-

ta te (14k ). The compound was prepared from ethyl bromoace-

tate by following the general procedure described above to

afford the ethylacetateoxime, which was then converted to

compound 14k in subsequent steps by removal of the Boc and

treatment of the resulting amine with 2,6-dimethylbenzoic

1′-(2-Hydr oxy-6-m eth ylben zoyl)-4-[(Z)-(4-br om oph en yl)-

(m eth oxyim in o)m eth yl]-4′-m eth yl-1,4′-bip ip er id in e (27).

The compound was prepared from methyl hydroxylamine

hydrochloride by following the general procedure described

above to afford the methoxime, which was then converted to

compound 27 in subsequent steps by removal of the Boc and

treatment of the resulting amine with 2-hydroxy-6-methyl

benzoic acid. Compound 27 exists as a mixture of nonseparable

1

acid: R_f0.49 (50% EtOAc/hexanes); HPLC t_R) 5.01 min; H

NMR CDCl₃δ (mix of isomers) 7.51 (m, 2 H), 7.24 (m, 2 H),

7.20 (m, 1 H), 7.00 (d, J ) 7.7 Hz, 2 H), 4.54 and 4.69 (s, 2 H),

4.10-4.25 (q, 2 H), 4.04 (m, 1 H), 3.55 (m, 1 H), 3.26 (m, 2 H),

2.99 (m, 2 H), 2.82 (m, 1 H), 2.41 (m, 1 H), 2.24 (s, 3 H), 2.22

(s, 3 H), 2.15-2.21 (m, 2 H), 1.36-1.99 (m, 7 H), 1.25-1.31 (t,

3 H), 0.93 and 0.91 (s, 3 H); mass spectrum FAB+ observed )

598.2272, estimated ) 598.2280.

rotational isomers: HPLC t_R) 4.41 min; ¹H NMR CDCl₃

δ

7.55 (m, 2 H), 7.15 (m, 1 H), 6.90 (m, 2 H), 6.35 (m, 1 H), 6.20

(m, 1 H), 4.40 (m, 2 H), 4.00-4.20 (m, 1 H), 3.80 and 3.75 (s,

3 H), 3.20-3.56 (m, 3 H), 2.80-3.20 (m, 4 H), 2.40 (m, 2 H),

2.10 (s, 3 H), 1.20-1.90 (m, 6 H), 0.90 (s, 3 H); Anal. Calcd for

C

₂₇H₃₅BrClN₃O₃‚H₂O (hydrochloride salt): C, 55.72; H, 6.01;

N, 7.22. Found: C, 55.91; H, 6.36; N, 6.86.

(Z)-2-[(4-Br om op h e n yl)[1′-(2,6-d im e t h ylb e n zoyl)-4′-

m et h yl-[1,4′-b ip ip er id in ]-4-yl]m et h ylen e]a m in ooxy-N-

m eth yla ceta m id e (14l). The compound was prepared from

carboxymethoxylamine hemihydrochloride by following the

general procedure described above to afford the carboxy-

methoxime, which was then converted to the amide in subse-

quent steps by removal of the Boc and treatment of the

resulting amine with 2,6-dimethylbenzoic acid. The car-

boxymethoxime was then converted to compound 14l by

treatment with methylamine (1 equiv), EDCI (1 equiv), and

HOBT (1 equiv) in methylene chloride for 10 h followed by

purification via chromatography: R_f0.55 (20% EtOH/EtOAc);

¹H NMR CDCl₃δ 7.47 (d, J ) 7.7 Hz, 2 H), 7.25 (m, 2 H), 7.12

(m, 1 H), 6.99 (d, J ) 7.8 Hz, 2 H), 4.81 (s, 2 H), 4.04 (m, 1 H),

3.55 (m, 1 H), 3.28 (m, 2 H), 2.80-3.02 (m, 3 H), 2.98 (s, 3 H),

2.27 (s, 3 H), 2.24 (s, 3 H), 2.18 (m, 2 H), 1.55-1.97 (m, 5 H),

1.20-1.52 (m, 3 H), 0.91 (s, 3 H); mass spectrum FAB+

observed ) 583.2295, estimated ) 583.2284.

1′-(2-Am in o-6-m eth ylben zoyl)-4-[(Z)-(4-br om op h en yl)-

(m eth oxyim in o)m eth yl]-4′-m eth yl-1,4′-bip ip er id in e (28).

The compound was prepared from methyl hydroxylamine

hydrochloride by following the general procedure described

above to afford the methoxime, which was then converted to

compound 28 in subsequent steps by removal of the Boc and

treatment of the resulting amine with 2-amino-6-methylben-

zoic acid. Compound 28 exists as a mixture of nonseparable

rotational isomers: HPLC t_R) 4.36 min; ¹H NMR CDCl₃

δ

7.55 (d, J ) 7.8 Hz, 2 H), 7.25 (m, 2 H), 7.15 (m, 1 H), 6.50-

6.60 (m, 2 H), 4.25 (m, 1 H), 4.05 (m, 1 H), 3.80 (s, 3 H), 3.50

(m, 1 H), 3.40 (m, 2 H), 3.17 (m, 1 H), 2.95 (m, 1 H), 2.83 (m,

1 H), 2.40 (m, 1 H), 2.02 and 1.98 (s, 3 H), 2.20 (m, 2 H), 1.95

(m, 1 H), 1.78 (m, 1 H), 1.22-1.65 (m, 4 H), 0.90 (s, 3 H); ¹³C

NMR (75.5 MHz, CDCl₃) δ 168.6, 168.4, 159.8, 143.0, 142.7,

134.7, 134.6, 132.9, 132.8, 131.3, 129.1, 129.0, 123.1, 122.9,

122.4, 120.0, 113.4, 113.4, 61.7, 53.9, 44.7, 42.6, 42.1, 42.0, 36.9,

36.8, 35.7, 36.5, 35.7, 35.6, 30.5, 35.7, 35.6, 30.6, 30.5, 19.2,

19.1, 17.9, 16.6; mass spectrum FAB+ observed ) 529.1017,

estimated ) 529.1015.

4-[(Z)-(4-Br om op h en yl)(p h en oxyim in o)m eth yl]-1′-(2,6-

d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (14m ). The

compound was prepared from O-phenylhydroxylamine hydro-

chloride by following the general procedure described above

to afford the phenyloxime, which was then converted to

compound 14m in subsequent steps by removal of the Boc and

treatment of the resulting amine with 2,6-dimethylbenzoic

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-1′-[2-flu -

or o-6-(tr iflu or om eth yl)ben zoyl]-4′-m eth yl-1,4′-bip ip er i-

d in e (29). The compound was prepared from ethyl hydroxy-

lamine hydrochloride by following the general procedure

described above to afford the ethoxime, which was then

converted to compound 29 in subsequent steps by removal of

the Boc and treatment of the resulting amine with 2-fluoro-

6-(trifluoromethyl)benzoic acid. Compound 29 exists as a

mixture of nonseparable rotational isomers: R_f0.65 (35%

EtOAc/hexanes); HPLC t_R) 5.36 min; ¹H NMR CDCl₃δ 7.48-

7.54 (m, 4 H), 7.30 (m, 1 H), 7.12 (d, J ) 7.7 Hz, 2 H), 4.19 (m,

1 H), 4.07 (q, J ) 8.0 Hz, 2 H), 3.39 (m, 2 H), 2.76-3.05 (m, 3

H), 2.40 (m, 1 H), 1.90-2.17 (m, 3 H), 1.78 (m, 3 H), 1.25-

1.62 (m, 4 H), 1.20 (t, J ) 8.0 Hz, 3 H), 0.91 (s, 3 H); mass

spectrum FAB+ observed ) 600.1688, estimated ) 600.1672.

1

acid: R_f0.55 (50% EtOAc/hexanes); HPLC t_R) 5.76 min; H

NMR CDCl₃δ 7.55 (d, J ) 7.8 Hz, 2 H), 6.95-7.30 (m, 10 H),

4.18 (m, 1 H), 3.49 (m, 2 H), 3.30 (m, 1 H), 3.01 (m, 2 H), 2.89

(m, 1 H), 2.54 (m, 1 H), 2.27 (s, 3 H), 2.24 (s, 3 H), 2.15 (m, 1

H), 1.82-2.04 (m, 3 H), 1.58-1.81 (m, 3 H), 1.20-1.50 (m, 2

H), 0.93 (s, 3 H); mass spectrum FAB+ observed ) 588.2222,

estimated ) 588.2228.

4-[(E /Z)-(4-Br om op h e n yl)[(p h e n ylm e t h oxy)im in o]-

m eth yl]-1′-(2,6-d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er i-

d in e (14n ). The compound was prepared from O-benzylhy-

droxylamine hydrochloride by following the general procedure

described above to afford the benzyloxime, which was then

converted to compound 14n in subsequent steps by removal

of the Boc and treatment of the resulting amine with 2,6-

dimethylbenzoic acid: R_f0.57 (50% EtOAc/hexanes); HPLC

4-[(Z)-(4-Br om oph en yl)(m eth oxyim in o)m eth yl]-1′-[(2,6-

d im et h yl-3-p yr id in yl)ca r b on yl]-4′-m et h yl-1,4′-b ip ip er i-

din e (30a). The compound was prepared from methyl hydroxyl-

amine hydrochloride by following the general procedure de-

Oximino-Piperidinio-Piperidine Amides

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3155

scribed above to afford the methoxime, which was then

converted to compound 30a in subsequent steps by removal

of the Boc and treatment of the resulting amine with 2,6-

dimethylnicotinic acid: R_f0.72 (20% EtOH/EtOAc); HPLC t_R

converted to compound 34 in the subsequent steps by removal

of the Boc and treatment of the resulting amine with 2-hy-

droxy-4,6-dimethylnicotinic acid: ¹H NMR CDCl₃δ 7.50 (d, J

) 7.8 Hz, 2 H), 7.11 (d, J ) 7.7 Hz, 2 H), 5.89 (s, 1 H), 4.11 (m,

1 H), 4.01-4.08 (q, 2 H), 3.10-3.53 (m, 3 H), 2.80-2.99 (m, 2

H), 2.39 (m, 1 H), 2.23 (s, 3 H), 2.15 and 2.12 (s, 3 H), 1.67-

2.01 (m, 5 H), 1.24-1.63 (m, 5 H), 1.18 (t, 3 H), 0.90 and 0.89

(s, 3 H).

1

) 3.66 min; H NMR CDCl₃δ 8.33 (d, J ) 7.8 Hz, 1 H), 7.51

(d, J ) 7.7 Hz, 2 H), 7.09 (d, J ) 7.8 Hz, 2 H), 6.98 (d, J ) 7.8

Hz, 1 H), 4.26 (m, 1 H), 3.80 (s, 3 H), 3.31 (m, 1 H), 2.91-3.04

(m, 4 H), 2.85 (m, 1 H), 2.48 and 2.45 (s, 3 H), 2.25 and 2.23

(s, 3 H), 1.71-2.19 (m, 7 H), 1.20-1.63 (m, 3 H), 0.92 (s, 3 H);

mass spectrum FAB+ observed ) 527.2021, estimated )

527.2022.

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-1′-[(4-h y-

d r oxy-2-m et h yl-3-p yr id in yl)ca r bon yl]-4′-m et h yl-1,4′-b i-

p ip er id in e (35). The compound was prepared from ethyl

hydroxylamine hydrochloride by following the general proce-

dure described above to afford the ethoxime, which was then

converted to compound 35 in the subsequent steps by removal

of the Boc and treatment of the resulting amine with 2-hy-

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-1′-[(2,6-

d im et h yl-3-p yr id in yl)ca r b on yl]-4′-m et h yl-1,4′-b ip ip er i-

d in e (30b). The compound was prepared from ethyl hydroxyl-

amine hydrochloride by following the general procedure de-

scribed above to afford the ethoxime, which was then converted

to compound 30b in the subsequent steps by removal of the

Boc and treatment of the resulting amine with 2,6-dimeth-

ylnicotinic acid: R_f0.75 (20% EtOH/EtOAc); HPLC t_R) 3.98

1

droxy-4-methylnicotinic acid: HPLC t_R) 4.21 min; H NMR

CDCl₃δ 7.51 (d, J ) 7.3 Hz, 2 H), 7.30 (d, J ) 10.3 Hz, 1 H),

7.10 (d, J ) 7.3 Hz, 2 H), 6.42 (d, J ) 10.3 Hz, 1 H), 4.10 (m,

1 H), 4.04 (q, J ) 7.7 Hz, 2 H), 3.41 (m, 2 H), 3.22 (m, 2 H),

2.90 (m, 2 H), 2.37 (s, 3 H), 2.12 (m, 2 H), 1.73-1.96 (m, 4 H),

1.35-1.60 (m, 4 H), 1.21 (t, J ) 7.7 Hz, 3 H), 0.91 (s, 3 H);

mass spectrum FAB+ observed ) 543.1974, estimated )

543.1971.

1

min; H NMR CDCl₃δ 8.35 (d, J ) 7.8 Hz, 1 H), 7.51 (d, J )

7.7 Hz, 2 H), 7.11 (d, J ) 7.6 Hz, 2 H), 6.97 (d, J ) 7.8 Hz, 1

H), 4.19 (m, 1 H), 4.06 (q, J ) 7.1 Hz, 2 H), 3.24-3.50 (m, 2

H), 2.97 (m, 2 H), 2.81 (m, 1 H), 2.47 and 2.49 (s, 3 H), 2.40

(m, 1 H), 2.26 and 2.28 (s, 3 H), 1.92-2.18 (m, 3 H), 1.35-

1.85 (m, 7 H), 1.19 (t, J ) 7.1 Hz, 3 H), 0.92 (s, 3 H); mass

spectrum FAB+ observed ) 541.2188, estimated ) 541.2178.

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-1′-[(2,6-

d im et h yl-3-p yr id in yl)ca r b on yl]-4′-m et h yl-1,4′-b ip ip er i-

d in e N-Oxid e (1). The compound was prepared from ethyl

hydroxylamine hydrochloride by following the general proce-

dure described above to afford the ethoxime, which was then

converted to compound 1 in the subsequent steps by removal

of the Boc and treatment of the resulting amine with 2,6-

dimethylnicotinic acid N-oxide: R_f0.29 (20% EtOH/EtOAc);

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-4′-m eth -

yl-1′-[(2-m et h yl-3-p yr id in yl)ca r b on yl]-1,4′-b ip ip er id in e

(31). The compound was prepared from ethyl hydroxylamine

hydrochloride by following the general procedure described

above to afford the ethoxime, which was then converted to

compound 31 in the subsequent steps by removal of the Boc

and treatment of the resulting amine with 2-methylnicotinic

1

HPLC t_R) 4.43 min; H NMR CDCl₃δ 8.15 (d, J ) 7.8 Hz, 1

H), 7.25 (AB system, 4 H), 7.00 (d, J ) 7.8 Hz, 1 H), 4.20 (m,

1 H), 4.02 (q, J ) 7.1 Hz, 2 H), 3.25-3.45 (m, 2 H), 2.80-3.00

(m, 3 H), 2.47 and 2.44 (s, 3 H), 2.24 and 2.27 (s, 3 H), 2.10

(m, 3 H), 1.20-1.85 (m, 8 H), 1.20 (t, J ) 7.1 Hz, 3 H), 0.92 (s,

3 H); ¹³C NMR (75.5 MHz, CDCl₃) δ 165.1, 164.7, 159.1, 145.0,

138.3, 133.0, 131.3, 129.3, 124.8, 122.3, 69.4, 53.8, 44.8, 44.7,

42.4, 42.0, 37.0, 36.9, 36.4, 36.3, 35.5, 32.5, 30.6, 18.4, 18.0,

17.8, 15.2, 15.2, 14.6; mass spectrum FAB+ observed )

557.2130, estimated ) 557.2127. Anal. Calcd for C₃₂H₄₃BrN₄O₉

(tartarate salt): C, 54.32; H, 6.13; N, 7.92. Found: C, 54.37;

H, 6.43; N, 7.58.

1

acid: HPLC t_R) 3.90 min; H NMR CDCl₃δ 8.53 (d, J ) 7.8

Hz, 1 H), 7.45-7.55 (m, 3 H), 7.09-7.55 (m, 3 H), 4.13 (m, 1

H), 4.01 (m, 2 H), 3.72 (m, 1 H), 3.39 (m, 2 H), 3.00 (m, 2 H),

2.83 (m, 1 H), 2.54 (s, 3 H), 2.41 (m, 1 H), 2.11 (m, 2 H), 1.98

(m, 1 H), 1.67-1.86 (m, 3 H), 1.35-1.67 (m, 3 H), 1.18-1.24

(m, 3 H), 0.92 (s, 3 H); mass spectrum FAB+ observed )

527.2025, estimated ) 527.2022.

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-4′-m eth -

yl-1′-(3-pyr idin ylcar bon yl)-1,4′-bipiper idin e (32). The com-

pound was prepared from ethyl hydroxylamine hydrochloride

by following the general procedure described above to afford

the ethoxime, which was then converted to compound 32 in

the subsequent steps by removal of the Boc and treatment of

the resulting amine with nicotinic acid: HPLC t_R) 4.15 min;

¹H NMR CDCl₃δ 8.66 (br s, 2 H), 7.74 (d, J ) 7.8 Hz, 1 H),

7.56 (d, J ) 7.7 Hz, 2 H), 7.34 (m, 1 H), 7.11 (d, J ) 7.8 Hz, 2

H), 4.03-4.10 (m, 2 H), 3.49 (m, 2 H), 3.30 (m, 1 H), 2.78-

3.02 (m, 2 H), 2.43 (m, 1 H), 2.12 (m, 2 H), 1.97 (m, 1 H), 1.79

(m, 3 H), 1.24-1.65 (m, 5 H), 1.18-1.22 (m, 3 H), 0.93 (s, 3

H); mass spectrum FAB+ observed ) 513.1863, estimated )

513.1865.

P r ep a r a tion of 2,6-Dim eth yln icotin ic Acid N-Oxid e. To

a stirred solution of 2,6-dimethylnicotinic acid (2.0 g, 13.2

mmol) in DMF-MeOH (100-40 mL) was added a 48% solution

of THF (1.0 mL, 23.8 mmol) followed by 3-chloroperoxybenzoic

acid (6.1 g, 26.5 mmol). The reaction mixture was stirred at

room temperature for 24 h before being poured into cold water

(300 mL) with stirring. The reaction mixture was then filtered,

and the filtrate was concentrated in vacuo. The resulting

precipitate was then washed with chloroform and dried to

afford 1.36 g (61%) of the N-oxide as a white solid: ¹H NMR

DMSO-d₆δ 8.2 (d, J ) 6.9 Hz, 1 H), 7.15 (d, J ) 6.9 Hz, 1 H),

2.30 (s, 3 H), 2.00 (s, 3 H).

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-1′-[(6-h y-

d r oxy-2,4-d im eth yl-3-p yr id in yl)ca r bon yl]-4′-m eth yl-1,4′-

bip ip er id in e (33). The compound was prepared from ethyl

hydroxylamine hydrochloride by following the general proce-

dure described above to afford the ethoxime, which was then

converted to compound 33 in the subsequent steps by removal

of the Boc and treatment of the resulting amine with 6-hy-

droxy-2,4-dimethylnicotinic acid: R_f0.60 (20% EtOH/EtOAc);

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-4′-m eth -

yl-1′-(3-pyr idin ylcar bon yl)-1,4′-bipiper idin e N-Oxide (36).

The compound was prepared from ethyl hydroxylamine hy-

drochloride by following the general procedure described above

to afford the ethoxime, which was then converted to compound

36 in the subsequent steps by removal of the Boc and

treatment of the resulting amine with nicotinic acid N-oxide:

1

HPLC t_R) 4.17 min; H NMR CDCl₃δ 7.53 (d, J ) 7.8 Hz, 2

HPLC t_R) 4.12 min; H NMR CDCl₃δ 8.22 (br s, 2 H), 7.54

H), 7.12 (d, J ) 7.8 Hz, 2 H), 6.28 (s, 1 H), 4.15 (m, 1 H), 4.07

(q, J ) 7.7 Hz, 2 H), 3.38 (m, 2 H), 3.17 (m, 1 H), 2.71-3.01

(m, 2 H), 2.02 (m, 1 H), 2.28 and 2.31 (s, 3 H), 2.13 and 2.15

(s, 3 H), 1.72-2.09 (m, 5 H), 1.24-1.65 (m, 5 H), 1.20 (t, J )

7.7 Hz, 3 H), 0.93 (s, 3 H); mass spectrum FAB+ observed )

557.2124, estimated ) 557.2127.

(d, J ) 7.8 Hz, 2 H), 7.24-7.35 (m, 2 H), 7.10 (d, J ) 7.7 Hz,

2 H), 4.10 (m, 1 H), 4.03-4.08 (q, 2 H), 3.20-3.55 (m, 3 H),

2.78-3.00 (m, 2 H), 2.44 (m, 1 H), 2.14 (m, 2 H), 1.98 (m, 1

H), 1.67-1.89 (m, 3 H), 1.25-1.61 (m, 4 H), 1.18-1.22 (t, 3

H), 0.92 (s, 3 H); mass spectrum FAB+ observed ) 529.1803,

estimated ) 529.1814.

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-1′-[(2-h y-

d r oxy-4,6-d im eth yl-3-p yr id in yl)ca r bon yl]-4′-m eth yl-1,4′-

bip ip er id in e (34). The compound was prepared from ethyl

hydroxylamine hydrochloride by following the general proce-

dure described above to afford the ethoxime, which was then

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-4′-m eth -

yl-1′-[(2-m eth yl-3-pyr idin yl)car bon yl]-1,4′-bipiper idin e N-

Oxid e (37). The compound was prepared from ethyl hydrox-

ylamine hydrochloride by following the general procedure

described above to afford the ethoxime, which was then

3156 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14

Palani et al.

converted to compound 37 in the subsequent steps by removal

of the Boc and treatment of the resulting amine with 2-me-

thylnicotinic acid N-oxide: R_f0.43 (20% EtOH/EtOAc); HPLC

t_R) 4.36 min; ¹H NMR CDCl₃δ 8.25 (d, 1 H), 7.51 (d, J ) 7.6

Hz, 2 H), 7.09-7.20 (m, 4 H), 4.14 (m, 1 H), 4.04 (q, J ) 8.0

Hz, 2 H), 3.38 (m, 2 H), 2.76-3.05 (m, 3 H), 2.49 and 2.46 (s,

3 H), 2.40 (m, 1 H), 2.10 (m, 2 H), 1.97 (m, 1 H), 1.78 (m, 3 H),

1.32-1.65 (m, 4 H), 1.20 (t, J ) 8.0 Hz, 3 H), 0.92 (s, 3 H);

mass spectrum FAB+ observed ) 543.1969, estimated )

543.1971.

4-[(Z)-(4-Br om op h en yl)(eth oxyim in o)m eth yl]-4′-m eth -

yl-1′-[(3-m eth yl-2-pyr idin yl)car bon yl]-1,4′-bipiper idin e N-

Oxid e (38). The compound was prepared from ethyl hydrox-

ylamine hydrochloride by following the general procedure

described above to afford the ethoxime, which was then

converted to compound 38 in the subsequent steps by removal

of the Boc and treatment of the resulting amine with 2-me-

thylpicolinic acid N-oxide: ¹H NMR CDCl₃δ 8.03 (m, 2 H),

7.51 (d, J ) 7.8 Hz, 2 H), 7.12 (m, 3 H), 4.17 (m, 1 H), 3.99-

4.08 (q, 2 H), 3.24-3.75 (m, 5 H), 2.39 (m, 1 H), 2.31 and 2.27

(s, 3 H), 1.83-2.18 (m, 5 H), 1.45-1.82 (m, 5 H), 1.15-1.22 (t,

3 H), 0.89 (s, 3 H).

2.43 and 2.41 (s, 3 H), 2.23 (br s, 3 H), 1.92-2.19 (m, 3 H),

1.70-1.87 (m, 3 H), 1.23-1.63 (m, 5 H), 1.15-1.19 (t, 3 H),

0.92 (br s, 3 H); mass spectrum FAB+ observed ) 557.2800,

estimated ) 557.2798.

P r ep a r a tion of 1′-(2,6-Dim eth ylben zoyl)-4′-m eth yl-4-

[[4-(m et h ylt h io)p h en yl]m et h yl]-1,4′-b ip ip er id in e (5k ).

Compound 12 was converted to the amide in subsequent steps

by removal of the Boc and treatment of the resulting amine

with 2,6-dimethylbenzoic acid. The aryl bromide was then

treated with sodium thiomethoxide (2.5 equiv) in DMF at 70

°C for 24 h to afford the methylsulfide compound. Next, the

ketone was reduced with NaBH₄(2.5 equiv) in methanol for 1

h followed by treatment with excess triethylsilane (50 equiv)

and excess TFA (100 equiv) at 50 °C for 1 h. The mixture was

concentrated and chromatographed to afford compound 5k : R_f

0.29 (75% EtOAc/hexanes); HPLC t_R) 4.85 min; ¹H NMR

CDCl₃δ 7.18 (d, J ) 7.8 Hz, 2 H), 6.98-7.15 (m, 5 H), 4.10

(m, 1 H), 3.52 (m, 1 H), 3.30 (m, 1 H), 3.00 (m, 1 H), 2.90 (m,

1 H), 2.74 (m, 1 H), 2.48 (m, 2 H), 2.45 (s, 3 H), 2.25 (s, 3 H),

2.22 (s, 3 H), 1.87-2.08 (m, 3 H), 1.64 (m, 2 H), 1.44 (m, 2 H),

1.10-1.33 (m, 4 H), 0.90 (s, 3 H); mass spectrum FAB+

observed ) 451.2776, estimated ) 451.2783.

P r ep a r a tion of 1′-(2,6-Dim eth ylben zoyl)-4′-m eth yl-4-

[[4-(m eth ylsu lfon yl)ph en yl]m eth yl]-1,4′-bipiper idin e (5l).

Compound 5k was treated with sodium perborate (2.1 equiv)

in acetic acid for 24 h, concentrated, and chromatographed to

4-[(Z)-(4-Br om oph en yl)(m eth oxyim in o)m eth yl]-1′-[(2,6-

d im et h yl-3-p yr id in yl)ca r b on yl]-4′-m et h yl-1,4′-b ip ip er i-

d in e N-Oxid e (39a ). The compound was prepared from

methyl hydroxylamine hydrochloride by following the general

procedure described above to afford the methoxime, which was

then converted to compound 39a in subsequent steps by

removal of the Boc and treatment of the resulting amine with

2,6-dimethylnicotinic acid N-oxide: R_f0.55 (20% EtOH/

1

afford compound 5l: HPLC t_R) 4.11 min; H NMR CDCl₃δ

7.85 (d, J ) 7.8 Hz, 2 H), 7.32 (d, J ) 7.7 Hz, 2 H), 7.12 (m, 1

H), 7.00 (d, J ) 7.8 Hz, 2 H), 4.11 (m, 1 H), 3.52 (m, 1 H), 3.29

(m, 1 H), 3.04 (s, 3 H), 3.00 (m, 1 H), 2.92 (m, 1 H), 2.78 (m, 1

H), 2.62 (m, 2 H), 2.27 (s, 3 H), 2.25 (s, 3 H), 1.89-2.09 (m, 3

H), 1.37-1.80 (m, 4 H), 1.16-1.33 (m, 4 H), 0.90 (s, 3 H); mass

spectrum FAB+ observed ) 483.2690, estimated ) 483.2681.

1

EtOAc); HPLC t_R) 4.16 min; H NMR CDCl₃δ 8.15 (d, J )

7.8 Hz, 1 H), 7.53 (d, J ) 7.7 HZ, 2 H), 7.09 (d, J ) 7.6 Hz, 2

H), 6.99 (d, J ) 7.8 Hz, 1 H), 4.19 (m, 1 H), 3.81 (s, 3 H), 3.33

(m, 2 H), 2.97 (m, 2 H), 2.82 (m, 1 H), 2.44 (s, 3 H), 2.25 (s, 3

H), 1.96-2.20 (m, 2 H), 1.70-1.90 (m, 5 H), 1.16-1.65 (m, 4

H), 0.92 (s, 3 H); mass spectrum FAB+ observed ) 545.1949,

estimated ) 545.1920.

P r ep a r a tion of 4-(4-Br om oben zoyl)-1′-(2,6-d im eth yl-

b en zoyl)-4′-m et h yl-1,4′-b ip ip er id in e (21). Compound 12

was converted to the amide in subsequent steps by removal

of the Boc and treatment of the resulting amine with 2,6-

dimethylbenzoic acid to afford compound 21: HPLC t_R) 4.86

1′-[(2,4-Dim et h yl-3-p yr id in yl)ca r b on yl]-4′-m et h yl-4-

[(Z)-[4-(m eth ylsu lfon yl)p h en yl](m eth oxyim in o)m eth yl]-

1,4′-bipiper idin e N-Oxide (39d). The bromide 12 was treated

with sodium thiomethoxide (2.5 equiv) in DMF at 70 °C for

24 h to afford the methylsulfide compound. The sulfide was

then oxidized with Oxone (3 equiv) in methanol at 0 °C for 4

h, concentrated, and chromatographed to afford the methyl-

sulfone (82%). The compound was then prepared from methyl

hydroxylamine hydrochloride by following the general proce-

dure described above to afford the methoxime, which was then

converted to compound 39d in subsequent steps by removal

of the Boc and treatment of the resulting amine with 2,6-

dimethylnicotinic acid N-oxide: R_f0.51 (20% EtOH/EtOAc);

1

min; H NMR CDCl₃δ 7.80 (d, J ) 9.7 Hz, 2 H), 7.60 (d, J )

9.7 Hz, 2 H), 7.00 (m, 3 H), 4.07 (m, 1 H), 2.86-3.51 (m, 6 H),

2.32 (s, 6 H), 2.24 (m, 2 H), 1.68-2.02 (m, 6 H), 1.49 (m, 1 H),

1.31 (m, 1 H), 0.96 (s, 3 H); mass spectrum FAB+ observed )

497.1801, estimated ) 497.1804.

P r ep a r a tion of 4-[(4-Br om op h en yl)h yd r oxym eth yl]-1′-

(2,6-d im et h ylb en zoyl)-4′-m et h yl-1,4′-b ip ip er id in e (22).

Compound 12 was converted to the amide in subsequent steps

by removal of the Boc and treatment of the resulting amine

with 2,6-dimethylbenzoic acid. The ketone was then reduced

by treatment with NaBH₄(25 equiv) in methanol for 1 h. The

mixture was concentrated and chromatographed to afford the

1

alcohol 22: HPLC t_R) 4.61 min; H NMR CDCl₃δ 7.47 (d, J

HPLC t_R) 3.16 min; H NMR CDCl₃δ 8.14 (d, J ) 7.8 Hz, 1

) 7.8 Hz, 2 H), 7.09-7.20 (m, 3 H), 6.99 (d, J ) 7.7 Hz, 2 H),

4.37 (m, 1 H), 4.10 (m, 1 H), 2.67-3.58 (m, 6 H), 2.25 (s, 6 H),

1.15-2.14 (m, 11 H), 0.89 (s, 3 H); mass spectrum FAB+

observed ) 501.1944, estimated ) 501.1944.

H), 7.95 (d, J ) 7.3 Hz, 2 H), 7.39 (d, J ) 7.0 Hz, 2 H), 6.99 (d,

J ) 7.8 Hz, 1 H), 4.16 (m, 1 H), 3.79 (s, 3 H), 3.24-3.40 (m, 2

H), 3.07 (s, 3 H), 2.97 (m, 2 H), 2.82 (m, 1 H), 2.43 and 2.42 (s,

3 H), 2.24 (br s, 3 H), 1.95-2.18 (m, 3 H), 1.70-1.88 (m, 3 H),

1.16-1.66 (m, 5 H), 0.92 (br s, 3 H); mass spectrum FAB+

observed ) 543.2654, estimated ) 543.2641.

P r ep a r a tion of 4-[1-(4-Br om op h en yl)eth yl]-1′-(2,6-d i-

m et h ylb en zoyl)-4′-m et h yl-1,4′-b ip ip er id in e (23). Com-

pound 12 was converted to the amide in subsequent steps by

removal of the Boc and treatment of the resulting amine with

2,6-dimethylbenzoic acid. The ketone was then treated with a

3.0 M MeMgBr solution (3 equiv) in THF for 1 h to afford the

tertiary alcohol, which was then reduced by treatment with

excess triethylsilane (50 equiv) and excess TFA (100 equiv) at

50 °C for 24 h. The mixture was concentrated and chromato-

graphed to afford compound 23: ¹H NMR CDCl₃δ 7.40 (d, J

) 7.7 Hz, 2 H), 7.13 (m, 1 H), 7.02 (m, 4 H), 4.98 (m, 1 H),

4.07 (m, 1 H), 3.19-3.75 (m, 5 H), 2.30-3.04 (m, 5 H), 2.25 (s,

3 H), 2.23 (s, 3 H), 1.35-2.19 (m, 6 H), 1.21 (br d, 3 H), 0.89

(s, 3 H); mass spectrum FAB+ observed ) 499.2142, estimated

) 499.2147.

1′-[(2,4-Dim et h yl-3-p yr id in yl)ca r b on yl]-4′-m et h yl-4-

[(Z)-[4-(m et h ylsu lfon yl)p h en yl](et h oxyim in o)m et h yl]-

1,4′-bip ip er id in e N-Oxid e (39h ). The bromide 12 was

treated with sodium thiomethoxide (2.5 equiv) in DMF at 70

°C for 24 h to afford the methylsulfide compound. The sulfide

was then oxidized with Oxone (3 equiv) in methanol at 0 °C

for 4 h, concentrated, and chromatographed to afford the

methylsulfone (82%). The compound was then prepared from

ethyl hydroxylamine hydrochloride by following the general

procedure described above to afford the ethoxime, which was

then converted to compound 39h in subsequent steps by

removal of the Boc and treatment of the resulting amine with

2,6-dimethylnicotinic acid N-oxide: R_f0.49 (20% EtOH/

1

EtOAc); HPLC t_R) 3.43 min; H NMR CDCl₃δ 8.13 (d, J )

P r ep a r a tion of 4-[1-(4-Br om op h en yl)eth en yl]-1′-(2,6-

d im eth ylben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (24). Methyl

triphenylphosphonium bromide (1.6 equiv) was dissolved in

THF, and BuLi (1.6 equiv) was added dropwise at -78 °C. The

7.8 Hz, 1 H), 7.95 (d, J ) 7.7 Hz, 2 H), 7.40 (d, J ) 7.7 Hz, 2

H), 6.99 (d, J ) 7.6 Hz, 1 H), 4.20 (m, 1 H), 4.01-4.10 (q, 2 H),

3.24-3.38 (m, 2 H), 3.18 (s, 3 H), 2.97 (m, 2 H), 2.82 (m, 1 H),

Oximino-Piperidinio-Piperidine Amides

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3157

mixture was stirred at -40 °C for 30 min. The mixture was

recooled to -78 °C, and 12 (1 equiv) in THF was added

dropwise. The mixture was stirred for 20 h, gradually warming

to room temperature. The crude material was then converted

to 24 in subsequent steps by removal of the Boc and treatment

of the resulting amine with 2,6-dimethylbenzoic acid: ¹H NMR

CDCl₃δ 7.41 (d, J ) 7.6 Hz, 2 H), 7.15 (d, J ) 7.7 Hz, 2 H),

7.09 (m, 1 H), 6.98 (d, J ) 7.6 Hz, 2 H), 5.14 (s, 1 H), 5.01 (s,

1 H), 4.13 (m, 1 H), 3.46 (m, 1 H), 3.27 (m, 1 H), 2.99 (m, 2 H),

2.81 (m, 1 H), 2.25 (s, 3 H), 2.22 (s, 3 H), 1.90-2.19 (m, 3 H),

1.61-1.84 (m, 4 H), 1.18-1.50 (m, 4 H), 0.91 (s, 3 H); mass

spectrum FAB+ observed ) 495.2002, estimated ) 495.2011.

H), 3.34 (m, 2 H), 2.79 (m, 2 H), 2.35 (m, 2 H), 1.97 (m, 2 H),

1.12-1.87 (m, 4 H), 1.46 (s, 9 H), 1.37 (m, 2 H), 0.93 (s, 3 H).

(6) To a stirred solution of the above Boc compound (0.08 g,

0.18 mmol) in methylene chloride (5 mL) was added TFA (0.5

mL), and the mixture was stirred at room temperature for 2

h. The mixture was concentrated, poured into 10% NaOH, and

extracted twice with methylene chloride. The combined ex-

tracts were dried and concentrated to afford 0.065 g (100%) of

amine. To a stirred solution of this crude amine (0.05 g, 0.14

mmol) in methylene chloride (3 mL) were added 2,6-dimeth-

ylbenzoic acid (0.03 g, 0.21 mmol), EDCI (0.04 g, 0.21 mmol),

DIPEA (0.3 mL), and HOBT (0.03 g, 0.21 mmol), and the

mixture was stirred for 18 h at room temperature. The reaction

was quenched with 10% NaOH, and the mixture was extracted

twice with methylene chloride. The combined extracts were

dried, concentrated, and chromatographed to afford 0.034 g

P r ep a r a tion of 4-(4-Br om op h en oxy)-1′-(2,6-d im eth yl-

ben zoyl)-4′-m eth yl-1,4′-bip ip er id in e (25). (1) To a stirred

solution of 1,4-dioxa-8-azaspiro[4.5]decane (32 mL, 249.6

mmol) and N-tert-butoxycarbonyl piperidinone (52.2 g, 262.1

mmol) in 1,2-dichloroethane (200 mL) was added titanium

isopropoxide (104 mL, 349.5 mmol), and the mixture was

stirred for 19 h at room temperature. The reaction mixture

was concentrated, and a 1.0 M solution of diethylaluminum

cyanide (27.2 mL) was added at room temperature. The

mixture was stirred for 4 h at room temperature; it was then

cooled to 0 °C, diluted with EtOH (500 mL) and water (50 mL),

and stirred a further 1 h. The mixture was then filtered

through Celite, and the resulting filtrate was then concen-

trated to afford 48.9 g (61%) of cyano compound: R_f0.73 (50%

(50%) of amide 25: R_f0.40 (50% EtOAc/hexanes); HPLC t_R

)

4.61 min; ¹H NMR CDCl₃δ 7.35 (d, J ) 7.7 Hz, 2 H), 7.11 (m,

1 H), 7.00 (d, J ) 7.6 Hz, 2 H), 6.76 (d, J ) 7.7 Hz, 2 H), 4.22

(m, 2 H), 3.48 (m, 1 H), 3.30 (m, 1 H), 3.03 (m, 1 H), 2.77 (m,

2 H), 2.34 (m, 1 H), 2.25 (s, 6 H), 1.96 (m, 3 H), 1.74 (m, 3 H),

1.20-1.53 (m, 3 H), 0.95 (s, 3 H); mass spectrum FAB+

observed ) 485.1790, estimated ) 485.1763.

P r ep a r a t ion of 4-F or m yl-1′-(ter t-b u t oxyca r b on yl)-4′-

m eth yl-1,4′-bip ip er id in e (15). (1) To a stirred solution of the

olefin 3 (15.6 g, 66.4 mmol) in THF (100 mL) was added a 1.0

M solution of borane in THF (79.7 mL, 79.7 mmol) at 0 °C

dropwise. The mixture was stirred for 18 h, gradually warming

to room temperature. The mixture was recooled to 0 °C, and

a THF/EtOH (1:1, 50 mL) solution was added followed by a

pH ) 7 buffer (50 mL) and a 30% aqueous H₂O₂solution (50

mL). The mixture was stirred at room temperature for 24 h.

The mixture was basified with 10% NaOH and extracted with

EtOAc (3 times). The combined organic layers were washed

with brine, dried, concentrated, and chromatographed to yield

1

EtOAc/hexanes); H NMR CDCl₃δ 3.91-4.07 (m, 6 H), 3.15

(m, 2 H), 2.75 (m, 4 H), 2.12 (m, 2 H), 1.61-1.81 (m, 6 H),

1.46 (s, 9 H).

(2) To a stirred solution of the above cyanide (48.9 g, 153.45

mmol) in THF (300 mL) was added a 3.0 M solution of

MeMgBr in ether (153.4 mL, 460.2 mmol) at room tempera-

ture, and the mixture was stirred for 4.5 h. The reaction was

quenched with saturated aqueous ammonium chloride, and

the mixture was extracted twice with methylene chloride. The

extracts were concentrated to afford 46.41 g (89%) of methy-

lated compound: R_f0.61 (50% EtOAc/hexanes); ¹H NMR CDCl₃

δ 3.90 (m, 4 H), 3.41 (m, 2 H), 3.30 (m, 2 H), 2.52 (m, 4 H),

1.59-1.81 (m, 6 H), 1.42 (s, 9 H), 1.31 (m, 2 H), 0.89 (s, 3 H).

1

7.0 g (41%) of alcohol: R_f0.45 (20% EtOH/EtOAc); H NMR

CDCl₃δ 3.43 (d, 2 H), 3.35 (m, 4 H), 2.89 (m, 2 H), 2.05 (m, 2

H), 1.73 (m, 4 H), 1.41 (s, 9 H), 1.07-1.40 (m, 5 H), 0.88 (s, 3

H).

(3) To a stirred solution of the above ketal (46.41 g, 136.5

mmol) in EtOAc (350 mL) were added 6 N HCl (200 mL) and

concentrated HCl (75 mL), and the mixture was stirred at room

temperature for 4 h. Concentration gave 30.0 g (100%) of crude

ketone. To a stirred solution of this crude ketone (136.5 mmol)

were added diethyl ether (500 mL) and 20% aqueous NaOH

(500 mL), and the solution was stirred for 30 min. BOC₂O (35.7

g, 163.8 mmol) was added incrementally, and the mixture was

stirred for 48 h. The layers were separated, and the organic

layer was washed with brine, dried, concentrated, and chro-

matographed to afford 17.1 g (42%) of Boc-protected amine:

R_f0.68 (50% EtOAc/hexanes); ¹H NMR CDCl₃δ 3.55 (m, 2 H),

3.36 (m, 2 H), 2.80 (m, 4 H), 2.40 (m, 4 H), 1.85 (m, 2 H), 1.48

(s, 9 H), 1.38-1.48 (m, 2 H), 0.95 (s, 3 H).

(4) To a stirred solution of the above ketone (1.7 g, 5.74

mmol) in methanol (7 mL) was added NaBH₄(0.33 g, 8.61

mmol) at 0 °C. The mixture was stirred for 1.5 h, gradually

warming to room temperature. The mixture was concentrated,

diluted with EtOAc, washed with water and brine, dried,

concentrated, and chromatographed to afford 0.82 g (50%) of

alcohol: R_f0.23 (75% EtOAc/hexanes); ¹H NMR CDCl₃δ 3.66

(m, 1 H), 3.27-3.55 (m, 4 H), 2.79 (m, 2 H), 2.21 (m, 2 H),

1.71-1.96 (m, 4 H), 1.44 (s, 9 H), 1.29-1.57 (m, 4 H), 0.90 (s,

3 H).

(5) To a stirred solution of the above alcohol (0.25 g, 0.84

mmol) in THF (6 mL) were added 4-bromophenol (0.146 g, 0.84

mmol), triphenylphosphine (0.26 g, 1.10 mmol), and diethyl

azodicarboxylate (0.16 mL, 1.01 mmol). The mixture was

stirred for 18 h at room temperature. The reaction was

quenched with saturated aqueous bicarbonate, and the mix-

ture was extracted twice with diethyl ether. The extracts were

washed with water and brine, dried, concentrated, and chro-

matographed to afford 0.08 g (22%) of Mitsunobu product: R_f

0.61 (50% EtOAc/hexanes); ¹H NMR CDCl₃δ 7.33 (d, J ) 7.6

Hz, 2 H), 6.77 (d, J ) 7.8 Hz, 2 H), 4.23 (m, 1 H), 3.47 (m, 2

(2) To a stirred solution of the above alcohol (2.33 g, 9.21

mmol) in methylene chloride (100 mL) at 0 °C were added

4-methylmorpholine N-oxide (NMO) (1.62 g, 13.81 mmol) and

tetrapropylammonium perruthenate (TPAP) (0.323 g, 0.92

mmol), and the mixture was stirred at room temperature for

1 h. The mixture was diluted with Et₂O and passed through a

pad of silica gel and Celite eluting with EtOAc. The filtrate

was concentrated to afford 1.47 g (64%) of crude aldehyde 15:

R_f0.67 (20% EtOH/EtOAc); ¹H NMR CDCl₃δ 9.63 (s, 1 H),

3.46 (m, 2 H), 3.30 (m, 2 H), 2.84 (m, 2 H), 2.20 (m, 2 H), 1.48-

2.00 (m, 6 H), 1.44 (s, 9 H), 1.34 (m, 3 H), 0.89 (s, 3 H).

Gen er a l P r oced u r e for P r ep a r a tion of Oxim es 39b,

39c, 39f, a n d 39g. (1) To a stirred solution of 1-bromo-4-

(trifluoromethoxy)benzene (1.4 equiv) or 4-bromobenzotrifluo-

ride (1.4 equiv) in THF was added nBuLi (1.3 equiv) at -78

°C, and the mixture was stirred at -78 °C for 20 min. Aldehyde

15 (1 equiv) was added as a THF solution at -78 °C, and the

mixture was stirred at -78 °C for 1 h, warmed to room

temperature, and stirred for 1 h. The reaction was quenched

with water, and the mixture was extracted with methylene

chloride (3 times). The combined extracts were washed with

brine, dried, concentrated, and chromatographed to afford 16

(62% for CF₃, 78% for OCF₃). For the CF₃compound: R_f0.40

(100% EtOAc); ¹H NMR CDCl₃δ 7.61 (d, J ) 8.7 Hz, 2 H),

7.43 (d, J ) 8.7 Hz, 2 H), 4.49 (m, 1 H), 3.27-3.52 (m, 4 H),

2.96 (m, 1 H), 2.87 (m, 1 H), 1.87-2.11 (m, 4 H), 1.75 (m, 2

H), 1.59 (m, 2 H), 1.46 (s, 9 H), 1.22-1.42 (m, 4 H), 0.88 (s, 3

H).

(2) To a stirred solution of the above alcohol 16 (1 equiv) in

methylene chloride at 0 °C were added NMO (1.5 equiv) and

TPAP (0.1 equiv), and the mixture was stirred at room

temperature for 1 h. The mixture was diluted with Et₂O and

passed through a pad of silica gel and Celite eluting with

EtOAc. The filtrate was concentrated to afford crude ketone

17 (63% for CF₃, 65% for OCF₃). To a stirred solution of this

3158 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14

Palani et al.

crude ketone 17 (1 equiv) in MeOH were added sodium acetate

(20 equiv) and O-methyl or O-ethyl hydroxylamine hydrochlo-

ride (20 equiv), and the mixture was stirred at room temper-

ature for 24 h. The resulting mixture was then poured into

aqueous NaOH (10%) and extracted twice with methylene

chloride. The combined extracts were then dried, concentrated,

and chromatographed to yield oxime 18 as a mixture of E and

Z isomers. The isomers were separated by chromatography.

For the CF₃(Z)-ethyl oxime compound: R_f0.35 (20% EtOAc/

hexanes); ¹H NMR CDCl₃δ 7.45 (d, J ) 8.7 Hz, 2 H), 7.15 (d,

J ) 8.7 Hz, 2 H), 3.89 (q, J ) 8.0 Hz, 2 H), 3.07-3.31 (m, 4

H), 2.75 (m, 2 H), 2.28 (m, 1 H), 1.93 (m, 2 H), 1.60 (m, 4 H),

1.39 (m, 2 H), 1.28 (s, 9 H), 1.19 (m, 2 H), 1.02 (t, J ) 8.0 Hz,

3 H), 0.73 (s, 3 H).

4-[(Z)-(4-Ch lor oph en yl)(m eth oxyim in o)m eth yl]-1′-[(2,4-

d im eth yl-3-p ip er id in yl)ca r bon yl]-4′-m eth yl-1,4′-bip ip er i-

d in e N-Oxid e (39e). The compound was prepared from

methyl hydroxylamine hydrochloride by following the general

procedure described above to afford the methoxime, which was

then converted to compound 39e in subsequent steps by

removal of the Boc and treatment of the resulting amine with

1

2,6-dimethylnicotinic acid N-oxide: HPLC t_R) 3.91 min; H

NMR CDCl₃δ 8.12 (d, J ) 7.8 Hz, 1 H), 7.33 (d, J ) 7.7 Hz,

2 H), 7.12 (d, J ) 7.6 Hz, 2 H), 6.98 (d, J ) 7.7 Hz, 1 H), 4.20

(m, 1 H), 3.79 (s, 3 H), 3.22-3.48 (m, 2 H), 2.95 (m, 2 H), 2.80

(m, 1 H), 2.40 and 2.44 (s, 3 H), 2.21 and 2.24 (s, 3 H), 1.90-

2.18 (m, 4 H), 1.70-1.88 (m, 3 H), 1.30-1.68 (m, 4 H), 0.92

(br s, 3 H); mass spectrum FAB+ observed ) 499.2471,

estimated ) 499.2476.

(3) To a stirred solution of 18 (1 equiv) in methylene chloride

was added trifluoroacetic acid (20 equiv), and the mixture was

stirred at room temperature for 2 h. The mixture was

concentrated, poured into 10% NaOH, and extracted twice with

methylene chloride. The combined extracts were dried and

concentrated to afford an amine. To a stirred solution of this

crude amine (1 equiv) in methylene chloride were added 2,6-

dimethylnicotinic acid N-oxide (1.5 equiv), EDCI (1.5 equiv),

DIPEA (2 equiv), and HOBT (1.5 equiv), and the mixture was

stirred for 12 h at room temperature. The reaction was

quenched with saturated NaHCO₃, and the mixture was

extracted twice with methylene chloride. The combined ex-

tracts were dried and concentrated to yield oxime 19. Purity

was checked by LC/MS analysis.

4-[(Z)-(E t h oxyim in o)[4-(t r iflu or om et h yl)p h en yl]m e-

th yl]-1′-[(2,4-d im eth yl-3-p ip er id in yl)ca r bon yl]-4′-m eth yl-

1,4′-bip ip er id in e N-Oxid e (39f). The compound was pre-

pared from ethyl hydroxylamine hydrochloride by following

the general procedure described above to afford the ethoxime,

which was then converted to compound 39f in subsequent

steps by removal of the Boc and treatment of the resulting

amine with 2,6-dimethylnicotinic acid N-oxide: HPLC t_R

)

4.56 min; ¹H NMR CDCl₃δ 8.18 (d, J ) 7.8 Hz, 1 H), 7.65 (d,

J ) 7.8 Hz, 2 H), 7.33 (d, J ) 7.6 Hz, 2 H), 6.97 (d, J ) 7.6 Hz,

1 H), 4.15 (m, 1 H), 4.05-4.09 (q, 2 H), 3.25-3.55 (m, 2 H),

2.98 (m, 2 H), 2.82 (m, 1 H), 2.42 and 2.46 (s, 3 H), 2.23 and

2.26 (s, 3 H), 1.92-2.20 (m, 2 H), 1.72-1.90 (m, 4 H), 1.35-

1.68 (m, 4 H), 1.20-1.29 (m, 1 H), 1.14-1.20 (t, 3 H), 0.92 (br

s, 3 H); mass spectrum FAB+ observed ) 547.2901, estimated

) 547.2896.

Gen er a l P r oced u r e for P r ep a r a tion of Oxim es 39e a n d

39i. To a stirred solution of aldehyde 15 (0.67 g, 2.07 mmol)

in THF (15 mL) at 0 °C was added a 1.0 M solution of

4-chlorophenylmagnesium bromide (4.14 mL) in THF. The

mixture was stirred for 5 h, gradually warming to room

temperature. The reaction was quenched with saturated NH₄-

Cl, and the mixture was extracted with methylene chloride (3

times). The combined extracts were washed with brine, dried,

concentrated, and chromatographed to afford 16 (47%): ¹H

NMR CDCl₃δ 7.16-7.27 (m, 4 H), 4.27 (d, 1 H), 3.31 (m, 4 H),

2.90 (m, 1 H), 2.79 (m, 1 H), 1.85-2.05 (m, 4 H), 1.56-1.80

(m, 4 H), 1.40 (s, 9 H), 1.10-1.32 (m, 4 H), 0.83 (s, 3 H).

4-[(Z)-(E t h oxyim in o)[4-(t r iflu or om e t h oxy)p h e n yl]-

m eth yl]-1′-[(2,4-dim eth yl-3-piper idin yl)car bon yl]-4′-m eth -

yl-1,4′-bip ip er id in e N-Oxid e (39g). The compound was

prepared from ethyl hydroxylamine hydrochloride by following

the general procedure described above to afford the ethoxime,

which was then converted to compound 39g in subsequent

steps by removal of the Boc and treatment of the resulting

amine with 2,6-dimethylnicotinic acid N-oxide: R_f0.47 (1:1

ratio of CH₂Cl₂:acetone); HPLC t_R) 4.43 min; ¹H NMR CDCl₃

δ 8.12 (d, J ) 7.8 Hz, 1 H), 7.15-7.30 (m, 4 H), 6.95 (d, J )

7.8 Hz, 1 H), 4.15 (m, 1 H), 3.95-4.15 (q, 2 H), 3.20-3.45 (m,

2 H), 2.93 (m, 2 H), 2.78 (m, 1 H), 2.40 and 2.44 (s, 3 H), 2.35-

2.45 (m, 1 H), 2.19 and 2.23 (s, 3 H), 1.70-2.20 (m, 6 H), 1.20-

1.65 (m, 4 H), 1.10-1.25 (t, 3 H), 0.89 (br s, 3 H); mass

spectrum FAB+ observed ) 563.2855, estimated ) 563.2845.

Alcohol 16 was converted to oxime 19 by following the

general procedure described above for compounds 39b, 39c,

39f, and 39g.

4-[(Z)-(Meth oxyim in o)[4-(tr iflu or om eth yl)p h en yl]m e-

th yl]-1′-[(2,4-d im eth yl-3-p ip er id in yl)ca r bon yl]-4′-m eth yl-

1,4′-bip ip er id in e N-Oxid e (39b). The compound was pre-

pared from methyl hydroxylamine hydrochloride by following

the general procedure described above to afford the methoxime,

which was then converted to compound 39b in subsequent

steps by removal of the Boc and treatment of the resulting

4-[(Z)-(4-Ch lor op h en yl)(eth oxyim in o)m eth yl]-1′-[(2,4-

d im eth yl-3-p ip er id in yl)ca r bon yl]-4′-m eth yl-1,4′-bip ip er i-

d in e N-Oxid e (39i). The compound was prepared from ethyl

hydroxylamine hydrochloride by following the general proce-

dure described above to afford the ethoxime, which was then

converted to compound 39i in subsequent steps by removal of

the Boc and treatment of the resulting amine with 2,6-

dimethylnicotinic acid N-oxide: R_f0.49 (20% EtOH/EtOAc);

amine with 2,6-dimethylnicotinic acid N-oxide: HPLC t_R

)

3.86 min; ¹H NMR CDCl₃δ 8.14 (d, J ) 7.3 Hz, 1 H), 7.64 (d,

J ) 7.3 Hz, 2 H), 7.31 (d, J ) 7.0 Hz, 2 H), 6.98 (d, J ) 7.6 Hz,

1 H), 4.20 (m, 1 H), 3.80 (s, 3 H), 3.32-3.40 (m, 2 H), 2.95 (m,

2 H), 2.71 (m, 1 H), 2.40 and 2.44 (s, 3 H), 2.21 and 2.25 (s, 3

H), 1.98-2.19 (m, 2 H), 1.81 (m, 5 H), 1.43-1.55 (m, 4 H), 0.92

(br s, 3 H); mass spectrum FAB+ observed ) 533.2758,

estimated ) 533.2740.

1

HPLC t_R) 4.01 min; H NMR CDCl₃δ 8.15 (d, J ) 7.8 Hz, 1

H), 7.35 (d, J ) 7.6 Hz, 2 H), 7.18 (d, J ) 7.7 Hz, 2 H), 6.98 (d,

J ) 7.7 Hz, 1 H), 4.04 (q, 2 H), 3.73-3.83 (m, 1 H), 3.25-3.53

(m, 2 H), 2.76-3.02 (m, 3 H), 2.46 and 2.42 (s, 3 H), 2.25 and

2.21 (s, 3 H), 1.95-2.19 (m, 1 H), 1.70-1.95 (m, 6 H), 1.35-

1.66 (m, 4 H), 1.15-1.20 (t, 3 H), 0.92 (br s, 3 H); mass

spectrum FAB+ observed ) 513.2642, estimated ) 513.2632.

4-[(Z)-(Met h oxyim in o)[4-(t r iflu or om et h oxy)p h en yl]-

m eth yl]-1′-[(2,4-dim eth yl-3-piper idin yl)car bon yl]-4′-m eth -

yl-1,4′-bip ip er id in e N-Oxid e (39c). The compound was

prepared from methyl hydroxylamine hydrochloride by fol-

lowing the general procedure described above to afford the

methoxime, which was then converted to compound 39c in

subsequent steps by removal of the Boc and treatment of the

resulting amine with 2,6-dimethylnicotinic acid N-oxide: R_f

1′-[(2,4-Dim eth yl-3-p yr id in yl)ca r bon yl]-4-[(Z)-(4-flu o-

r op h en yl)(eth oxyim in o)m eth yl]-4′-m eth yl-1,4′-bip ip er i-

d in e N-Oxid e (39j). (1) To a stirred solution of 4-(4-

fluorobenzoyl)piperidine hydrochloride (4.9 g, 20 mmol) in

ether (200 mL) were added 10% NaOH (100 mL) and BOC₂O

(4.4 g, 20 mmol), and the mixture was stirred at room

temperature overnight. The layers were separated, and the

organic layer was washed with brine, dried, and concentrated

to give a crude Boc-protected amino ketone. To a stirred

solution of this crude ketone (5.0 g, 17.3 mmol) in MeOH were

added sodium acetate (7.3 g, 86.8 mmol) and O-ethyl hydroxy-

lamine hydrochloride (8.4 g, 86.8 mmol), and the mixture was

stirred at room temperature for 24 h. The resulting mixture

1

0.27 (96:4:1 ratio of CH₂Cl₂:MeOH:NH₄OH); H NMR CDCl₃

δ 8.12 (d, J ) 7.8 Hz, 1 H), 7.12-7.25 (m, 4 H), 6.95 (d, J )

7.8 Hz, 1 H), 4.25 (m, 1 H), 3.75 (s, 3 H), 3.20-3.45 (m, 2 H),

2.90 (m, 2 H), 2.78 (m, 2 H), 2.38 and 2.42 (s, 3 H), 2.19 and

2.22 (s, 3 H), 1.85-2.15 (m, 2 H), 1.65-1.85 (m, 4 H), 1.10-

1.84 (m, 4 H), 0.88 (br s, 3 H); mass spectrum FAB+ observed

) 549.2686, estimated ) 549.2689.

Oximino-Piperidinio-Piperidine Amides

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3159

was then poured into aqueous NaOH (10%) and extracted

twice with methylene chloride. The combined extracts were

then dried and concentrated to yield 5.36 g (94%) of crude

constant, K_i, was determined from the experimental IC₅₀

values using GraphPad PRISM software analysis.

Vir a l En tr y Assa y. Replication-defective HIV-1 virus

containing the reported gene for luciferase was used to infect

U-87 cells expressing CD4 and CCR5. Infections were carried

out in the presence or absence of compound, and luciferase

activity was measured after 3 days. The data are reported as

the concentration of compound required to reduce luciferase

production by 50% compared with control cultures. Compounds

were tested in triplicate at 8 concentrations ranging from 0.1

to 100 nM. The triplicates were averaged, and dose-response

curves were generated using GraphPad PRISM software.

Typically, the 95% confidence limit for experimental IC₅₀was

within 1 log and the R²variance between 0.9 and 1.0. Intra-

experimental IC₅₀values typically varied less than 0.5 log.

HIV-1 Rep lica tion Assa y. Peripheral blood mononuclear

cells (PBMCs) were pretreated with compound for 1 h at 37

°C and subsequently infected in triplicate with a panel of

CCR5-tropic HIV-1 isolates for 3 h. Following infection, the

cells were washed to remove residual viral inoculum and

cultured in the presence of compound for 4-6 days. Culture

supernatants were harvested, and viral replication was mea-

sured by determination of viral p24 antigen concentration by

ELISA. Compounds were tested in triplicate at 11 concentra-

tions ranging from 1000 to 0.001 nM. The triplicates were

averaged, and dose-response curves were generated using

GraphPad PRISM software. Typically, the 95% confidence

limit for experimental IC₅₀was within 1 log or less and the R²

variance between 0.85 and 1.0. Because primary PBMCs from

different donors can vary widely in both CCR5 expression and

viral infectivity, the IC₅₀values for a single viral isolate could

vary as much as 1.5 log between experiments using different

donor cells. Therefore, compounds were typically compared

head to head in the same experiment using the same donor

and viral inoculum.

oxime as a mixture of E and Z isomers: ¹H NMR CDCl₃

δ

7.20-7.37 (m, 2 H), 7.00-7.10 (m, 2 H), 4.18 and 4.05 (q, 2

H), 3.30 and 2.60 (m, 1 H), 2.75 (m, 2 H), 1.62-1.80 (m, 6 H),

1.44 (s, 9 H), 1.22 and 1.30 (t, 3 H).

(2) To a stirred solution of the above oxime (5.4 g, 16.2 mmol)

in methylene chloride (50 mL) was added trifluoroacetic acid

(25 mL, 324 mmol), and the mixture was stirred at room

temperature for 2 h. The mixture was concentrated, poured

into 10% NaOH, and extracted twice with methylene chloride.

The combined extracts were dried and concentrated to afford

2.25 g (61%) of crude amine. To a stirred solution of this crude

amine (2.2 g, 9 mmol) and N-tert-butoxycarbonyl-4-piperidi-

none (1.9 g, 9.5 mmol) in 1,2-dichloroethane (20 mL) was added

titanium isopropoxide (5.6 mL, 18.9 mmol), and the mixture

was stirred for 12 h at room temperature. The mixture was

concentrated, and a 1.0 M solution of diethylaluminum cyanide

(18.9 mL) was added at room temperature. The mixture was

stirred for 3 h, and then diluted with EtOAc. The reaction was

quenched with water (5 mL), and the mixture was stirred a

further 2 h. The mixture was then filtered through Celite, and

the resulting filtrate was then concentrated to afford 4.61 g of

crude cyano compound:

E isomer, R_f0.54 (20% EtOAc/

hexanes); Z isomer, R_f0.48 (20% EtOAc/hexanes); ¹H NMR

CDCl₃δ 7.22-7.37 (m, 2 H), 7.00-7.10 (m, 2 H), 4.18 and 4.04

(q, 2 H), 3.95 (m, 2 H), 3.10 (m, 4 H), 2.22 (m, 2 H), 2.10 (m,

2 H), 1.58-1.90 (m, 7 H), 1.44 (s, 9 H), 1.30 and 1.20 (t, 3 H).

(3) To a stirred solution of the above cyanide (4.5 g, 9.8

mmol) in THF (100 mL) was added a 1.4 M solution of

MeMgBr in toluene/THF (35.0 mL, 49.1 mmol) at room

temperature, and the mixture was stirred for 4 h. The reaction

was then quenched with saturated aqueous ammonium chlo-

ride, and the mixture was extracted twice with methylene

chloride. The extracts were washed with brine, dried, concen-

trated, and chromatographed to afford 0.93 g (22%) of the

desired methylated Z isomer: R_f0.26 (20% EtOAc/hexanes);

¹H NMR CDCl₃δ 7.00 (m, 2 H), 6.85 (m, 2 H), 3.85 (q, 2 H),

3.23 (m, 2 H), 3.09 (m, 2 H), 2.70 (m, 2 H), 2.21 (m, 1 H), 1.89

(m, 2 H), 1.57 (m, 4 H), 1.36 (m, 2 H), 1.24 (s, 9 H), 1.10 (m, 2

H), 0.99 (t, 3 H), 0.68 (s, 3 H).

Ack n ow led gm en t. We thank Drs. A. K. Ganguly,

J . J . Piwinski, and G. R. Reyes for their strong support

and Drs. S. McCombie and J . Tagat for many helpful

discussions. We thank Dr. B. Neustadt for the procedure

for the synthesis of 2,6-dimethylnicotinic acid N-oxide.

We are also grateful to S. Cox, S. Xu, L. Wojcik, and N.

Wagner from Antiviral Research for their technical

assistance. We also thank Dr. T. M. Chan for NMR

characterization of oxime isomers as well as Dr. J . Wong

and his group for the synthesis of intermediates.

(4) To a stirred solution of the above Z oxime (0.93 g, 2.08

mmol) in methylene chloride (10 mL) was added trifluoroacetic

acid (3.2 mL, 41.6 mmol), and the mixture was stirred at room

temperature for 1 h. The mixture was concentrated, poured

into 10% NaOH, and extracted twice with methylene chloride.

The combined extracts were dried and concentrated to afford

0.73 g (100%) of crude amine. To a stirred solution of this crude

amine (0.05 g, 0.16 mmol) in methylene chloride (3 mL) were

added 2,6-dimethylnicotinic acid N-oxide (0.05 g, 0.32 mmol),

EDCI (0.06 g, 0.32 mmol), DIPEA (0.3 mL), and HOBT (0.04

g, 0.32 mmol), and the mixture was stirred for 12 h at room

temperature. The reaction was quenched with saturated

NaHCO₃, and the mixture was extracted twice with methylene

chloride. The combined extracts were dried, concentrated, and

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(20% EtOH/EtOAc); HPLC t_R) 3.88 min; H NMR CDCl₃

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J M0200815

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Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity

DOI: 10.1021/jm0200815

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