Synthesis and structure-activity relationship studies of CD4 down-modulating cyclotriazadisulfonamide (CADA) analogues

J. Med. Chem. 2006, 49, 1291-1312

1291

Synthesis and Structure-Activity Relationship Studies of CD4 Down-Modulating

Cyclotriazadisulfonamide (CADA) Analogues

Thomas W. Bell,*^,†Sreenivasa Anugu,^†Patrick Bailey,^†Vincent J. Catalano,^†Kaka Dey,^†Michael G. B. Drew,^‡

Noah H. Duffy,^†Qi Jin,^†Meinrado F. Samala,^†Andrej Sodoma,^§William H. Welch,^|Dominique Schols, and Kurt Vermeire

Departments of Chemistry and Biochemistry, UniVersity of NeVada, Reno, NeVada 89557, and Department of Chemistry, The UniVersity,

Reading, UK, Department of Chemistry, State UniVersity of New York, Stony Brook, New York, and Rega Institute for Medical Research,

Katholieke UniVersiteit, LeuVen, Belgium

ReceiVed July 21, 2005

HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV

chemotherapy. Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically down-

modulating cell-surface and intracellular CD4. An effective five-step synthesis of CADA in 30% overall

yield is reported. This synthesis has also been modified to produce more than 50 analogues. Many tail-

group analogues have been made by removing the benzyl tail of CADA and replacing it with various alkyl,

acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of sidearm analogues, including two

unsymmetrical compounds, have also been prepared by modifying the CADA synthesis, replacing the

toluenesulfonyl sidearms with other sulfonyl groups. Testing 30 of these compounds in MT-4 cells shows

a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Three-

dimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using

comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis

(CoMSIA) approaches. The X-ray crystal structures of four compounds, including CADA, show the same

major conformation of the central 12-membered ring. The solid-state structure of CADA was energy

minimized and used to generate the remaining 29 structures, which were similarly minimized and aligned

to produce the 3D-QSAR models. Both models indicate that steric bulk of the tail group, and, to a lesser

extent, the sidearms mainly determine CD4 down-modulation potency in this series of compounds.

Introduction

The CD4 glycoprotein, a major functional cell surface

molecule, is predominantly expressed on T-lymphocytes, an

important helper T-cell subset.¹It is also present on the

membranes of several other immune cell types such as mac-

rophages/monocytes, dendritic, and Langerhans cells. Various

in vitro and in vivo studies have implicated CD4 in several steps

of physiological T-cell activation.^2,3Because of the central role

of CD4⁺T cells as regulators of immune function, they are

Figure 1. Molecular structure of cyclotriazadisulfonamide (CADA )

believed to play an important part in the pathogenesis of a

variety of immunologically based diseases (e.g. asthma, rheu-

matoid arthritis, and diabetes), and anti-CD4 monoclonal

antibodies have been explored as a therapeutic approach for

these diseases.^4-8CD4 is also the main receptor enabling

infection by the human immunodeficiency virus (HIV),^9,10so

it is receiving attention as an important target for therapeutic

intervention. Viral entry inhibitors are actively being pursued

as novel anti-HIV agents,^11-13including anti-CD4 antibodies^14,15

and chemokine receptor antagonists.^16,17Multiple domains of

CD4 are involved in the viral entry process;¹⁸therefore, down-

regulation of the complete CD4 receptor^19,20may be considered

a more effective method for CD4 blocking in the treatment of

HIV infections. Antisense oligonucleotides have been demon-

strated to partially reduce lymphocyte surface CD4 expression.²¹

9-benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclodo-

decane) and general formula of sidearm (X,Y) and tail (Z) analogues,

with ring numbering scheme.

However, treatment of the cells with the small molecule

cyclotriazadisulfonamide (CADA, Figure 1) results in more

profound CD4 down-modulation.²²

CADA has been found to specifically decrease the amounts

of cell-surface and intracellular CD4 by almost 90% in MT-4

cells, without altering the expression of any other cellular

receptor examined, including HIV coreceptors.²²Similar reduc-

tion of CD4 expression was observed in other T-cell lines (i.e.,

SupT1, MOLT-4, CEM, and Jurkat), in freshly isolated blood

lymphocytes and monocytes, in monocytic cell lines (i.e., THP-1

and U937) and in CD4 transfected cells (i.e., U87, A2.01 and

C3.2).^19,20Time course experiments revealed that CD4 down-

modulation by CADA differs in its mechanism of action from

aurintricarboxylic acid, which binds to CD4, and phorbol

myristate acetate, which activates protein kinase C.²²CD4

mRNA levels are not affected by CADA, suggesting that CD4

expression is not inhibited at a transcriptional level. Despite its

superficial structural resemblance to bicyclams,^16,23CADA does

not inhibit HIV replication by simply binding to a cell surface

* To whom correspondence should be addressed at Department of

Chemistry/216, University of Nevada. Phone: 775-784-1842. Fax: 775-

784-6804. E-mail: twb@unr.edu.

^†Department of Chemistry, University of Nevada.

^‡The University, Reading.

^§State University of New York.

^|Department of Biochemistry, University of Nevada.

Rega Institute.

Published on Web 02/02/2006

1292 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

Scheme 1^a

Scheme 2^a

^aReagents and conditions: (a) BnCl, NaI, Na₂CO₃, CH₃CN (83%); (b)

H₂, Ni, NaOH, EtOH (72%); (c) TsCl, NaOH, CH₂Cl₂, H₂O (89%); (d)

3-chloro-2-chloromethyl-1-propene, NaH, DMF, 100 °C (54%); (e) HCl,

H₂O, CH₂Cl₂(100%).

^aReagents and conditions: (a) methyl, ethyl or propyl chloroformate,

1,2-dichloroethane, reflux (76-83%); (b) 1-chloroethyl chloroformate, 1,2-

dichloroethane, reflux; methanol, reflux (86%); (c) 3-chloromethylpyridine

hydrochloride, triethylamine, DMF; HCl (15%); (d) formic acid, formal-

dehyde, NaOH, H₂O (58%).

receptor or coreceptor and preventing the interaction of gp120

with the receptors. Recently, it was found that the anti-HIV

effect of CADA is synergistic with those of antiviral drugs

operating by diverse mechanisms, including inhibitors of HIV

reverse transcriptase, protease and attachment/entry.²⁴

overall) is an effective method for production of CADA as an

intermediate for synthesis of tail analogues. This route also

serves as a model for preparation of sidearm analogues, as

described subsequently.

The specific molecular target of CADA remains unknown,

and studies have been initiated to map its structure-activity

relationships.²⁵In a series of more than 25 CADA analogues,

anti-HIV potency was directly correlated with CD4 down-

modulation ability.²⁵Most of the analogues prepared to date

have various sidearms (X and Y) or tail groups (Z, cf. Figure

1). Several “headgroup” analogues have also been synthesized

in which the exocyclic CdC bond is removed or replaced by a

polar group, but these compounds generally show decreased

potency.²⁵Here we detail the synthesis of CADA and a wide

range of sidearm and tail analogues, as well as the X-ray crystal

conformations of four of these compounds. These analogues

were designed to determine how varying the physicochemical

characteristics of sidearm and tail groups affects CD4 down-

modulating potency in cell culture assays. These results have

been used, in turn, to develop 3D QSAR models for predicting

potencies of novel CADA analogues.

Methyl, ethyl, and isopropyl carbamate tail analogues (4, 95-

213, and QJ033, respectively), were prepared in high yield by

reaction of CADA with the corresponding chloroformate in

refluxing 1,2-dichloroethane (Scheme 2). As reported previ-

ously,²⁶reaction of CADA with R-chloroethyl chloroformate

(ACE-Cl)^29,30under the same conditions, followed by cleavage

of the intermediate carbamate in hot methanol, results in

complete removal of the tail group. Hydrochloride salt 94-

129 is isolated in high yield from reactions starting with several

grams of CADA per batch. An alternate procedure involving

cleavage of ethyl carbamates with boron triiodide N,N-diethyl-

aniline complex in hot toluene³¹was also investigated. Low

solubilities of intermediate 95-213 and the cleavage product

in the reaction medium, as well as losses suffered during

purification, resulted in a 34% yield of 94-129 from this

reaction. Debenzylation of CADA by the ACE-Cl method is

the preferred route to this key intermediate.

Results and Discussion

Synthesis. CADA was first prepared as an intermediate in

the attempted synthesis of a bicyclic triamine.²⁶The current

synthesis (Scheme 1) follows the same plan, involving Atkins-

Richman macrocyclization of a bis(tosylamide) dianion with a

dihalide,^27,28though most steps have been increased in scale

and improved in yield. The starting material, bis(2-cyanoethyl)-

amine (1) is now obtained in 84% yield by reaction of

acrylonitrile with ammonia. Benzylation in acetonitrile gives

bis(cyanoethyl)benzylamine (2) in 83% yield. Catalytic hydro-

genation over Raney nickel²⁶gives triamine 3, which is tosylated

by the Schotten-Bauman method using aqueous base. Bis-

(tosylamide) 94-127 is readily purified via its crystalline

hydrochloride, which is deprotonated in situ in the next step.

Macrocyclization (step d) is best conducted with very slow

(30 h) addition of the dichloride to the bis(tosylamide) dianion

derived from 94-127, to avoid the formation of side products

that are difficult to remove from CADA. Hence, the procedure

given here is smaller in scale than that published previously,²⁶

but 9 g of pure product is reliably obtained per batch. CADA

can be quantitatively converted to the hydrochloride salt (94-

128), which has better solubility than the free base in polar

solvents. The 5-step synthesis shown in Scheme 1 (ca. 30%

Prior to determining that reductive alkylation of 94-129 is

the best route to N-alkyl tail analogues, direct alkylation with

3-picolyl chloride was investigated. Reaction of 94-129 free

base with 3-chloromethylpyridine hydrochloride and triethyl-

amine in DMF resulted in partial conversion and isolation of

dihydrochloride ASN6P6 in low yield. Use of stronger bases

or higher temperature gave decomposition or polymerization

of 3-picolyl chloride. The N-methyl analogue 5 was prepared

directly from HCl salt 94-129 in fair yield by Eschweiler-

Clarke methylation³²(Scheme 2).

The most versatile method used for synthesis of tail analogues

is reductive alkylation by reaction of secondary amine hydro-

chloride 94-129 with various aldehydes or ketones and sodium

cyanoborohydride (Scheme 3). These reactions were conducted

in methanol at room temperature for periods of 1-3 days. The

yields of crude products were generally excellent. Those reported

for the 25 tail analogues in Scheme 3 (see also Experimental

Section) are for analytically pure samples. The reaction did not

go to completion if the free base corresponding to 94-129 was

used. Higher yields from the hydrochloride salt are consistent

with the knowledge that iminium salts are reduced rapidly at

pH 6-7, while reduction of aldehydes or ketones is negligible

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1293

Scheme 3^a

^aReagents and conditions: (a) RCHO, NaBH₃CN, MeOH (25-89%); (b) pivaldehyde, NaBH₃CN, ZnCl₂, MeOH (12%); (c) RCOR′, NaBH₃CN, ZnCl₂,

MeOH (62-75%).

Scheme 4^a

at this pH.³³Reaction times for ketones were far longer than

for aldehydes, and zinc chloride was required to activate the

ketone carbonyl group³⁴to produce QJ035, QJ036, and QJ040.

However, the reaction of pivaldehyde to produce 16 was very

slow, even in the presence of zinc chloride. In the case of this

sterically hindered aldehyde, a mixture of starting material and

product was obtained, and 16 was isolated in low yield by

chromatography.

As complements of the primary alkyl carbamates prepared

directly by reaction of chloroformates with CADA (Scheme 2),

other carbonyl group tail analogues were synthesized from

intermediate hydrochloride salt 94-129. Reaction with various

acyl chlorides, isopropyl chloroformate, or carbamoyl chlorides

in the presence of triethylamine gave 97-269 and analogues

17-22, generally in good yields, as shown in Scheme 4.

^aReagents and conditions: (a) RCOCl, Et₃N, CHCl₃(42-77%); (b)

iPrOCOCl, Et₃N, CHCl₃(69%); (c) Me₂NCOCl, Et₃N, CHCl₃(64%); (d)

4-morpholinecarbonyl chloride, Et₃N, CHCl₃(74%).

The synthetic route to CADA (Scheme 1) was applied to

several sidearm analogues, as shown in Scheme 5. One

analogue, bis(methanesulfonamide) MFS105, lacks benzene

rings in the sidearms. It was prepared in good yield by Atkins-

Richman cyclization of hydrochloride salt 23, reflecting similar

properties of methanesulfonamide and arenesulfonamide anions.

Attempts to apply this cyclization method to carboxamide

sidearm analogues have failed, so far. Seven arenesulfonamide

analogues having different steric and electronic characteristics

were prepared by macrocyclization of the corresponding di-

anions. An eighth, bis(p-aminobenzenesulfonamide) MFSPB1,

was synthesized by reduction of bis(p-nosylamide) AS114. The

bis(arenesulfonamide) intermediates (24-30) were prepared from

triamine 3 by Schotten-Bauman sulfonylation, using brine to

decrease the solubility of the arenesulfonyl chloride in the

aqueous layer, as in CADA synthesis. Most of the disulfon-

amides are oils and were purified via crystalline HCl salts,

though the bis(p-bromobenzenesulfonamide) free base 25 was

obtained as a crystalline solid. Macrocyclization yields for these

arenesulfonamide analogues were comparable to those obtained

for CADA.

Conversion of bis(p-bromobenzenesulfonamide) ASPB127 to

other sidearm analogues was briefly investigated, but the

corresponding bis(aryllithium) and bis(Grignard) reagents were

not formed in reasonable yield. One attempt involving treatment

of ASPB127 with tert-butyllithium and trapping of the putative

dianion with ethyl chloroformate resulted in fortuitous synthesis

of carbamate tail analogue MFS034. After discovering the CD4

down-modulating potencies of KKD023 and 3-methylbutyl tail

analogue of CADA, QJ038,²⁵combination of these features

appeared attractive. Debenzylation of KKD023 proceeded in

similar yield as cleavage of CADA (cf. Scheme 2), and

1294 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

Scheme 5^a

^aReagents and conditions: (a) MsCl, Et₃N, CH₂Cl₂; HCl, Et₂O (64%); (b) NaH, 3-chloro-2-chloromethyl-1-propene, DMF; HCl, CH₂Cl₂, Et₂O (21%);

(c) ArSO₂Cl, Et₂O or CH₂Cl₂, NaOH, H₂O (82-98%); (d) NaH, 3-chloro-2-chloromethyl-1-propene, DMF (12-85%); (e) NaBH₄, Cu(OAc)₂, EtOH (55%);

(f) EtOCOCl, THF (38%); (g) 1-chloroethyl chloroformate, 1,2-dichloroethane; MeOH, reflux (83%); (h) 1-bromo-3-methylbutane, Na₂CO₃, NaI, CH₃CN,

reflux (58%).

Scheme 6^a

alkylation of intermediate secondary amine KKD025 gave

KKD027 in moderate yield.

Unsymmetrical analogues having two different sidearms are

also of interest for testing as CD4 down-modulating agents.

Adaptation of the CADA synthesis (Scheme 1) to unsymmetrical

analogues requires monofunctionalization of triamine 3, which

is difficult to achieve selectively. Hence, desymmetrization of

triamine 31, an inexpensive starting material, was explored via

cyclic aminal 32 (Scheme 6). Unsymmetrical analogues incor-

porating the fluorescent 5-(dimethylamino)-1-naphthalene-

sulfonyl (dansyl) group were the initial targets.

Condensation of 31 with acetaldehyde was carried out in the

manner described for spermidine and propane-1,3-diamines.³⁵

The resulting hexahydropyrimidine (32) bears primary, second-

ary, and tertiary nitrogen atoms. Prior work indicated that the

secondary nitrogen would react with electrophilic reagents,³⁶

though quaternization of the tertiary nitrogen (with subsequent

reaction) or functionalization of the less nucleophilic primary

nitrogen could compete. Reaction of 32 with tosyl chloride under

Schotten-Bauman conditions (diethyl ether, aq NaOH), or in

CH₂Cl₂with triethylamine as the base, gave complex mixtures

of products. A mixture of THF and aq NaOH cleanly gave a

monotosylated product, identified as 33 on the basis of its NMR

and IR spectra. Dansylation of the primary nitrogen and ring

opening gave 34, which was converted to the N-benzyl (35)

and N-cyclohexylmethyl (36) derivatives. These unsymmetrical

^aReagents and conditions: (a) MeCHO, CHCl₃, 3 °C (83%); (b) TsCl,

NaOH, THF, H₂O (35%); (c) DnCl, Na₂CO₃, NaOH, CH₂Cl₂, H₂O (50%);

(d) BnCl or BrCH₂Cy, Na₂CO₃, NaI, MeCN (19-50%); (e) NaH, 3-chloro-

2-chloromethyl-1-propene, DMF (27-35%); Cy ) cyclohexyl, Dn )

5-(dimethylamino)-1-naphthalenesulfonyl.

triamines underwent Atkins-Richman macrocyclization to

produce the corresponding CADA analogues, KKD015 and

KKD016.

X-ray Structures. Solid-state structures of drugs can provide

indirect information about preferred conformation and flexibility

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1295

Figure 2. Solid state conformations of ASPB127 (upper left), CADA (upper right), KKD023 (lower left), and 15 (lower right). Color code:

carbon, gray; hydrogen, white; nitrogen, blue; oxygen, light red; sulfur, yellow; bromine, dark red. See Supporting Information for crystallographic

details.

and can be used as templates for modeling quantitative

Table 1. Ring Torsional Angles for X-ray Structures of ASPB127,

CADA, KKD023, and 15^a

structure-activity relationships (QSAR), especially when the

mechanism of action is unknown. The crystal structures of four

compounds (ASPB127, CADA, KKD023, and 15) were deter-

mined by X-ray diffraction analysis, and their solid state

conformations are displayed in Figure 2. Each of these analogues

crystallized in the free base form, so the tertiary nitrogen atom

shown at the bottom of each diagram in Figure 2 is unpro-

tonated. The central, 12-membered ring adopts the same overall

conformation in each structure. This is clear from inspection

of the diagrams in Figure 2 and by comparison of the torsions

(dihedral angles) about each of the 12 bonds in the ring. These

torsions, listed in Table 1, display some minor variations, but

each corresponding bond for all four molecules lies in the same

energy well. Most of the ring atoms are sp³hybridized,

producing 3-fold rotational potentials for each of these bonds

in the central ring. The same combination of torsions is observed

in the solid state structures of all four analogues, suggesting

that this is a low energy conformation. The tail group at the

bottom of each diagram and the two arenesulfonamide sidearms

are expected to be more flexible than the central ring. The tail

group has approximately the same orientation in each case, as

well as one of the two arenesulfonamide sidearms. The other

sidearm, shown on the right side of each diagram, has one

orientation in two structures and a different orientation in the

other two. Overall, these compounds show a high degree of

conformational homology, which should facilitate their align-

ring atoms

ASPB127

57.2(12)

CADA^b

48.6(3)

KKD023^b

15

N1-C2-C3-C4

C2-C3-C4-N5

C3-C4-N5-C6

C4-N5-C6-C7

N5-C6-C7-C8

C6-C7-C8-N9

C7-C8-N9-C10

53.1(7)

49.4(3)

-176.9(9) -175.0(2) -173.9(5) -174.0(2)

64.3(13)

87.3(12)

69.0(3)

89.8(3)

62.2(7)

91.2(6)

68.2(3)

90.2(3)

-62.6(12) -62.3(3) -63.9(7) -62.2(3)

-50.4(13) -49.3(3) -49.2(8) -54.0(4)

164.7(9)

163.9(2)

166.3(5)

162.8(2)

C8-N9-C10-C11 -166.0(8) -164.1(2) -166.0(5) -160.9(2)

N9-C10-C11-C12

C10-C11-C12-N1

55.7(12)

55.3(12)

56.8(3)

56.7(3)

55.1(7)

56.1(7)

59.2(3)

57.2(3)

C11-C12-N1-C2 -152.6(9) -154.6(2) -152.5(5) -155.6(2)

C12-N1-C2-C3

72.5(11)

74.0(3)

74.8(6)

73.1(3)

^aAngles in degrees; see Supporting Information for crystallographic data;

see Figure 2 for numbering scheme; errors shown in parentheses. ^bTorsional

angles multiplied by -1.

ment for modeling three-dimensional quantitative structure-

activity relationships (3D-QSAR).

Structure-Activity Relationships. The CD4 down-modula-

tion potencies of most CADA compounds described in this

publication have been reported previously.²⁵They appear in

Table 2 as IC₅₀values (concentration producing 50% decrease

of CD4 on surfaces of MT-4 cells) and as pIC₅₀values (-log

IC₅₀). The CD4 down-modulation potencies of KKD015,

KKD016, KKD023, KKD025, KKD027, and MFS034 are also

reported in Table 2. Activity data is not listed for the remaining

1296 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

Table 2. Experimental and CoMFA Predicted CD4 Down-Modulation

Activities of CADA Compounds in MT-4 Cells

compound^a

IC₅₀(exptl)^b

>15^f

11.1 ( 0.7

>75^f

10.3 ( 3.3

>75^f

>15^f

5.4 ( 1.4

pIC₅₀(exptl)^cpIC₅₀(pred)^dresidual^e

95-211

95-213

97-269

98-035

98-037

AS112

ASN6P6

ASPB127

CADA

KKD015

KKD016

KKD023

KKD025

KKD027

MFS034

MFS105

MFS117

MFSPB1

QJ023

QJ027

QJ028

QJ029

QJ030

QJ033

QJ035

QJ036

QJ037

4.82

4.95

4.12

4.99

4.12

4.82

5.27

5.74

6.10

5.89

6.21

6.66

5.28

6.54

4.91

4.12

4.82

6.24

5.10

6.47

5.39

5.26

5.68

4.96

5.52

6.01

6.17

5.08

5.18

4.91

5.14

4.18

5.21

4.83

4.52

5.30

5.23

5.27

5.81

6.73

6.12

5.43

6.67

5.06

3.96

4.85

5.14

6.17

5.41

6.24

5.11

5.42

5.48

5.02

5.37

5.89

5.97

5.40

5.39

-0.09

-0.19

-0.06

-0.22

-0.71

0.30

-0.03

0.51

0.83

0.08

1.8 ( 0.3

0.80 ( 0.35

1.3 ( 0.3

0.61 ( 0.05

0.22 ( 0.06

5.3 ( 1.2

-0.52

0.54

-0.15

-0.13

-0.15

0.16

-0.03

-0.32

0.07

-0.31

0.23

0.28

-0.16

0.20

-0.06

0.15

0.12

0.20

-0.32

-0.21

0.29 ( 0.12

12.4 ( 3.5

>75^f

>15^f

0.57 ( 0.27

7.9 ( 1.6

0.34 ( 0.06

4.1 ( 0.8

5.5 ( 2.1

2.1 ( 0.3

11.0 ( 1.5

3.0 ( 1.6

0.98 ( 0.16

0.67 ( 0.09

8.3 ( 1.2

6.6 ( 2.9

Figure 3. Correlation between anti-HIV-1 (NL4.3) activity and CD4

expression/down-modulation in MT-4 cells by 30 different CADA

compounds listed in Table 2 (nonparametric Spearman rank correlation;

the probability P indicates significance at the 0.05 level). For each

analogue, the anti-HIV activity (IC₅₀value) was plotted against the

CD4 down-modulating capability (IC₅₀value calculated from the mean

fluorescence intensity of MT-4 cells labeled with the FITC-conjugated

anti-CD4 mAb).²⁵

QJ038

QJ040

QJ041

^aCompounds KKD015, KKD016, KKD023, KKD025, KKD027, and

MFS034 were used in the free base or salt forms, as described in the

Experimental Section; data for the remaining compounds are from ref 25.

^bIC₅₀(µM) for CD4 down-modulation was the concentration of the

compound required for 50% inhibition of cell surface CD4 expression in

MT-4 cells, determined exactly as described in ref 25. ^cpIC₅₀) -log IC₅₀.

^dpIC₅₀predicted by CoMFA QSAR model derived from all 30 compounds

in this table (see Experimental Section). ^epIC₅₀(pred) - pIC₅₀(exptl).

^fMinimum IC₅₀estimated from upper limit of concentration used in CD4

down-modulation assay.

steric and electrostatic properties according to Lennard-Jones

and Coulomb potentials.³⁷We examined hydrophobic potentials

using Hansch parameters separately. Hydrophobic potential was

insufficient to be the sole predictor of biological activity. Energy

minimized structures of all 30 compounds listed in Table 2 were

aligned by means of a template based on the X-ray crystal

structure of CADA (cf. Figure 2). A CoMFA model was

calculated by the partial least squares (PLS) method and

validated by the standard “leave-one-out” approach. The pIC₅₀

values calculated by this model and residuals (differences

between experimental and calculated values) shown in Table 2

have strong statistical significance (r²) 0.80, P < 0.001) and

internal predictive ability (q²) 0.41). Potencies of all 30

compounds are predicted well by the model, which gives

calculated IC₅₀values within 10-fold of the experimental values.

Steric and electrostatic contour maps generated from this

CoMFA model are shown in Figure 4. The steric and electro-

static contributions to this model are 59% and 41%, respectively.

As shown in Figure 4, increased steric bulk in the tail region

clearly enhances drug potency. In contrast, the strongest

electrostatic correlations involve the macrocyclic ring and the

sidearms. The effect of using estimated values for the seven

“inactive” compounds was examined by recalculating the

CoMFA model, leaving out these seven values (15 or 75 µM).

This improved the correlation (r²) 0.87, P < 0.001) and

predictive ability (q²) 0.50) of the model for the remaining

23 compounds, but it predicted 4-50-fold greater potencies for

the seven “inactives,” relative to experimental estimates. This

indicates that without these “inactive” compounds, the CoMFA

model lacks the diversity of compounds needed to be useful

for predictions. Current efforts are aimed at testing further

compounds and further refining the model.

compounds described here because they were not tested or they

gave ambiguous testing results. In seven cases listed in Table

2, no CD4 down-modulation activity was observed. Toxicities

of these compounds prevented reliable testing at concentrations

above either 15 µM (95-211, AS112, MFS117, and MFSPB1)

or 75 µM (97-269, 98-037, and MFS105). IC₅₀values for

these “inactive” compounds are given in Table 2 as >15 or

>75 µM, respectively, to indicate that these are lower limits.

Anti-HIV activities and toxicities are not listed in Table 2,

but these data have been reported for 24 of the 30 compounds.²⁵

Antiviral potencies (IC₅₀) for NL4.3 infection and cytotoxicities

(CC₅₀), determined for MT-4 cells exactly as described previ-

ously,²⁵are as follows for five of the remaining six compounds

(IC₅₀/CC₅₀, µM): KKD015, 9.5 ( 1.0/>75; KKD016, 1.8 (

0.3/49 ( 25; KKD023, 0.62 ( 0.21/26 ( 1; KKD025, 6.3 (

0.6/43 ( 13; KKD027, 0.63 ( 0.05/53 ( 29. The anti-HIV

potency of MFS034 was not measured, though its cytotoxicity

(CC₅₀) was found to be 29 ( 4 µM. As observed previously

for CADA compounds,²⁵the anti-HIV potencies of these

additional analogues directly correlate with their CD4 down-

modulation abilities. This correlation is displayed in Figure 3

for the 30 compounds listed in Table 2.

Three-dimensional quantitative structure-activity relationship

(3D-QSAR) modeling was performed to provide a tool for future

selection of target compounds for synthesis. When the structure

of the molecular target for drug binding is unknown, compara-

tive molecular field analysis (CoMFA) can be used to correlate

A second 3D-QSAR analysis, CoMSIA (comparative mo-

lecular similarity indices analysis), was also performed on the

30 compounds listed in Table 2. CoMSIA correlates activity

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1297

Figure 4. 3-D QSAR contour maps shown for CADA (perpendicular views): CoMFA steric (top) and electrostatic (center), and CoMSIA steric

(bottom). Plots contoured at 1/3 of maximum field value, showing only most important correlating points. Top and bottom: mesh in green shows

areas correlating increasing steric bulk with increasing potency (greater pIC₅₀value); mesh in yellow shows areas correlating decreasing steric bulk

with increasing potency. Center: mesh in red shows areas correlating increasing positive charge with increasing potency; mesh in blue shows areas

correlating increasing negative charge with increasing potency.

data with hydrogen bonding and hydrophobicity, in addition to

the steric and electrostatic indices included in CoMFA.^38-40

examined vary in their physicochemical properties. The cor-

relation between changes in hydrogen bonding and efficacy may

be obscured by other correlations. In contrast, the effect of

changing steric bulk is so strong that other factors do not obscure

the correlation between steric bulk and potency.

A

PLS analysis of each CoMSIA index was run independently of

the other indices (i.e. hydrophobic alone, steric alone, etc.), and

the same settings were used as in the CoMFA PLS. The results

of the CoMSIA and CoMFA analyses agree with respect to steric

effects. A correlation between CD4 down-modulation and

hydrogen bonding (acceptor and donor), electrostatics, and

hydrophobics could not be found (i.e., q²< 0.3). A correlation

was found for sterics, and the PLS analysis returned a q²)

0.44 and an r²) 0.75. This agrees with the CoMFA result that

changes in steric bulk are the most strongly correlated with

changes in pIC₅₀value. The correlation of the change in sterics

with pIC₅₀is shown in Figure 4. Both CoMFA and CoMSIA

show a strong correlation with increasing steric bulk in the tail

region; however, the CoMSIA also has correlation with changes

in steric bulk in the sidearm regions. These 3D-QSAR analyses

show that changes in substituent size mainly determine changes

in CD4 down-modulation potency in CADA compounds. This

finding does not diminish the importance of hydrogen bonding,

hydrophobicity, and electrostatics in determining efficacy. It

indicates that variations of these properties individually prove

to be poor predictors of potency. For example, all compounds

Summary and Conclusions

Effective approaches have been developed for the synthesis

of cyclotriazadisulfonamide (CADA) and more than 50 ana-

logues. Most of these are symmetrical compounds bearing two

identical arenedisulfonamide sidearms, but an alternate approach

has been used to produce two unsymmetrical analogues

(KKD015 and KKD016). Thirty tested compounds show a wide

range of CD4 down-modulation potencies, which correlate with

their abilities to inhibit HIV-1 infection in MT-4 cells. Com-

putational three-dimensional quantitative structure-activity

relationship (3D-QSAR) studies based on conformations ob-

served in the X-ray crystal structures of four of the compounds

have produced models that can be used to design analogues for

future synthesis. These models show steric bulk of the tail group

and, to a lesser extent, the sidearms to be the main determinant

of CD4 down-modulation potency.

1298 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

N,N′-Bis(p-toluenesulfonyl)bis(3-aminopropyl)benzylamine Hy-

drochloride (94-127). A solution of 16 g (71 mmol) of triamine

3, 80 mL of 2 N aq NaOH, and 150 mL of saturated aqueous NaCl

was added dropwise over 5 h to a stirred solution of 28 g (0.15

mol) of p-toluenesulfonyl chloride and 120 mL of ether, then the

reaction mixture was stirred for 12 h at room temperature. The

mixture was poured into a separatory funnel, and three layers were

observed. The upper two layers were poured into a flask and stirred

with 80 mL of 2 N aq HCl and 100 mL of saturated aqueous NaCl

for 1 h. The mixture was filtered, and the solid was washed with

3 × 100 mL of distilled water, followed by 3 × 100 mL of ether,

then dried (0.5 mm), yielding 35.8 g (89%) of 94-127 as a white

solid, mp 124-126 °C (lit.²⁶150-152 °C; 160-161 °C after drying

at 78 °C, 1 mm).

Experimental Section

General Methods. All reactions were performed under an

atmosphere of dry nitrogen. Reagents and solvents purchased from

Aldrich Chemical Co., Acros Organics, or Fisher Scientific were

of ACS reagent grade or better and were used without purification,

unless indicated otherwise. Tetrahydrofuran (THF) was distilled

from sodium/benzophenone, and butanol was distilled from sodium.

Dichloromethane and 1,2-dichloroethane were distilled from P₂O₅.

Anhydrous dimethylformamide (DMF) was purchased from Aldrich

in Sure-Seal bottles or distilled from calcium hydride in vacuo.

Methanol was distilled from CaH₂or Mg/I₂. Melting points are

uncorrected. All NMR chemical shifts (δ) are reported in ppm units

relative to internal standard or solvent resonances, as follows: ¹H,

(CDCl₃) TMS ) 0.00, DMSO-d₆) 2.50; ¹³C, CDCl₃) 77.23,

DMSO-d₆) 39.7. Infrared spectra were recorded on a Nicolet

Prote´ge´ 460 FTIR spectrometer, and the frequencies were reported

as cm^-1. Fast atom bombardment (FAB) mass spectra were obtained

on a Finnigan SSQ 710 mass spectrometer with Cs cations. Electron

impact mass spectra (3 kV) were acquired on a Finnigan MAT

FSQ710 (analytical electrospray source) mass spectrometer. MALDI

mass spectra were acquired on a Bruker Profex TOF mass

spectrometer. Elemental analysis was performed by NuMega

Resonance Labs, Inc.

Bis(2-cyanoethyl)amine (1). To a flask equipped with an addi-

tion funnel, a dry ice/acetone-cooled Dewar condenser, thermom-

eter, and nitrogen inlet was added 354 g (6.7 mol) of acrylonitrile.

The flask was heated in an 80 °C oil bath, and 208 mL (3.2 mol)

of concentrated aqueous ammonia was added dropwise to the

vigorously stirred reaction mixture over a period of 2 h. The reaction

mixture was stirred without external heating for 30 min, then at

70-75 °C for an additional 30 min. Excess acrylonitrile and most

of the water were removed by rotary evaporation, and the residue

was dried to constant weight under vacuum (0.5 mm). A solution

of the crude product in 500 mL of CH₂Cl₂was dried over MgSO₄

for 16 h. Filtration, evaporation and drying (0.5 mm) gave 330 g

(84%) of 1 as a pale yellow oil which was sufficiently pure by ¹H

NMR spectroscopy²⁶to be used in the next step.

9-Benzyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triaza-

cyclododecane (CADA). NaH (4.0 g, 0.1 mol, 60% w/w slurry in

mineral oil) was washed with hexane under nitrogen. A solution

of 18.0 g (32 mmol) of 94-127 in 650 mL of anhydrous DMF

was added, and the mixture was stirred at room temperature for 1

h. The resulting cloudy solution was stirred at 80-85 °C under

nitrogen as a solution of 4.0 g (32 mmol) of 3-chloro-2-chloro-

methyl-1-propene in 20 mL of anhydrous DMF was added over

30 h by means of a syringe pump, then the reaction mixture was

stirred at 80-85 °C for 20 h. The solvent was completely removed

by vacuum distillation at 40 °C (10 mm). A solution of residue in

300 mL of CHCl₃was washed with water (3 × 150 mL) and

saturated aqueous NaCl (3 × 150 mL), then dried over Na₂SO₄.

Filtration, concentration by rotary evaporation, and by drying under

vacuum gave 16.9 g (91%) of crude product as a beige solid.

Recrystallization from hot EtOAc gave 9.0 g (54%) of CADA as

a white solid (mp 160-164 °C, lit.²⁶156-158 °C), giving identical

spectroscopic data to that reported.²⁶Prior to recrystallization, less

soluble side products can be precipitated by adding hexane to a

solution of the crude product in hot toluene.²⁶CADA‚HCl. A

solution of 2.0 g (3.4 mmol) of pure CADA in 20 mL of chloroform

was vigorously stirred with 4 mL of 2 N aq HCl and 4 mL of

saturated aqueous NaCl for 1 h, over which period CADA‚HCl

gradually precipitated. The mixture was transferred to a separatory

funnel with the aid of 10 mL of chloroform. The cloudy organic

layer was separated and heated to boiling. Ethanol was added slowly

to the boiling solution, which became clear. Addition of ethanol

was continued to maintain a constant, total volume, until the boiling

solution became cloudy again. The mixture was cooled to room

temperature, and the precipitated white solid was collected by

suction filtration and dried at 65-100 °C (0.4 mm, 12 h) to remove

chloroform, yielding 2.15 g (100%) of CADA‚HCl, mp 210-212

Bis(2-cyanoethyl)benzylamine (2). A mixture of 183 g (1.48

mol) of 1, 450 mL of acetonitrile, 3.75 g (25 mmol) of sodium

iodide, 78.4 g (0.74 mol) of sodium carbonate, and 187 g (1.48

mol) of benzyl chloride was stirred mechanically and heated at

reflux under nitrogen for 5 h. The cooled reaction mixture was

filtered, and the solids were washed with 550 mL of acetonitrile.

The combined filtrates were concentrated by rotary evaporation to

a thick, deep yellow-orange liquid. A solution of the residue in

350 mL of CH₂Cl₂was stirred vigorously for 5 min with 124 mL

of saturated aqueous Na₂S₂O₃. The layers were separated, and the

organic layer was washed with saturated aqueous NaCl (2 × 150

mL). The combined aqueous layers were extracted with CH₂Cl₂(3

× 90 mL). The combined CH₂Cl₂solutions were dried over MgSO₄,

filtered and concentrated by rotary evaporation. The residue was

dried (0.5 mm), yielding 262 g (83%) of 2 as a yellow oil, which

1

°C (dec). H NMR (300 MHz, DMSO-d₆) δ 11.0 (br, 1 H, NH⁺),

7.67 (m, 6 H, o-Ts, o-Bn), 7.45 (m, 7 H, m-Ts, m,p-Bn), 5.36 (s,

2 H, CdCH₂), 4.31 (d, J ) 5.1 Hz, 2 H, CH₂Ph), 3.65 (s, 4 H, H2,

H4), 3.13 (m, 8 H, H6, H8, H10, H12), 2.40 (s, 6 H, CH₃), 1.91

1

(m, 4 H, H7, H11). H NMR (300 MHz, CDCl₃) δ 12.5 (br, 1 H,

NH⁺), 7.76 (m, 2 H, o-Bn), 7.60 (d, J ) 7.9 Hz, 4 H, o-Ts), 7.44

(m, 3 H, m,p-Bn), 7.34 (d, J ) 7.9 Hz, 4 H, m-Ts), 5.35 (s, 2 H,

CdCH₂), 4.11 (d, J ) 4 Hz, 2 H, CH₂Ph), 3.72 (d, J ) 15 Hz, 2

H, H2, H4), 3.67 (d, J ) 15 Hz, 2 H, H2, H4), 3.38, 3.12 (m, 8 H,

H6, H8, H10, H12), 2.43 (s, 6 H, CH₃), 2.29, 1.96 (m, 4 H, CH₂,

H7, H11). ¹³C NMR (75 MHz, DMSO-d₆) δ 143.8, 141.6, 134.0,

131.0, 130.3, 130.0, 129.4, 128.8, 127.3, 118.6, 57.2, 51.9, 48.1,

46.3, 21.1, 20.1. IR (KBr) 3029 (w), 2972 (w), 2923 (w), 2864

(w), 2446 (br), 2396 (br), 1465 (m), 1345 (s), 1162 (s), 1119 (m),

1089 (m). UV (CH₃OH): λ_max(logꢀ), 230 (4.4). Anal. Calcd for

C₃₁H₃₉N₃S₂O₄‚HCl: C, 60.23; H, 6.52; N, 6.80; S, 10.37; Cl, 5.73.

Found: C, 60.19; H, 6.55; N, 6.87; S, 10.35; Cl, 5.70.

1

was pure by H NMR spectroscopy.²⁶

Bis(3-aminopropyl)benzylamine (3). A mixture of 262 g (1.23

mol) of 2, 47.2 g of a 50% aq slurry of Raney nickel, and 544 mL

of a 1.4 M solution of NaOH in 95% ethanol was placed in a 2 L,

heavy walled, glass bottle and hydrogenated with shaking in a Parr

apparatus at 20-30 psi for 48 h. The catalyst was removed by

filtration (caution: flammable solid) and washed with 150 mL of

95% ethanol. The combined filtrates were concentrated by rotary

evaporation. A solution of the residue in 400 mL of diethyl ether

was dried over Na₂SO₄, filtered and concentrated by rotary

evaporation to give 241 g (89%) of a pale yellow, clear oil. Vacuum

distillation of a 430 g sample provided 349 g (81%) of 3 as a

colorless oil, bp 145-147 °C, 0.2 mm (lit.²⁶151-155 °C, 0.5 mm).

¹H NMR (300 MHz, CDCl₃) δ 7.31 (m, 5 H, Ph), 3.49 (s, 2 H,

CH₂Ph), 2.65 (t, J ) 7 Hz, 4 H, H3), 2.42 (t, J ) 7 Hz, 4 H, H1),

1.56 (quint., J ) 7 Hz, 4 H, H2), 1.26 (s, 4 H, NH). The previously

9-Methoxycarbonyl-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (4). A solution of 0.49 g (0.84 mmol)

of CADA and 0.1 mL (0.12 g, 1.3 mmol) of methyl chloroformate

in 25 mL of 1,2-dichloroethane was stirred and heated under reflux

for 16 h. The reaction mixture was cooled to room temperature

and concentrated by rotary evaporation, and the residue was

recrystallized (EtOAc) to give 0.35 g (76%) of 4 as white crystals,

1

reported H NMR data are believed to be in error.²⁶

mp 159-160 °C. H NMR (300 MHz, CDCl₃) δ 7.68 (d, J ) 8

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1299

Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.23 (s, 2 H,

CdCH₂), 3.86 (s, 4 H, H2, H4), 3.63 (s, 3 H, OCH₃), 3.33 (t, J )

6 Hz, 4 H, H6, H12), 3.12 (m, 4 H, H8, H10), 2.45 (s, 6 H, ArCH₃),

1.85 (m, 4 H, H7, H11). ¹³C NMR (75 MHz, CDCl₃) δ 157.8, 143.9,

139.9, 130.1, 127.4, 117.2, 52.8, 51.9, 46.0, 45.4, 28.1, 21.7. IR

(KBr) 2956 (m), 1702 (s), 1597 (m), 1481 (s), 1405 (s), 1346 (s),

1226 (s), 1159 (s), 1122 (s), 1094 (s), 1021 (s), 907 (s), 817 (s),

777 (s), 725 (s), 658 (s). MS (FAB) m/z 550.2 (MH⁺). Anal. Calcd

for C₂₆H₃₅N₃O₆S₂: C, 56.81; H, 6.42; N, 7.64. Found: C, 56.83;

H, 6.47; N, 7.65.

9-(3-Pyridylmethyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (ASN6P6). A solution of 0.70 g (1.3

mmol) of 94-129 in 10 mL of CHCl₃was stirred vigorously with

3 mL of 1 N NaOH and 10 mL of saturated aqueous NaCl for 1 h.

The organic layer was dried (MgSO₄) and concentrated by rotary

evaporation, and the residue was dried (1 mm) giving 0.60 g (92%)

of 94-129 free base as a white foam. ¹H NMR (300 MHz, CDCl₃)

δ 7.67 (d, J ) 7.8 Hz, 4 H, o-Ts), 7.31 (d, J ) 7.8 Hz, 4 H, m-Ts),

5.02 (s, 2 H, CdCH₂), 3.79 (s, 4 H, H2, H4), 3.18 (t, J ) 6 Hz, 4

H, H6, H12), 2.60 (t, J ) 6 Hz, 4 H, H8, H10), 2.43 (s, 6 H,

ArCH₃), 1.64 (quint., J ) 6 Hz, 4 H, H7, H11), 0.37 (br, 1 H,

NH). ¹³C NMR (75 MHz, CDCl₃) δ 143.3, 138.3, 135.7, 129.7,

127.4, 115.3, 51.8, 44.4, 43.2, 27.9, 21.4. IR (KBr) 3330 (w), 3030

(w), 2947 (m), 2854 (m), 2819 (m), 1598 (m), 1450 (m), 1333 (s),

1160 (s), 1091 (m), 915 (m), 815 (m), 733 (m), 688 (m), 657 (m).

A solution of 0.56 g (1.14 mmol) of 94-129 free base and 0.23 g

(2.27 mmol) of triethylamine in 8 mL of anhydrous DMF was

stirred for 18 h at room temperature, then the solvents were removed

under vacuum (1 mm) at 25-27 °C. A solution of the residue in

20 mL of CHCl₃was washed with 5 mL of 1 N aq NaOH and 15

mL of saturated aqueous NaCl solution. The combined aqueous

layers were extracted with 10 mL of CHCl₃. The combined organic

solutions were dried (MgSO₄), concentrated by rotary evaporation,

and the residue was purified by silica gel flash column chroma-

tography, eluting with 69:23:8 (v/v/v) chloroform/ethyl acetate/

triethylamine. A solution of the resulting mixture of 94-129 free

base and ASN6P6 in 10 mL of chloroform and 2.5 mL of 1 N HCl

in ether was stirred for 1 h at room temperature under N₂. The

solvents were removed by rotary evaporation, and the residue was

dissolved in 15 mL of acetone. Ethyl acetate (40 mL) was layered

on top of the solution, causing a precipitate to form overnight at

room temperature. The precipitate was collected by filtration, and

the precipitation procedure was repeated, giving 110 mg (15%) of

9-Ethoxycarbonyl-3-methylene-1,5-bis-(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (95-213). A solution of 8.20 g (14.1

mmol) of CADA and 1.7 mL (18 mmol) of ethyl chloroformate in

1,2-dichloroethane was stirred and heated under reflux for 5 h.

Concentration by rotary evaporation gave an oily residue which

was crystallized from 60 mL of 2:3 (v/v) ethyl acetate/hexane.

Filtration, washing with 3 × 30 mL of cold 2:3 (v/v) ethyl acetate/

hexane, and drying at 78 °C (0.9 mm, 19 h) gave 6.63 g (83%) of

1

95-213 as a white solid, mp 125-126 °C. H NMR (300 MHz,

CDCl₃) δ 7.68 (d, J ) 8.3 Hz, 4 H, o-Ts), 7.33 (d, J ) 8.3 Hz, 4

H, m-Ts), 5.21 (s, 2 H, CdCH₂), 4.07 (q, J ) 7 Hz, 2 H, OCH₂Me),

3.85 (s, 4 H, H2, H4), 3.33 (t, J ) 6.4 Hz, 4 H, H8, H10), 3.11 (m,

4 H, H6, H12), 2.44 (s, 6 H, ArCH₃), 1.85 (m, 4 H, H7, H11), 1.21

(t, J ) 7 Hz, 3 H, CH₂CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 157.0,

143.6, 139.4 135.7, 129.8, 127.2, 116.9, 61.2, 51.4, 45.5, 45.2, 28.0,

21.4, 14.7. IR (KBr) 2990 (w), 2948 (w), 1688 (s), 1598 (w), 1485

(m), 1424 (m), 1343 (s), 1230 (s), 1154 (s), 1093 (s), 1027 (m),

903 (m), 818 (m), 788 (m). UV (CH₃OH): λ_max(logꢀ), 232 (4.4).

MS (FAB) m/z 564 (M + H⁺, 100). Anal. Calcd for C₂₇H₃₇N₃S₂O₆:

C, 57.53; H, 6.62; N, 7.45; S, 11.37. Found: C, 57.36; H, 6.54; N,

7.73; S, 11.74.

9-Propyloxycarbonyl-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (QJ033). A solution of 0.48 g (0.83

mmol) of CADA and 0.15 mL (0.16 g, 1.3 mmol) of propyl

chloroformate in 50 mL of 1,2-dichloroethane was stirred and heated

under reflux for 18 h. The reaction mixture was cooled to room

temperature and concentrated by rotary evaporation, and the residue

was chromatographed on silica, eluting with dichloromethane/ethyl

acetate (9:1, v/v), then with ethyl acetate/hexane (6:4, v/v). The

resulting 0.41 g of colorless oil was recrystallized from methanol

to yield 0.34 g (80%) of QJ033 as white crystals, mp 134-135

°C. ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J ) 8 Hz, 4 H, o-Ts),

7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.21 (s, 2 H, CdCH₂), 3.96 (t, J )

7 Hz, 2 H, OCH₂), 3.85 (s, 4 H, H2, H4), 3.33 (t, J ) 6 Hz, 4 H,

H6, H12), 3.11 (m, 4 H, H8, H10), 2.44 (s, 6 H, ArCH₃), 1.85 (m,

4 H, H7, H11), 1.59 (m, 2 H, CH₂CH₂CH₃), 0.91 (t, J ) 7 Hz, 3

H, CH₂CH₃). ¹³C NMR (75 MHz, CDCl3) δ 157.4, 143.8, 139.9,

136.2, 130.1, 127.5, 117.2, 67.3, 51.9, 45.9, 45.5, 28.4, 22.6, 21.7,

10.7. IR (KBr) 3063 (w), 3028 (w), 2969 (m), 1686 (s), 1597 (m),

1481 (m), 1423 (s), 1341 (s), 1163 (s), 1092 (s), 943 (m), 748 (m).

MS (FAB) m/z 578.2 (MH⁺). Anal. Calcd for C₂₆H₃₅N₃O₆S₂: C,

58.21; H, 6.80; N, 7.27. Found: C, 58.24; H, 6.73; N, 7.37.

1

ASN6P6 that was 99% pure by hplc, mp 176-178 °C. H NMR

(300 MHz, DMSO-d₆) δ 11.5 (br, 1 H, NH⁺), 9.01 (s, 1 H, 2-Py),

8.82 (d, J ) 5 Hz, 1 H, 6-Py), 8.53 (d, J ) 8 Hz, 1 H, 4-Py), 7.81

(t, J ) 6 Hz, 1 H, 5-Py), 7.67 (d, J ) 8 Hz, 4 H, o-Ts), 7.46 (d, J

) 8 Hz, 4 H, m-Ts), 5.36 (s, 2 H, CdCH₂), 4.46 (s, 2 H, CH₂Ph),

3.67 (s, 4 H, H2, H4), 3.13 (m, 8 H, H6, H8, H10, H12), 2.41 (s,

6 H, ArCH₃), 1.90 (m, 4 H, H7, H14). ¹³C NMR (75 MHz, DMSO-

d₆) δ 146.6, 145.0, 143.9, 141.6, 134.1, 130.1, 128.9, 127.3, 125.9,

118.6, 53.6, 51.8, 48.0, 46.6, 21.0, 20.2. IR (KBr) 3052 (w), 2956

(w), 2452 (br, w), 1560 (w), 1462 (m), 1339 (s), 1161 (s), 1090

(m). UV (CH₃OH): λ_max(logꢀ), 230 (4.4), 260 (3.6). MS (FAB)

m/z 583 (MH⁺, 100).

9-Methyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triaza-

cyclododecane (5). A mixture of 143 mg (0.27 mmol) of 94-129,

4.0 mL (4.3 g, 53 mmol) of 37% aq formaldehyde, and 5.0 mL

(6.1 g, 0.13 mol) of formic acid was stirred at room temperature

for 24 h. The pH of the mixture was adjusted to at least 13 with

25% aq NaOH, then the mixture was extracted with CH₂Cl₂(5 ×

5 mL). The combined extracts were washed with 1 N aq NaOH (4

× 10 mL), water (2 × 10 mL), and saturated aqueous NaCl (10

mL), then dried (Na₂SO₄). Concentration by rotary evaporation and

drying in vacuo gave 96 mg (64%) of a yellow oil. Recrystallization

from chloroform/hexane gave 87 mg (58%) of 5 as a white

3-Methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triazacyclodo-

decane Hydrochloride (94-129).²⁶A solution of 8.32 g (14.3

mmol) of CADA and 1.7 mL (2.25 g, 15.8 mmol) of 1-chloroethyl

chloroformate in 50 mL of 1,2-dichloroethane was stirred and heated

under reflux for 1.5 h, cooled to room temperature, then concen-

trated by rotary evaporation. A solution of the residue in 70 mL of

methanol was stirred and heated under reflux overnight, then cooled

to room temperature. Filtration, concentration by rotary evaporation,

and recrystallization of the residue from ethyl acetate/ethanol gave

6.50 g (86%) of HCl salt 94-129 as a white solid, mp 188-189

crystalline solid, mp 134-135.5 °C. ¹

H NMR (75 MHz CDCl₃) δ

7.68 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 4.98

(s, 2 H, CdCH₂), 3.83 (s, 4 H, H2, H4), 3.11 (t, J ) 6 Hz, 4 H,

H6, H12), 2.44 (s, 6 H, ArCH₃), 2.33 (t, J ) 6 Hz, 4 H, H8, H10),

1.98 (s, 3 H, NCH₃), 1.70 (m, 4 H, H7, H11). ¹³C NMR (300 MHz,

CDCl₃) δ 146.9, 143.6, 138.7, 136.2, 129.9, 127.6, 115.3, 53.6,

52.1, 43.5, 40.9, 25.9, 21.6. IR (KBr) 2954 (w), 2802 (w), 1593

(w), 1449 (m), 1329 (s), 1166 (s), 1099 (s), 924 (m), 909 (m), 811

(m), 735 (m), 688 (s), 551 (s). MS (FAB) m/z 506 (MH⁺). Anal.

Calcd for C₂₅H₃₅N₃O₄S₂‚0.4 CHCl₃: C, 55.12; H, 6.45; N, 7.59.

Found: C, 55.18; H, 6.50; N, 7.31.

1

°C (lit.²⁶185-186 °C). H NMR (300 MHz, CDCl₃) δ 9.50 (s, 2

H, NH⁺), 7.65 (d, J ) 8 Hz, 4 H, o-Ts), 7.35 (d, J ) 8 Hz, 4 H,

m-Ts), 5.41 (s, 2 H, CdCH₂), 3.76 (s, 4 H, H2, H4), 3.24 (bs, 8 H,

H6, H8, H10, H12), 2.44 (s, 6 H, ArCH₃), 2.11 (bs, 4 H, H7, H11).

¹³C NMR (75 MHz, CDCl₃) δ 143.9, 139.6, 134.5, 129.8, 127.3,

119.6, 52.3, 47.1, 40.4, 22.5, 21.3. IR (KBr) 3621 (b), 3439 (b),

3086 (w), 2954 (m), 2490 (b), 2361 (b), 1597 (m), 1449 (s), 1339

(s), 1159 (s), 1090 (s), 887 (m).

9-Ethyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triaza-

cyclododecane (6). A solution of 0.47 g (0.89 mmol) of 94-129,

1 mL (0.79 g, 18 mmol) of acetaldehyde, and 0.18 g (2.9 mmol)

of sodium cyanoborohydride in 25 mL of methanol was stirred at

1300 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

room temperature for 40 h, then the solvent was removed by rotary

evaporation. A solution of the residue in 20 mL of dichloromethane

was washed with water (3 × 10 mL) and saturated aqueous NaCl

(10 mL), then dried (Na₂SO₄), concentrated by rotary evaporation,

and the residue was dried in vacuo. The crude product was dissolved

in 2 mL of dichloromethane, and 10 mL of a 1 N solution of HCl

in diethyl ether was added, producing a yellow precipitate. The

mixture was sonicated and filtered. A solution of the solid in 20

mL of dichloromethane was stirred with 10 mL of 1 N aq NaOH

for 2 h. The organic layer was washed with water (2 × 10 mL),

saturated aq NaCl (2 × 10 mL), and dried (Na₂SO₄). Concentration

by rotary evaporation and drying in vacuo gave 0.45 g (98%) of a

colorless oil. Purification by radial chromatography on silica gel,

eluting with ethyl acetate/hexane/triethylamine (35:65:5, v/v/v),

4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.19 (s, 2 H, CdCH₂),

3.80 (s, 4 H, H2, H4), 3.15 (t, J ) 7 Hz, 4 H, H6, H12), 2.44 (s,

6 H, ArCH₃), 2.27 (t, J ) 5 Hz, 4 H, H8, H10), 1.92 (d, J ) 7 Hz,

2 H, NCH₂iPr), 1.61 (m, 5 H, H7, H11, CHMe₂), 0.75 (d, J ) 6

Hz, 6 H, CH(CH₃)₂). ¹³C NMR (75 MHz, CDCl₃) δ 143.6, 138.3,

136.1, 130.0, 127.6, 116.9, 64.1, 51.2, 50.7, 44.5, 26.6, 24.8, 21.7,

21.2. IR (KBr) 2952 (m), 2801 (m), 1598 (m), 1458 (m), 1332 (s),

1162 (s), 1091 (s), 1038 (m), 935 (m), 816 (s), 743 (m), 718 (m),

708 (m), 689 (s), 550 (s). MS (FAB) m/z 548 (MH⁺). Anal. Calcd

for C₂₈H₄₁N₃O₄S₂: C, 61.40; H, 7.54; N, 7.67. Found: C, 61.62;

H, 7.32; N, 7.63. QJ006‚HCl. A solution of 0.49 g (0.93 mmol) of

94-129, 0.52 mL (0.41 g, 5.7 mmol) of isobutyraldehyde, and 0.18

g (2.9 mmol) of sodium cyanoborohydride in 25 mL methanol was

stirred at room temperature for 40 h. The reaction mixture was

worked up as described for QJ029, and the crude product was

purified via radial chromatography on silica gel, eluting with

dichloromethane/ethyl acetate/triethylamine (95:5:5, v/v/v) to give

0.48 g (95%) of QJ006 as a colorless oil. A solution of 30 mL of

0.33 N HCl in diethyl ether was added to a solution of 0.48 g (0.84

mmol) of QJ006, producing a white precipitate. The mixture was

sonicated and filtered. The white solid was dried in vacuo at 60 °C

for 3 days to give 0.43 g (78%) of QJ006‚HCl, mp 146-147 °C.

IR (KBr) 2967 (m), 2424 (b), 1598 (m), 1457 (m), 1339 (s), 1162

(s), 1110 (s), 1090 (s), 899 (m), 816 (s), 737 (s), 688 (s), 658 (s),

590 (s), 550 (s). Anal. Calcd for C₂₈H₄₁N₃O₄S₂‚HCl: C, 57.56; H,

7.25; N, 7.19. Found: C, 57.31; H, 7.26; N, 7.20.

1

yielded 0.25 g (54%) of 6 as a colorless oil. H NMR (300 MHz,

CDCl₃) δ 7.67 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H,

m-Ts), 5.11 (s, 2 H, CdCH₂), 3.81 (s, 4 H, H2, H4), 3.13 (t, J )

6 Hz, 4 H, H6, H12), 2.44 (s, 6 H, ArCH₃), 2.38 (t, J ) 5 Hz, 4 H,

H8, H10), 1.66 (m, 6 H, H7, H11, NCH₂Me), 0.85 (t, J ) 6 Hz, 3

H, CH₂CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 143.6, 138.6, 136.2,

130.0, 127.5, 116.2, 51.6, 50.2, 46.8, 44.3, 25.2, 21.7, 11.1. MS

(FAB) m/z 520 (MH⁺). 6‚HCl. A solution of 30 mL of 0.33 N

HCl in diethyl ether was added to a solution of 0.25 g (0.48 mmol)

of 6 in 2 mL of ethyl acetate, producing a white precipitate. The

mixture was sonicated and filtered, yielding 0.22 g (43%) of a white

solid. Recrystallization from dichloromethane/diethyl ether gave

0.17 g (35%) of 6‚HCl as white crystals, mp 188-193 °C. IR (KBr)

3421 (bw), 2978 (m), 2944 (m), 2605 (s), 2498 (s), 1597 (w), 1476

(s), 1398 (s), 1336 (s), 1161 (s), 1037 (s), 903 (w), 807 (m), 737

(m), 690 (m), 656 (m), 587 (m), 548 (s). Anal. Calcd for

C₂₆H₃₇N₃O₄S₂‚HCl‚1.75 H₂O: C, 54.07; H, 6.97; N, 7.01. Found:

C, 54.13; H, 7.32; N, 7.07.

9-Butyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triaza-

cyclododecane (7). A solution of 0.48 g (0.91 mmol) of 94-129,

0.85 mL (0.68 g, 9.5 mmol) of butyraldehyde and 0.18 g (2.9

mmol) of sodium cyanoborohydride in 25 mL of methanol was

stirred at room temperature for 40 h. The reaction mixture was

worked up as described as described for QJ029. 7‚HCl. A solution

of 30 mL of 0.33 N HCl in diethyl ether was added to a solution

of 0.93 g (1.70 mmol) of crude 7 in 2 mL of ethyl acetate, producing

a white precipitate. The mixture was sonicated and filtered. Radial

chromatography of the residue on silica gel, eluting with di-

chloromethane, then dichloromethane/methanol (95:5, v/v) gave

0.33 g (62%) of 7‚HCl as a white powder, mp 131-132 °C. IR

(KBr) 3417 (bw), 2960 (m), 2874 (w), 2442 (b), 1597 (m), 1453

(m), 1338 (s), 1160 (s), 1108 (s), 1090 (s), 1020 (m), 900 (m), 817

(s), 724 (s), 688 (s), 656 (s), 585 (s), 548 (s). MS (3 kV) m/z 548.1

(MH⁺). Anal. Calcd for C₂₈H₄₁N₃O₄S₂‚HCl‚H₂O: C, 55.84; H, 7.36;

N, 6.98. Found: C, 56.14; H, 7.45; N, 7.01. NMR Sample. A

solution of 20 mg of 7‚HCl in 5 mL of dichloromethane was stirred

with 3 mL of 1 N aq NaOH at room temperature for 1 h. The

organic layer was washed with water (2 × 5 mL) and saturated

aqueous NaCl (2 × 5 mL), then dried (Na₂SO₄). Concentration by

9-Propyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triaza-

cyclododecane (QJ029). A solution of 0.49 g (0.93 mmol) of 94-

129, 0.41 mL (0.33 g, 5.7 mmol) of propionaldehyde, and 0.18 g

(2.9 mmol) of sodium cyanoborohydride in 25 mL of methanol

was stirred at room temperature for 40 h, then the solvent was

removed by rotary evaporation. A solution of the residue in 20 mL

of dichloromethane was washed with water (3 × 10 mL) and

saturated aqueous NaCl (10 mL), dried (Na₂SO₄), and concentrated

by rotary evaporation. The residue was dried in vacuo to give 0.47

g (94%) of crude product. Column chromatography on silica gel,

eluting with ethyl acetate/hexane/triethylamine (35:65:5, v/v/v), gave

1

QJ029 as a colorless oil. H NMR (300 MHz, CDCl₃) δ 7.67 (d,

J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.14 (s, 2 H,

CdCH₂), 3.80 (s, 4 H, H2, H4), 3.14 (t, J ) 7 Hz, 4 H, H6, H12),

2.44 (s, 6 H, H16), 2.33 (t, J ) 5 Hz, 4 H, H8, H10), 2.18 (t, J )

6 Hz, 2 H, NCH₂Et), 1.63 (m, 4 H, H7, H11), 1.28 (m, 2 H,

NCH₂CH₂Me), 0.77 (t, J ) 7 Hz, 3 H, CH₂CH₃). ¹³C NMR (75

MHz, CDCl₃) δ 143.6, 138.6, 136.2, 130.0, 127.6, 116.4, 56.2, 51.4,

50.1, 44.1, 25.3, 21.7, 20.0, 12.1. QJ029‚HCl. A solution of 30

mL of 0.33 N HCl in diethyl ether was added to a solution of 0.47

g (0.85 mmol) of QJ029 in 2 mL of ethyl acetate, producing a

white precipitate. The mixture was sonicated and filtered. The white

solid was washed with water, dried and recrystallized from

dichloromethane/diethyl ether to give 0.41 g (77%) of QJ029‚HCl

as white crystals, mp 204-205 °C. IR (KBr) 3405 (bm), 3067 (w),

2978 (m), 2878 (m), 2403 (bm), 1596 (m), 1455 (m), 1341 (s),

1261 (m), 1164 (s), 1090 (s), 943 (s), 896 (m), 815 (m), 726 (s),

687 (s). MS (3 kV) m/z 548.1 (M - Cl). Anal. Calcd for

C₂₇H₃₉N₃O₄S₂‚HCl‚0.75 H₂O: C, 55.56; H, 7.17; N, 7.20. Found:

C, 55.72; H, 7.35; N, 7.24.

1

rotary evaporation and drying in vacuo gave a colorless oil. H

NMR (300 MHz, CDCl₃) δ 7.68 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d,

J ) 8 Hz, 4 H, m-Ts), 5.14 (s, 2 H, CdCH₂), 3.80 (s, 4 H, H2,

H4), 3.14 (t, J ) 7 Hz, 4 H, H6, H12), 2.44 (s, 6 H, ArCH₃), 2.33

(t, J ) 6 Hz, 4 H, H8, H10), 2.21 (t, J ) 7 Hz, 2 H, NCH₂Pr), 1.61

(m, 4 H, H7, H11), 1.21 (m, 4 H, NCH₂CH₂CH₂Me), 0.84 (t, J )

7 Hz, 3 H, CH₂CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 143.6, 138.4,

136.0, 130.0, 127.5, 116.4, 53.7, 51.4, 49.9, 44.3, 28.9, 25.1, 21.7,

20.9, 14.2.

9-(2-Methylbutyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-

triazacyclododecane (QJ037). A solution of 0.19 g (0.36 mmol)

of 94-129, 0.25 mL (197 mg, 2.3 mmol) of 2-methylbutyraldehyde,

and 78 mg (1.2 mmol) of sodium cyanoborohydride in 25 mL of

methanol was stirred at room temperature for 24 h. The reaction

mixture was worked up as described for QJ029. Chromatography

on silica gel, eluting with ethyl acetate/hexane/triethylamine (30:

60:5, v/v/v), gave 0.18 g (90%) of a colorless oil. QJ037‚HCl. A

solution of 25 mL of 0.2 N HCl in diethyl ether was added to a

solution of 0.18 g (0.32 mmol) of crude QJ037 in 2 mL of ethyl

acetate, producing a white precipitate. The mixture was sonicated

and filtered. The white solid was dried in vacuo (60 °C, 3 d) to

give 0.15 g (64%) of QJ037‚HCl, mp 129-130 °C. IR (KBr) 2964

(m), 2877 (w), 2610 (w), 1597 (m), 1457 (m), 1337 (s), 1161 (s),

1111 (m), 1090 (m), 896 (m), 817 (s), 737 (m), 689 (s), 656 (s),

9-Isobutyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triaza-

cyclododecane (QJ006). A solution of 0.30 g (0.53 mmol) of 94-

129, 0.26 mL (0.21 g, 2.9 mmol) of isobutyraldehyde, and 62 mg

(1.0 mmol) of sodium cyanoborohydride in 20 mL of methanol

was stirred at room temperature for 24 h. After workup as described

for QJ029, 0.24 g (78%) of crude product was obtained as a yellow

oil. Sequential recrystallization from methanol, followed by chlo-

roform/hexane gave 0.17 g (48%) of white crystalline QJ006, mp.

127-127.5 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz,

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1301

587 (s), 551 (s). MS (3 kV) m/z 562 (M - Cl). Anal. Calcd for

C₂₉H₄₃N₃O₄S₂‚HCl‚H₂O: C, 56.52; H, 7.52; N, 6.82. Found: C,

56.61; H, 7.35; N, 6.80. NMR Sample. A solution of 20 mg of

QJ037‚HCl in 5 mL of dichloromethane was stirred with 3 mL of

1 N aqueous NaOH at room temperature for 1 h. The organic layer

was washed with water (2 × 5 mL) and saturated aqueous NaCl (2

× 5 mL), dried (Na₂SO₄), then concentrated by rotary evaporation.

Drying in vacuo gave a colorless oil. ¹H NMR (300 MHz, CDCl₃)

δ 7.68 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts),

5.19 (s, 2 H, CdCH₂), 3.87 (d, J ) 16 Hz, 2 H, H2, H4), 3.73 (d,

J ) 16 Hz, 2 H, H2, H4), 3.15 (m, 4 H, H6, H12), 2.44 (s, 6 H,

ArCH₃), 2.24 (m, 4 H, H8, H10), 1.95 (m, 2 H, NCH₂2-Bu), 1.61

(m, 4 H, H7, H11), 1.31 (m, 2 H, CHCH₂Me), 0.81 (m, 1 H,

CHCH₃), 0.74 (t, J ) 7 Hz, 3 H, CH₂CH₃), 0.74 (d, J ) 6 Hz, 3

H, CHCH₃). ¹³C NMR (125 MHz, CDCl₃) δ 143.6, 138.1, 135.8,

130.0, 127.5, 116.9, 62.2, 51.1, 50.5, 44.4, 33.0, 27.8, 24.6, 21.7,

18.1, 11.5.

H, H6, H12), 2.44 (s, 10 H, H8, H10, ArCH₃), 2.14 (d, J ) 7 Hz,

2 H, CH₂cyloPr), 1.64 (t, J ) 6 Hz, 4 H, H7, H11), 0.69 (m, 1 H,

1-cycloPr), 0.41 (m, 2 H, 2-cycloPr), -0.04 (m, 2 H, 2-cycloPr).

¹³C NMR (75 MHz, CDCl₃) δ 143.6, 138.6, 136.1, 130.0, 128.1,

116.3, 58.6, 51.5, 49.9, 44.4, 25.3, 21.7, 8.4, 4.1.

9-Cyclohexylmethyl-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (QJ028). A solution of 0.47 g (0.89

mmol) of 94-129, 0.70 mL (0.65 mg, 5.8 mmol) of cyclohexane-

carboxaldehyde, and 0.18 g (2.9 mmol) of sodium cyanoborohydride

in 20 mL of methanol was stirred at room temperature for 24 h.

The reaction mixture was worked up as described for QJ029.

QJ028‚HCl salt. A solution of 30 mL of 0.33 N HCl in diethyl

ether was added to a solution of 0.93 g (1.87 mmol) of crude QJ028

(prepared as described above) in 2 mL of ethyl acetate, producing

a white precipitate, which was collected by filtration. Recrystalli-

zation from dichloromethane/ether gave 0.33 g (59%) of QJ028‚

HCl as white crystals, mp 138.5-140 °C. IR (KBr) 2928 (w), 2855

(w), 2360 (w), 1597 (w), 1449 (m), 1339 (m), 1160 (m), 1091 (m),

900 (w), 816 (m), 726 (s), 686 (s), 584 (s), 548 (s). MS (3 kV) m/z

588 (M - Cl). Anal. Calcd for C₃₁H₄₅N₃O₄S₂‚HCl‚H₂O: C, 57.97;

H, 7.53; N, 6.54. Found: C, 58.32; H, 7.67; N, 6.66. NMR Sample

of QJ028. A solution of 15 mg of QJ028‚HCl in 5 mL of

dichloromethane was stirred with 3 mL of a 1 N aq NaOH at room

temperature for 1 h. The organic layer was washed with water (2

× 5 mL) and saturated aqueous NaCl (2 × 5 mL), then dried

(Na₂SO₄), and concentrated by rotary evaporation. The residue was

dried in vacuo to give a colorless oil. ¹H NMR (300 MHz, CDCl₃)

δ 7.68 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts),

5.18 (s, 2 H, CdCH₂), 3.80 (s, 4 H, H2, H4), 3.15 (t, J ) 7 Hz, 4

H, H6, H12), 2.44 (s, 6 H, ArCH₃), 2.26 (t, J ) 6 Hz, 4 H, H8,

H10), 1.96 (d, J ) 6 Hz, 2 H, NCH₂Cy), 1.60 (m, 9 H, H7, H11,

Cy), 1.14 (m, 4 H, Cy), 0.68 (m, 2 H, Cy). ¹³C NMR (75 MHz,

CDCl₃) δ 143.6, 138.4 136.1, 130.0, 127.6, 116.7, 62.5, 51.2, 50.7,

44.5, 36.2, 32.2, 27.0, 26.3, 24.9, 21.7.

9-(3-Methylbutyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-

triazacyclododecane (QJ038). A solution of 0.19 g (0.36 mmol)

of 94-129, 0.25 mL (0.20 g, 2.3 mmol) of isovaleraldehyde and

72 mg (1.1 mmol) of sodium cyanoborohydride in 25 mL of

methanol was stirred at room temperature for 24 h. The reaction

mixture was worked up as described for QJ029. Column chroma-

tography on silica gel, eluting with ethyl acetate/hexane/ triethyl-

amine (30:60:5, v/v/v), gave 0.21 g (98%) of a colorless oil. QJ038‚

HCl. A solution of 30 mL of 0.3 N HCl in diethyl ether was added

to a solution of 0.21 g (0.37 mmol) of crude QJ038 in 2 mL of

ethyl acetate, producing a white precipitate. The residue was dried

in vacuo (60 °C, 3 d) to give 0.20 g (87%) of QJ038‚HCl as a

white solid, mp 137-138 °C. IR (KBr) 2957 (m), 2498 (b), 1597

(m), 1453 (s), 1337 (s), 1161 (s), 1113 (s), 1090 (s), 1019 (m), 816

(s), 736 (m), 725 (m), 689 (s), 656 (s), 586 (s), 589 (s). MS (3 kV)

m/z 562 (M - Cl). Anal. Calcd for C₂₉H₄₃N₃O₄S₂‚HCl‚H₂O: C,

56.52; H, 7.52; N, 6.82. Found: C, 56.43; H, 7.64; N, 6.85. NMR

Sample. A solution of 15 mg of QJ038‚HCl in 5 mL of

dichloromethane was stirred with 3 mL of 1 N aq NaOH at room

temperature for 1 h. The organic layer was washed with water (2

× 5 mL) and saturated aqueous NaCl (2 × 5 mL), dried (Na₂SO₄),

then concentrated by rotary evaporation. Drying in vacuo gave a

9-(3-Cyclohexenylmethyl)-3-methylene-1,5-bis(p-toluenesul-

fonyl)-1,5,9-triazacyclo-dodecane (QJ023). A solution of 0.49 g

(0.93 mmol) of 94-129, 0.67 mL (0.63 g, 5.7 mmol) of 3-cyclo-

hexene-1-carboxaldehyde, and 0.18 g (2.9 mmol) of sodium

cyanoborohydride in 25 mL of methanol was stirred at room

temperature for 40 h. The reaction mixture was worked up as

described for QJ029. QJ023‚HCl. A solution of 30 mL of 0.33 N

HCl in diethyl ether was added to a solution of 0.94 g (1.9 mmol)

of QJ023 in 2 mL of ethyl acetate, producing a white precipitate.

Chromatography on silica gel, eluting with dichloromethane/

methanol (95:5, v/v) followed by recrystallization from dichloro-

methane/diethyl ether, gave 0.50 g (86%) of white crystalline

QJ023‚HCl, mp 148-149 °C. ¹³C NMR (75 MHz, CDCl₃S) δ

144.5, 141.7, 130.3, 127.8, 127.7, 127.2, 124.9, 119.6, 60.7, 53.0,

48.8, 47.8, 30.7, 30.1, 27.5, 24.4, 21.7, 20.5. IR (KBr) 2921 (m),

1597 (m), 1456 (s), 1344 (s), 1160 (s), 1091 (s), 1019 (m), 928

(m), 898 (m), 817 (m), 737 (m), 657 (s), 585 (s), 547 (s). MS (3

kV) m/z 586 (M - Cl). Anal. Calcd for C₃₁H₄₃N₃O₄S₂‚HCl‚H₂O:

C, 58.15; H, 7.24; N, 6.56. Found: C, 58.54; H, 7.36; N, 6.56.

NMR Sample. A solution of 15 mg of QJ023‚HCl in 5 mL of

dichloromethane was stirred with 3 mL of 1 N aq NaOH at room

temperature for 1 h. The organic layer was washed with water (2

× 5 mL) and saturated aqueous NaCl (2 × 5 mL), dried (Na₂SO₄),

and concentrated by rotary evaporation. Drying in vacuo gave a

1

colorless oil. H NMR (300 MHz, CDCl₃) δ 7.68 (d, J ) 8 Hz, 4

H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.13 (s, 2 H, CdCH₂),

3.80 (s, 4 H, H2, H4), 3.14 (t, J ) 6 Hz, 4 H, H6, H12), 2.44 (s,

6 H, ArCH₃), 2.33 (t, J ) 5 Hz, 4 H, H8, H10), 2.24 (t, J ) 8 Hz,

2 H, NCH₂iBu), 1.63 (m, 4 H, H7, H11), 1.46 (m, 1 H, CHMe₂),

1.15 (m, 2 H, CH₂iPr), 0.81 (d, J ) 7 Hz, 6 H, CHCH₃). ¹³C NMR

(75 MHz, CDCl₃) δ 143.6, 138.6, 136.2, 129.9, 127.6, 116.3, 52.0,

51.5, 50.1, 44.4, 35.7, 26.5, 25.3, 22.9, 21.7, 14.4.

9-Cyclopropylmethyl-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (QJ041). A solution of 0.20 g (0.37

mmol) of 94-129, 0.20 mL (188 mg, 2.7 mmol) of cyclopropane-

carboxaldehyde, and 77 mg (1.2 mmol) of sodium cyanoboro-

hydride in 25 mL of methanol was stirred at room temperature for

24 h. The reaction mixture was worked up as described for QJ029.

QJ041‚HCl. A solution of 25 mL of 0.2 N HCl in diethyl ether

was added to a solution of 0.23 g (0.41 mmol) of crude QJ041 in

2 mL of ethyl acetate, producing a white precipitate. The mixture

was sonicated and filtered. The residue was dried in vacuo (60 °C,

3 d) to give 0.20 g (89%) of QJ041‚HCl, as a white solid, mp

134-135 °C. IR (KBr) 2950 (w), 2581 (w), 2360 (m), 2341 (m),

1597 (m), 1455 (m), 1338 (s), 1161 (s), 1091 (m), 1018 (w), 900

(w), 816 (m), 737 (m), 689 (s), 656 (s), 584 (s), 549 (s). MS (3

kV) m/z 546 (M - Cl). Anal. Calcd for C₂₈H₃₉N₃O₄S₂‚HCl‚H₂O:

C, 56.03; H, 7.05; N, 7.00. Found: C, 56.41; H, 6.84; N, 6.94.

NMR Sample. A solution of 20 mg of QJ041‚HCl in 5 mL of

dichloromethane was stirred with 3 mL of 1 N aq NaOH at room

temperature for 1 h. The organic layer was washed with water (2

× 5 mL) and saturated aqueous NaCl (2 × 5 mL), dried (Na₂SO₄),

and concentrated by rotary evaporation. The residue was dried in

vacuo to give QJ041 as a colorless oil. ¹H NMR (300 MHz, CDCl₃)

δ 7.67 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts),

5.12 (s, 2 H, CdCH₂), 3.81 (s, 4 H, H2, H4), 3.16 (t, J ) 6 Hz, 4

1

colorless oil. H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz, 4

H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.59 (m, 2 H, CdCH),

5.19 (s, 2 H, CdCH₂), 3.81 (s, 4 H, H2, H4), 3.15 (t, J ) 7 Hz, 4

H, H6, H12), 2.44 (s, 6 H, ArCH₃), 2.30 (m, 3 H, H8, H10,

NCH₂CH), 2.06 (d, J ) 6 Hz, 2 H, NCH₂Cy), 2.05 (m, 2 H, H8,

H10), 1.60 (m, 8 H, H7, H11, CH₂CdCCH₂), 1.06 (m, 2 H,

CHCH₂CH₂). ¹³C NMR (75 MHz, CDCl₃) δ 143.7, 138.5, 136.1,

130.0, 127.6, 127.4, 126.4, 116.7, 61.6, 51.2, 50.7, 44.5, 32.0, 30.6,

27.4, 24.9, 24.8, 21.7.

9-(2-Pyridylmethyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (98-037). A solution of 0.49 g (0.93

mmol) of 94-129, 0.54 mL (0.61 g, 5.7 mmol) of 2-pyridine-

carboxaldehyde, and 0.15 g (2.4 mmol) of sodium cyanoborohydride

1302 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

in 25 mL of methanol was stirred at room temperature for 40 h.

The resulting white precipitate was removed by filtration, then

washed with cold methanol, followed by water. Recrystallization

from methanol/chloroform gave 0.32 g (59%) of 98-037 as white

CDCl₃) δ 7.66 (d, J ) 8 Hz, 4 H, o-Ts), 7.31 (d, J ) 8 Hz, 4 H,

m-Ts), 7.11 (m, 2 H, m-FBn), 6.94 (m, 2 H, o-FBn), 5.21 (s, 2 H,

CdCH₂), 3.84 (s, 4 H, H2, H4), 3.36 (s, 2 H, CH₂Ar), 3.11 (t, J )

7 Hz, 4 H, H6, H12), 2.44 (s, 6 H, ArCH₃), 2.35 (t, J ) 5 Hz, 4 H,

H8, H10), 1.65 (m, 4 H, H7, H11). ¹³C NMR (75 MHz, CDCl₃) δ

143.7, 138.9, 136.0, 135.3, 130.4, 130.0, 127.5, 116.4, 115.4, 115.1,

58.7, 51.4, 49.8, 44.4, 24.9, 21.7. MS (FAB) m/z 600 (MH⁺). Anal.

Calcd for C₃₁H₃₈FN₃O₄S₂: C, 62.08; H, 6.39; N, 7.01. Found: C,

61.94; H, 6.44; N, 6.90.

1

crystals, mp 202.5-203 °C. H NMR (300 MHz, CDCl₃) δ 8.47

(d, J ) 3 Hz, 1 H, 6-Py), 7.66 (d, J ) 8 Hz, 4 H, o-Ts), 7.60 (m,

1 H, 4-Py), 7.31 (d, J ) 8 Hz, 4 H, m-Ts), 7.21 (d, J ) 8 Hz, 1 H,

3-Py), 7.13 (m, 1 H, 5-Py), 5.22 (s, 2 H, CdCH₂), 3.85 (s, 4 H,

H2, H4), 3.58 (s, 2 H, CH₂Py), 3.14 (t, J ) 6 Hz, 4 H, H6, H12),

2.44 (bm, 10 H, ArCH₃, H8, H10), 1.67 (m, 4 H, H7, H11). ¹³C

NMR (75 MHz, CDCl₃) δ 160.0, 149.3, 143.6, 139.1, 136.3, 136.2,

130.0, 127.6, 123.1, 122.1, 116.2, 61.1, 51.5, 50.3, 44.5, 25.1, 21.7.

IR (KBr) 2949 (w), 2838 (w), 1597 (m), 1145 (m), 1329 (s), 1164

(s), 1091 (s), 1038 (m), 930 (s), 910 (m), 822 (s), 744 (s), 689 (s),

555 (s). MS (3 kV) m/z 583 (MH⁺). Anal. Calcd for C₃₀H₃₈N₄O₄S₂:

C, 61.83; H, 6.57; N, 9.61. Found: C, 61.63; H, 6.65; N, 9.53.

9-(4-Pyridylmethyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (QJ030). A solution of 0.49 g (0.93

mmol) of 94-129, 0.55 mL (0.61 g, 5.7 mmol) of 4-pyridinecar-

boxaldehyde, and 0.15 g (2.4 mmol) sodium cyanoborohydride in

25 mL of methanol was stirred at room temperature for 24 h. The

reaction mixture was worked up as described for QJ029. Column

chromatography on silica gel, eluting with chloroform/ethyl acetate/

triethylamine (90:5:5, v/v/v), yielded 0.26 g (48%) of QJ030 as a

9-(p-Hydroxybenzyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (QJ010). A solution of 0.11 g (0.21

mmol) of 94-129, 0.25 g (2.0 mmol) of 4-hydroxybenzaldehyde,

and 43 mg (0.68 mmol) of sodium cyanoborohydride in 20 mL of

methanol was stirred at room temperature for 24 h. The reaction

mixture was worked up as described for QJ029. Three recrystal-

lizations from chloroform/hexane gave 75 mg (60%) of QJ010 as

1

white crystals, mp 175-176 °C. H NMR (300 MHz, CDCl3) δ

7.66 (d, J ) 8 Hz, 4 H, o-Ts), 7.31 (d, J ) 8 Hz, 4 H, m-Ts), 7.00

(d, J ) 8 Hz, 2 H, o-OHBn), 6.71 (d, J ) 8 Hz, 2 H, m-OHBn),

5.21 (s, 2 H, CdCH₂), 4.66 (bs, 1 H, OH), 3.83 (s, 4 H, H2, H4),

3.31 (s, 2 H, CH₂Ar), 3.10 (t, J ) 7 Hz, 4 H, H6, H12), 2.44 (s, 6

H, ArCH₃), 2.33 (t, J ) 5 Hz, 4 H, H8, H10), 1.64 (m, 4 H, H7,

H11). ¹³C NMR (75 MHz, CDCl₃) δ 154.8, 143.7, 138.6, 135.8,

131.6, 130.3, 130.0, 127.5, 116.5, 115.2, 58.5, 51.3, 49.6, 44.3,

24.7, 21.8. IR (KBr) 3454 (bm), 2949 (w), 1614 (m), 1597 (m),

1541 (m), 1443 (m), 1321 (s), 1156 (s), 1090 (s), 923 (m), 742

(m), 551 (s). MS (FAB) m/z 598 (MH⁺). Anal. Calcd for

C₃₁H₃₉N₃O₅S₂: C, 62.29; H, 6.58; N, 7.03; S, 10.73. Found: C,

61.99; H, 6.84; N, 6.92l; S, 11.11.

1

colorless oil. H NMR (300 MHz, CDCl₃) δ 8.49 (d, J ) 5 Hz, 2

H, 2-Py), 7.66 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H,

m-Ts), 7.10 (d, J ) 5 Hz, 2 H, 3-Py), 5.24 (s, 2 H, CdCH₂), 3.86

(s, 4 H, H2, H4), 3.42 (s, 2 H, CH₂Py), 3.14 (t, J ) 7 Hz, 4 H, H6,

H12), 2.44 (s, 4 H, ArCH₃), 2.39 (t, J ) 5 Hz, 4 H, H8, H10), 1.67

(m, 4 H, H7, H11). ¹³C NMR (75 MHz, CDCl₃) δ 150.5, 149.4,

144.2, 139.4, 136.3, 130.5, 127.9, 124.3, 116.9, 59.3, 51.7, 50.5,

44.8, 25.2, 22.2. MS (FAB) m/z 583 (MH⁺). QJ030‚HCl. A solution

of 30 mL of 0.3 N HCl in diethyl ether was added to a solution of

0.26 g (0.45 mmol) of QJ030 in 2 mL of ethyl acetate, producing

a white precipitate. The mixture was sonicated and filtered. The

white solid was dried in vacuo (60 °C, 3 days) to give 0.22 g (38%)

of white crystalline QJ030‚HCl, mp 162-163 °C. IR (KBr) 3424

(bm), 3059 (w), 2924 (w), 2578 (bm), 1641 (m), 1598 (m), 1450

(m), 1337 (s), 1161 (s), 1090 (s), 901 (w), 805 (s), 727 (m), 688

(s), 656 (s), 559 (s). MS (3 kV) m/z 583 (M - Cl). Anal. Calcd for

C₃₀H₃₈N₄O₄S₂‚HCl‚1.5 H₂O: C, 52.78; H, 6.35; N, 8.21. Found:

C, 52.61; H, 6.42; N, 8.04.

9-(3-Furylmethyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (10). A solution of 0.11 g (0.20 mmol)

of 94-129, 0.15 mL (0.16 g, 1.7 mmol) of 3-furaldehyde, and 39

mg (0.63 mmol) of sodium cyanoborohydride in 20 mL of methanol

was stirred at room temperature for 20 h, producing a pale yellow

precipitate. Filtration and recrystallization from chloroform/hexane

gave 78 mg (68%) of 10 as white crystals, mp 139.5-140.5 °C.

¹H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz, 4 H, o-Ts), 7.32

(d, J ) 8 Hz, 4 H, m-Ts), 7.31 (s, 1 H, 2-furyl), 7.21 (bs, 1 H,

5-furyl), 6.17 (bs, 1 H, 4-furyl), 5.17 (s, 2 H, CdCH₂), 3.82 (s, 4

H, H2, H4), 3.27 (s, 2 H, CH₂Ar), 3.12 (t, J ) 6 Hz, 4 H, H6,

H12), 2.44 (s, 6 H, ArCH₃), 2.35 (m, 4 H, H8, H10), 1.66 (m, 4 H,

H7, H11). ¹³C NMR (75 MHz, CDCl₃) δ 143.6, 143.3, 140.7, 138.9,

136.2, 130.0, 127.6, 122.2, 116.2, 111.3, 51.5, 49.7, 48.4, 44.2,

25.1, 21.7. IR (KBr) 2930 (w), 2822 (w), 1589 (m), 1441 (m), 1336

(s), 1169 (s), 1083 (s), 1037 (m), 877 (m), 819 (s), 730 (s). MS

(FAB) m/z 572 (MH⁺). Anal. Calcd for C₂₉H₃₇N₃O₅S₂: C, 60.92;

H, 6.52; N, 7.35. Found: C, 60.53; H, 6.49; N, 7.09.

9-(p-Methylbenzyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (8). A solution of 0.15 g (0.28 mmol)

of 94-129, 0.15 mL (153 mg, 1.3 mmol) of 4-methylbenzaldehyde,

and 28 mg (0.44 mmol) of sodium cyanoborohydride in 20 mL of

methanol was stirred at room temperature for 40 h. The reaction

mixture was worked up as described for QJ029, yielding 86 mg

(60%) of a white solid. Two recrystallizations from chloroform/

diethyl ether followed by one recrystallization from ethyl acetate/

hexane gave 64 mg (45%) of 8 as white crystals, mp 260-261 °C.

¹H NMR (300 MHz, CDCl₃) δ 7.65 (d, J ) 8 Hz, 4 H, o-Ts), 7.31

(d, J ) 8 Hz, 4 H, m-Ts), 7.05 (m, 2 H, o-Bn), 7.01 (m, 2 H,

m-Bn), 5.22 (s, 2 H, CdCH₂), 3.82 (s, 4 H, H2, H4), 3.33 (s, 2 H,

CH₂Ar), 3.11 (t, J ) 6 Hz, 4 H, H6, H12), 2.43 (s, 6 H, SO₂ArCH₃),

2.33 (t, J ) 6 Hz, 4 H, H8, H10), 2.30 (s, 3 H, CH₂ArCH₃), 1.63

(m, 4H, H7, H11). ¹³C NMR (75 MHz, CDCl₃) δ 143.2, 138.4

(2C), 136.3, 136.1, 135.8, 129.6, 128.7, 128.6, 127.2, 58.6, 51.0,

49.5, 44.0, 24.5, 21.3, 20.9. IR (KBr) 2949 (m), 2918 (m), 2819

(m), 1597 (m), 1445 (m), 1330 (s), 1157 (s), 1092 (m), 927 (m),

897 (m), 743 (m), 688 (s), 551 (s). MS (FAB) m/z 596 (MH⁺),

618 (MNa⁺). Anal. Calcd for C₃₂H₄₁N₃O₄S₂‚0.25(CH₃CO₂C₂H₅):

C, 64.15; H, 7.01; N, 6.80. Found: C, 64.04; H, 7.16; N, 7.15.

9-(p-Fluorobenzyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (9). A solution of 0.11 g (0.21 mmol)

of 94-129, 0.25 mL (0.28 g, 2.3 mmol) of 4-fluorobenzaldehyde

and 43 mg (0.68 mmol) of sodium cyanoborohydride in 20 mL of

methanol was stirred at room temperature for 24 h. The reaction

mixture was worked up as described for QJ029, yielding 0.12 g

(95%) of crude product. Two recrystallizations from ethyl acetate

9-Furfuryl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-tri-

azacyclododecane (11). A solution of 0.11 g (0.20 mmol) of 94-

129, 0.15 mL (0.17 g, 1.8 mmol) of 2-furaldehyde, and 63 mg (0.68

mol) of sodium cyanoborohydride in 20 mL of methanol was stirred

at room temperature for 20 h, producing a pale yellow precipitate,

which was collected by filtration and recrystallized from ethyl

acetate, yielding 66 mg (58%) of 11 as white crystals, mp 162-

1

162.5 °C. H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz, 4 H,

o-Ts), 7.31 (d, J ) 8 Hz, 4 H, m-Ts), 7.29 (d, J ) 1 Hz, 1 H,

5-furyl), 6.26 (dd, J ) 3 Hz, 1 Hz, 1 H, 4-furyl), 6.04 (d, J ) 3

Hz, 1 H, 3-furyl), 5.09 (s, 2 H, CdCH₂), 3.82 (s, 4 H, H2, H4),

3.44 (s, 2 H, CH₂Ar), 3.12 (t, J ) 6 Hz, 4 H, H6, H12), 2.44 (s, 6

H, ArCH₃), 2.42 (t, J ) 6 Hz, 4 H, H8, H10), 1.69 (m, 4 H, H7,

H11). ¹³C NMR (75 MHz, CDCl₃) δ 152.8, 143.6, 142.0, 138.5,

136.1, 130.0, 127.6, 116.0, 110.3, 108.3, 51.7, 49.9, 49.5, 43.9,

25.4, 21.7. IR (KBr) 2952 (w), 2835 (w), 1598 (m), 1446 (m), 1331

(s), 1163 (s), 1092 (s), 929 (s), 910 (m), 818 (s), 743 (s), 689 (s).

MS (FAB) m/z 572 (MH⁺). Anal. Calcd for C₂₉H₃₇N₃O₅S₂: C,

60.92; H, 6.52; N, 7.35. Found: C, 60.83; H, 6.90; N, 7.62.

9-(5-Methylfurfuryl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (98-038). A solution of 0.49 mg (0.93

mmol) of 94-129, 0.57 mL (0.63 g, 6.2 mmol) of 5-methylfurfural,

and 0.17 g (2.7 mmol) of sodium cyanoborohydride in 25 mL of

methanol was stirred at room temperature for 40 h, producing a

1

gave 43 mg (34%) of 9 as white crystals. H NMR (300 MHz,

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1303

pale yellow precipitate. Filtration and recrystallization from methanol/

chloroform gave 0.32 g (59%) of 98-038 as white crystals, mp

204-205 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz, 4

H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.90 (s, 1 H, furyl), 5.83

(s, 1 H, furyl), 5.10 (s, 2 H, CdCH₂), 3.82 (s, 4 H, H2, H4), 3.38

(s, 2 H, CH₂Ar), 3.12 (t, J ) 5 Hz, 4 H, H6, H12), 2.44 (m, 10 H,

H8, H10, SO₂ArCH₃), 2.20 (s, 3 H, furylCH₃), 1.69 (m, 4 H, H7,

H11). ¹³C NMR (300 MHz, CDCl₃) δ 151.1, 150.4, 143.1, 138.2,

135.8, 129.5, 127.2, 115.6, 108.7, 105.7, 51.5, 49.6, 49.2, 43.6,

24.9, 21.3, 13.3. IR (KBr) 2955 (w), 2834 (w), 1598 (w), 1445

(w), 1331 (m), 1164 (s), 1116 (m), 1092 (m), 930 (m), 912 (m),

821 (m), 743 (m), 688 (s), 551 (s). MS (FAB) m/z 586 (MH⁺).

Anal. Calcd for C₃₀H₃₉N₃O₅S₂: C, 61.51; H, 6.71; N, 7.17.

Found: C, 61.13; H, 6.77; N, 7.07.

tallization from chloroform/hexane gave 0.26 g (48%) of white

crystalline 14, mp 171-171.5 °C. H NMR (300 MHz, CDCl₃) δ

1

8.17 (bs, 1 H, NH), 7.66 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8

Hz, 4 H, m-Ts), 6.69 (m, 1 H, 5-pyrryl), 6.08 (m, 1 H, 3-pyrryl),

5.94 (m, 1 H, 4-pyrryl), 5.22 (s, 2 H, CdCH₂), 3.84 (s, 4 H, H2,

H4), 3.44 (s, 2 H, CH₂Ar), 3.12 (t, J ) 6 Hz, 4 H, H6, H12), 2.44

(s, 6 H, ArCH₃), 2.40 (t, J ) 6 Hz H8, H10), 1.65 (m, 4 H, H7,

H11). ¹³C NMR (125 MHz, CDCl₃) δ 143.8, 140.2, 135.8, 130.0,

127.7, 117.8, 116.3, 108.4, 107.8, 52.3, 51.8, 50.2, 45.6, 25.0, 21.9.

IR (KBr) 3416 (bm), 2953 (m), 1597 (m), 1445 (m), 1323 (s), 1160

(s), 1092 (s), 1039 (m), 929 (s), 895 (m), 817 (s), 743 (s), 717 (s),

690 (s), 547 (s). MS (3 kV) m/z 492 (MH⁺- C₅H₆N). Anal. Calcd

for C₂₉H₃₈N₄O₄S₂: C, 61.0; H, 6.7; N, 9.8. Found: C, 60.88; H,

6.88; N, 9.66.

9-(3-Thienylmethyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (12). A solution of 0.49 g (0.93 mmol)

of 94-129, 0.50 mL (0.64 g, 5.7 mmol) of 3-thiophenecarbox-

aldehyde, and 0.18 g (2.9 mmol) of sodium cyanoborohydride in

25 mL of methanol was stirred at room temperature for 40 h. The

reaction mixture was worked up as described for QJ029. Column

chromatography on neutral alumina, eluting with ethyl acetate/

hexane/triethylamine (30:60:5, v/v/v), followed by recrystallization

from ethyl acetate, gave 0.13 mg (25%) of 12 as white crystals,

9-[(1-Methyl-2-pyrryl)methyl]-3-methylene-1,5-bis(p-toluene-

sulfonyl)-1,5,9-triaza-cyclododecane (15). A solution of 0.50 g

(0.95 mmol) of 94-129, 0.31 mL (0.31 mg, 2.9 mmol) of

N-methylpyrrole-2-carboxaldehyde, and 0.18 g (2.9 mmol) of

sodium cyanoborohydride in 25 mL of methanol was stirred at room

temperature for 40 h. The reaction mixture was worked up as

described for QJ029, obtaining a mixture of starting material and

product. Methanol (25 mL), 0.31 mL (0.31 g, 2.9 mmol) of

N-methylpyrrole-2-carboxyaldehyde, and 0.18 g (2.9 mmol) of

sodium cyanoborohydride were added, and the resulting solution

was stirred at room temperature for 40 h. The reaction mixture

was worked up as described for QJ029 to give 0.35 g (63%) of

crude 15 as a brown solid. Column chromatography on neutral

alumina, eluting with ethyl acetate/hexane/triethylamine (30:60:5,

v/v/v), followed by recrystallization from chloroform/methanol,

1

mp 149-149.5 °C. H NMR (300 MHz, CDCl₃) δ 7.66 (d, J ) 8

Hz, 4 H, o-Ts), 7.31 (d, J ) 8 Hz, 4 H, m-Ts), 7.23 (m, 1 H,

4-thienyl), 7.00 (s, 1 H, 2-thienyl), 6.89 (d, J ) 4 Hz, 1 H,

5-thienyl), 5.20 (s, 2 H, CdCH₂), 3.83 (s, 4 H, H2, H4), 3.46 (s,

2 H, CH₂Ar), 3.13 (t, J ) 6 Hz, 4 H, H6, H12), 2.44 (s, 6 H,

ArCH₃), 2.40 (m, 4 H, H8, H10), 1.68 (m, 4 H, H7, H11). ¹³C

NMR (75 MHz, CDCl₃) δ 143.6, 140.0, 139.0, 136.2, 130.0, 128.4,

127.6, 125.8, 122.6, 116.3, 53.4, 51.5, 49.9, 44.4, 25.0, 21.7. IR

(KBr) 2949 (m), 2816 (m), 2360 (m), 2341 (m), 1655 (w), 1598

(m), 1444 (m), 1329 (s), 1162 (s), 1091 (s), 1039 (m), 929 (s), 898

(m), 816 (s), 743 (s), 725 (s), 689 (s), 551 (s). MS (3 kV) m/z 588

(MH⁺). Anal. Calcd for C₂₉H₃₇N₃O₄S₃‚0.5H₂O: C, 58.36; H, 6.42;

N, 7.04. Found: C, 58.07; H, 6.28; N, 6.99.

1

gave 0.20 g (36%) of 15 as white crystals, mp 146-146.5 °C. H

NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz, 4 H, o-Ts), 7.31 (d,

J ) 8 Hz, 4 H, m-Ts), 6.53 (m, 1 H, 5-pyrryl), 5.98 (m, 1 H,

4-pyrryl), 5.91 (m, 1 H, 3-pyrryl), 5.20 (s, 2 H, CdCH₂), 3.84 (s,

4 H, H2, H4), 3.48 (s, 3 H, NCH₃), 3.34 (s, 2 H, CH₂Ar), 3.11 (t,

J ) 6 Hz, 4 H, H6, H12), 2.44 (s, 6 H, ArCH₃), 2.35 (t, J ) 6 Hz,

4 H, H8,10), 1.56 (m, 4 H, H7, H11). ¹³C NMR (125 MHz, CDCl₃)

δ 143.6, 139.2, 136.0, 129.9, 129.5, 127.4, 122.6, 116.2, 109.8,

106.6, 52.2, 51.1, 49.6 44.7, 33.8, 24.6, 21.7. IR (KBr) 2939 (m),

2839 (m), 1598 (m), 1494 (m), 1444 (m), 1327 (s), 1172 (s), 1115

(s), 1090 (s), 927 (s), 898 (m), 817 (s), 743 (s), 719 (s), 690 (s),

551 (s). MS (3 kV) m/z 492 (MH⁺- C₆H₈N). Anal. Calcd for

C₃₀H₄₀N₄O₄S₂: C, 61.62; H, 6.89; N, 9.58. Found: C, 61.99; H,

7.03; N, 9.54.

9-(2-Thienylmethyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (13). A solution of 0.47 g (0.89 mmol)

of 94-129, 0.55 mL (0.69 g, 5.7 mmol) of 2-thiophenecarbox-

aldehyde, and 0.18 g (2.9 mmol) of sodium cyanoborohydride in

25 mL of methanol was stirred at room temperature for 40 h. The

reaction mixture was worked up as described for QJ029. Recrys-

tallization from dichloromethane/methanol gave 0.45 g (85%) of

1

13 as pale yellow crystals, mp 264-265 °C. H NMR (300 MHz,

9-Neopentyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-tri-

azacyclododecane (16). A solution of 0.25 g (0.47 mmol) of 94-

129, 0.25 mL (0.20 g, 2.2 mmol) of trimethylacetaldehyde in 12

mL of methanol was stirred for 30 min at room temperature. A

solution of 76 mg (1.2 mmol) of sodium cyanoborohydride and 50

mg (0.36 mmol) of zinc chloride in 13 mL of methanol was added

over 30 min. The resulting solution was stirred at room temperature

for 3 days, then worked up as described for QJ029. Column

chromatography on silica gel, eluting with ethyl acetate/hexane/

triethylamine (30:60:5, v/v/v), gave 55 mg (26%) of 16 as a

CDCl₃) δ 7.67 (d, J ) 8 Hz, 4 H, o-Ts), 7.31 (d, J ) 7 Hz, 4 H,

m-Ts), 7.17 (d, J ) 4 Hz, 1 H, 5-thienyl), 6.89 (bs, 1 H, 4-thienyl),

6.79 (m, 1 H, 3-thienyl), 5.21 (s, 2 H, CdCH₂), 3.83 (s, 4 H, H2,

H4), 3.61 (s, 2 H, CH₂Ar), 3.16 (m, 4 H, H6, H12), 2.44 (bs, 10 H,

H8, H10, ArCH₃), 1.68 (m, 4 H, H7, H11). ¹³C NMR (75 MHz,

CDCl₃) δ 143.6, 142.9, 138.5, 136.3, 130.0, 127.6, 126.4, 125.7,

125.0, 116.7, 53.2, 51.5, 49.8, 44.2, 25.1, 21.7. IR (KBr) 3063 (w),

2946 (w), 2929 (w), 2821 (w), 1598 (m), 1444 (m), 1329 (s), 1154

(s), 1091 (m), 1035 (m), 929 (m), 896 (m), 817 (m), 743 (m), 688

(s), 574 (m). MS (FAB) m/z 588 (MH⁺). Anal. Calcd for

C₂₉H₃₇N₃O₄S₃: C, 59.26; H, 6.34; N, 7.15. Found: C, 59.50; H,

6.67; N, 7.30.

1

colorless oil. H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz, 4

H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.24 (s, 2 H, CdCH₂),

3.82 (s, 4 H, H2, H4), 3.22 (t, J ) 6 Hz, 4 H, H6, H12), 2.44 (s,

6 H, ArCH₃), 2.34 (t, J ) 6 Hz, 4 H, H8, H10), 1.99 (s, 2 H,

NCH₂tBu), 1.59 (m, 4 H, H7, H11), 0.77 (s, 9 H, CCH₃). ¹³C NMR

(125 MHz, CDCl₃) δ 143.6, 138.4, 135.9, 130.0, 127.4, 116.9, 68.3,

52.3, 51.0, 44.5, 32.9, 28.9, 25.1, 21.7. 16‚HCl. A solution of 30

mL of 0.33 N HCl in diethyl ether was added to a solution of 55

mg (0.12 mmol) of 16 in 2 mL of ethyl acetate, producing a white

precipitate. The mixture was sonicated and filtered. The residue

was dried in vacuo (60 °C, 3 d) to give 35 mg (12%) of 16‚HCl,

mp 140-142 °C. IR (KBr) 3421 (bm), 2956 (m), 1597 (m), 1457

(m), 1336 (s), 1157 (s), 1090 (m), 1021 (w), 936 (w), 889 (w), 816

(m), 737 (m), 689 (m), 657 (m), 587 (m), 549 (s). MS (FAB) m/z

562 (M - Cl). Anal. Calcd for C₂₉H₄₃N₃O₄S₂‚HCl‚1.25 H₂O: C,

56.11; H, 7.55; N, 6.77. Found: C, 56.0; H, 7.55; N, 6.77.

9-Isopropyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-tri-

azacyclododecane (QJ035). A solution of 0.25 g (0.47 mmol) of

9-(2-Pyrrylmethyl)-3-methylene-1,5-bis(p-toluenesulfonyl)-

1,5,9-triazacyclododecane (14). A solution of 0.50 g (0.94 mmol)

of 94-129, 0.54 g (5.6 mmol) of pyrrole-2-carboxyaldehyde, and

0.18 g (2.9 mmol) of sodium cyanoborohydride in 25 mL of

methanol was stirred for 40 h at room temperature. The reaction

mixture was worked up as described for QJ029. The HCl salt was

formed as described for 6‚HCl. A solution of the resulting dark

red solid in 30 mL of CH₂Cl₂was stirred with 10 mL of 1 N aq

NaOH overnight. The mixture was filtered, and the residue was

washed with CH₂Cl₂. The combined filtrates were concentrated by

rotary evaporation to a brown oil. Column chromatography on silica

gel, eluting with AcOEt/CH₂Cl₂/Et₃N (5:93:2, v/v/v), then AcOEt/

CH₂Cl₂/Et₃N (10:88:2, v/v/v), yielded 0.47 g (89%) of a brown

solid. A solution of the product in ethyl acetate was filtered through

neutral alumina, then concentrated by rotary evaporation. Recrys-

1304 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

94-129, 0.35 mL (0.28 g, 4.8 mmol) of acetone, 89 mg (1.4 mmol)

of sodium cyanoborohydride, and 39 mg (0.24 mmol) of zinc

chloride in 25 mL of methanol was stirred at room temperature for

3 d. The reaction mixture was worked up as described for QJ029

to give 0.21 g (84%) of crude QJ035. Column chromatography on

silica gel, eluting with ethyl acetate/hexane/triethylamine (30:60:

5, v/v/v), gave 0.18 g (72%) of QJ035 as a colorless oil. ¹H NMR

(300 MHz, CDCl₃) δ 7.68 (d, J ) 8 Hz, 4 H, o-Ts), 7.33 (d, J )

8 Hz, 4 H, m-Ts), 5.20 (s, 2 H, CdCH₂), 3.80 (s, 4 H, H2, H4),

3.14 (t, J ) 7 Hz, 4 H, H6, H12), 2.76 (m, 1 H, NCH), 2.44 (s, 6

H, ArCH₃), 2.33 (t, J ) 5 Hz, 4 H, H8, H10), 1.59 (m, 4 H, H7,

H11), 0.84 (d, J ) 6.4 Hz, 6 H, NCHCH₃). ¹³C NMR (75 MHz,

CDCl₃): δ 143.6, 138.5, 136.1, 130.0, 127.5, 116.8, 51.1, 49.8,

45.4, 44.4, 25.6, 21.7, 21.6, 17.8. QJ035‚HCl. A solution of 30

mL of 0.33 N HCl in diethyl ether was added to a solution of 0.18

g (0.34 mmol) of the QJ035 in 2 mL of ethyl acetate, producing a

white precipitate. The mixture was sonicated and filtered. The

precipitate was dried in vacuo (60 °C, 3 d) to give 0.17 g (62%) of

QJ035‚HCl, mp 137.5-138.5 °C. IR (KBr) 3422 (bm), 2943 (m),

2585 (bm), 1597 (m), 1451 (m), 1335 (s), 1150 (s), 1090 (m), 816

(m), 725 (m), 687 (m), 656 (m), 586 (m), 549 (s). Anal. Calcd for

C₂₇H₃₉N₃O₄S₂‚HCl‚H₂O: C, 55.13; H, 7.20; N, 7.14. Found: C,

55.19; H, 7.19; N, 7.14.

9-sec-Butyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-tri-

azacyclododecane (QJ036). A solution of 0.19 g (0.37 mmol) of

94-129, 0.34 mL (0.27 g, 3.8 mmol) of 2-butanone, 72 mg (1.1

mmol) of sodium cyanoborohydride, and 30 mg (0.22 mmol) of

zinc chloride in 25 mL of methanol was stirred at room temperature

for 3 d. The reaction mixture was worked up as described for

QJ029. Column chromatography on silica gel, eluting with ethyl

acetate/hexane/triethylamine (30:60:5, v/v/v) followed by recrys-

tallization from ethyl acetate/hexane, gave 0.15 g (75%) of QJ036

as white crystals, mp 187-188 °C. ¹H NMR (300 MHz, CDCl₃) δ

7.68 (d, J ) 8 Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.21

(s, 2 H, CdCH₂), 4.00 (d, J ) 16 Hz, 2 H, H2, H4), 3.62 (d, J )

16 Hz, 2 H, H2, H4), 3.15 (m, 4 H, H6, H12), 2.44 (s, 6 H, ArCH₃),

2.40 (m, 4 H, H8, H10), 2.28 (m, 1 H, NCH), 1.57 (m, 4 H, H7,

H11), 1.20 (m, 2 H, CH₂CH₃), 0.77 (m, 6 H, CH₃CHCH₂CH₃).

¹³C NMR (75 MHz, CDCl₃) δ 143.6, 138.8, 136.4, 130.0, 127.6,

116.9, 56.9, 51.2, 45.3, 44.6, 26.6, 25.7, 21.7, 13.7, 12.1. IR (KBr)

2962 (m), 1598 (m), 1458 (m), 1346 (s), 1162 (s), 1091 (m), 921

(m), 744 (m). MS (3 kV) m/z 548 (MH⁺). Anal. Calcd for

C₂₈H₄₁N₃O₄S₂: C, 61.39; H, 7.54; N, 7.67. Found: C, 61.62; H,

7.59; N, 7.66.

9-Acetyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triaza-

cyclododecane (97-269). A solution of 0.11 mL (0.29 g, 2.9 mmol)

of acetic anhydride in 5 mL of chloroform was added dropwise

over 30 min to a stirred solution of 0.15 g (0.19 mmol) of 94-129

and 0.25 mL (0.29 g, 2.9 mmol) of triethylamine in 5 mL of

chloroform at room temperature. The reaction mixture was heated

under reflux for 18 h, then concentrated by rotary evaporation. A

solution of the residue in 10 mL of CH₂Cl₂was washed with 1 N

aq HCl (2 × 5 mL), 1 N aq NaOH (5 mL), water (3 × 10 mL),

and saturated aqueous NaCl (10 mL), then dried (Na₂SO₄).

Concentration by rotary evaporation, drying in vacuo, and recrys-

tallization from diethyl ether/acetone gave 82 mg (54%) of white

1

crystalline 97-269, mp 163 °C. H NMR (300 MHz, CDCl₃) δ

7.70 (d, J ) 8 Hz, 2 H, o-Ts), 7.66 (d, J ) 8 Hz, 2 H, o-Ts), 7.34

(d, J ) 8 Hz, 4 H, m-Ts), 5.31 (s, 2 H, CdCH₂), 3.94 (s, 2 H, H2

or H4), 3.78 (s, 2 H, H4 or H2), 3.41 (m, 4 H, H8, H10), 3.24 (t,

J ) 6 Hz, 2 H, H6 or H12), 3.10 (t, J ) 6 Hz, 2 H, H12 or H6),

2.45 (s, 6 H, ArCH₃), 2.03 (s, 3 H, CH₃CdO), 1.89 (m, 4 H, H7,

H11). ¹³C NMR (75 MHz, CDCl₃) δ 171.2, 144.0, 140.8, 130.1,

127.5, 117.6, 54.0, 50.9, 48.5, 46.7, 46.2, 43.3, 28.1, 27.4, 22.0,

21.7. IR (KBr) 2950 (w), 2858 (w), 1644 (s), 1597 (m), 1449 (m),

1332 (s), 1162 (s), 1103 (m), 1018 (m), 923 (m), 723 (s), 680 (s),

548 (s). MS (FAB) m/z 534 (MH⁺). Anal. Calcd for C₂₆H₃₅N₃O₅S₂:

C, 58.51; H, 6.67; N, 7.87; S, 12.01. Found: C, 58.82; H, 6.93; N,

8.11; S, 12.43.

9-Propanoyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-tri-

azacyclododecane (17). A solution of 75 µL (80 mg, 0.86 mmol)

of propionyl chloride in 5 mL of chloroform was added dropwise

to a solution of 0.15 g (0.28 mmol) of 94-129 and 0.24 mL (0.17

g, 1.7 mmol) of triethylamine in 5 mL of chloroform over 30 min

at 0 °C. The reaction mixture was warmed to room temperature

and stirred for 18 h, then concentrated by rotary evaporation. A

solution of the residue in 15 mL of methanol was stirred with 5

mL of 1 N aq NaOH for 10 h at room temperature. The reaction

mixture was then worked up as described for 97-269. Recrystal-

lization from diethyl ether/dichloromethane gave 0.12 g (77%) of

1

white crystalline 17, mp 130.5-131.5 °C. H NMR (300 MHz,

CDCl₃) δ 7.70 (d, J ) 8 Hz, 4 H, o-Ts), 7.66 (d, J ) 8 Hz, 4 H,

o-Ts), 7.33 (d, J ) 8 Hz, 4 H, m-Ts), 5.31 (s, 2 H, CdCH₂), 3.94,

(s, 2 H, H2 or H4), 3.77 (s, 2 H, H4 or H2), 3.40 (m, 4 H, H8,

H10), 3.24 (t, J ) 6 Hz, 2 H, H6 or H12), 3.10 (t, J ) 6 Hz, 2 H,

H12 or H6), 2.45 (s, 6 H, ArCH₃), 2.26 (q, J ) 7 Hz, 2 H,

CH₂CdO), 1.90 (m, 4 H, H7, H11), 1.10 (t, J ) 7 Hz, 3 H,

CH₂CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 174.5, 144.0, 140.5, 130.2,

127.5, 117.7, 54.2, 50.4, 48.8, 45.9, 45.6, 43.4, 28.3, 27.0, 26.9,

21.8, 9.7. IR (KBr) 2938 (m), 2872 (m), 1645 (s), 1597 (m), 1448

(m), 1331 (s), 1159 (s), 1104 (s), 1019 (m), 923 (m), 820 (m), 722

(s), 630 (s), 549 (s). MS (FAB) m/z 548 (MH⁺), 570 (MNa⁺). Anal.

Calcd for C₂₇H₃₇N₃O₅S₂: C, 59.21; H, 6.81; N, 7.67; S, 11.71.

Found: C, 59.18; H, 7.06; N, 7.99; S, 12.08.

9-Cyclopentyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-

triazacyclododecane (QJ040). A solution of 0.20 g (0.37 mmol)

of 94-129, 1.0 mL (0.95 g, 11 mmol) of cyclopentanone, and 30

mg (0.22 mmol) of zinc chloride in 12 mL of methanol was stirred

for 30 min at room temperature. A solution of 76 mg (1.2 mmol)

of sodium cyanoborohydride in 13 mL methanol was added over

30 min. The resulting solution was stirred at room temperature for

24 h. The reaction mixture was worked up as described for QJ029.

Column chromatography on silica gel, eluting with ethyl acetate/

hexane/triethylamine (30:60:5, v/v/v), gave 0.17 g (80%) of QJ040

9-Isobutanoyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-tri-

azacyclododecane (18). A solution of 0.10 mL (0.10 g, 0.95 mmol)

of isobutyryl chloride in 5 mL of chloroform was added dropwise

to a solution of 0.20 g (0.38 mmol) of 94-129 and 0.26 mL (0.19

g, 1.9 mmol) of triethylamine in 5 mL of chloroform over 30 min

at 0 °C. The reaction mixture was warmed to room temperature

and stirred for 16 h, then worked up as described for 97-269.

Recrystallization from ethanol gave 89 mg (42%) of white

1

as a colorless oil. H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8

Hz, 4 H, o-Ts), 7.32 (d, J ) 8 Hz, 4 H, m-Ts), 5.23 (s, 2 H,

CdCH₂), 3.79 (s, 4 H, H2, H4), 3.15 (t, J ) 7 Hz, 4 H, H6, H12),

2.92 (m, 1 H, NCH), 2.44 (s, 6 H, ArCH₃), 2.40 (m, 4 H, H8,

H10), 1.58-1.65 (m, 8 H, H7, H11, cyclopentyl), 1.43 (m, 2 H,

cyclopentyl), 1.21 (m, 2 H, cyclopentyl). ¹³C NMR (75 MHz,

CDCl₃) δ 143.6, 139.1, 136.0, 130.0, 127.5, 117.1, 63.7, 51.3, 47.8,

45.4, 28.5, 25.7, 24.2, 21.7. QJ040‚HCl. A solution of 30 mL of

0.33 N HCl in diethyl ether was added to a solution of 0.50 g (0.89

mmol) of QJ040 in 2 mL of ethyl acetate, producing a white

precipitate. The mixture was sonicated and filtered. The precipitate

was dried in vacuo (60 °C, 3 d) to give 0.15 g (67%) of QJ040‚

HCl, mp 200-201 °C. IR (KBr) 3422 (b), 2954 (m), 2870 (m),

2357 (bs), 1597 (m), 1456 (s), 1340 (s), 1160 (s), 1103 (s), 900

(m), 816 (m), 737 (s), 695 (s), 652 (s), 552 (s). MS (3 kV) m/z 560

(M - Cl). Anal. Calcd for C₂₉H₃₉N₃O₄S₂‚HCl‚0.75 H₂O: C, 57.12;

H, 7.19; N, 6.89. Found: C, 56.91; H, 6.77; N, 6.80.

1

crystalline 18, mp 135-136 °C. H NMR (300 MHz, CDCl₃) δ

7.70 (d, J ) 8 Hz, 2 H, o-Ts), 7.66 (d, J ) 8 Hz, 2 H, o-Ts), 7.34

(d, J ) 8 Hz, 4 H, m-Ts), 5.30 (s, 2 H, CdCH₂), 3.93 (s, 2 H, H2

or H4), 3.78 (s, 2 H, H4 or H2), 3.41 (m, 4 H, H8, H10), 3.23 (t,

J ) 7 Hz, 2 H, H6 or H12), 3.07 (t, J ) 5 Hz, 2 H, H12 or H6),

2.75 (m, 1 H, CHMe₂), 2.45 (s, 6 H, ArCH₃), 1.89 (m, 4 H, H7,

H11), 1.07 (d, J ) 7 Hz, 6 H, CHCH₃). ¹³C NMR (75 MHz, CDCl₃)

δ 177.9, 144.0, 140.6, 130.2, 127.5, 127.3, 117.7, 54.0, 50.5, 48.4,

45.9, 45.7, 43.8, 30.7, 28.5, 27.4, 21.7, 19.9. IR (KBr) 2957 (m),

2870 (m), 1636 (s), 1597 (m), 1449 (m), 1337 (s), 1160 (s), 1101

(s), 921 (m), 819 (M), 743 (m), 720 (m), 680 (s), 659 (m), 549 (s).

MS (FAB) m/z 562 (MH⁺). Anal. Calcd for C₂₈H₃₉N₃O₅S₂: C,

59.87; H, 7.00; N, 7.48. Found: C, 60.20, H, 7.28, N, 7.59.

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1305

9-Benzoyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triaza-

cyclododecane (19). A solution of 0.11 mL (0.13 g, 0.95 mmol)

of benzoyl chloride in 5 mL of chloroform was added dropwise to

a solution of 0.20 g (0.38 mmol) of 94-129 and 0.26 mL (0.19 g,

1.9 mmol) of triethylamine in 5 mL of chloroform over 30 min at

0 °C. The reaction mixture was warmed to room temperature and

stirred for 18 h, then worked up as described for 97-269.

Recrystallization from ethanol/water yielded 0.13 g (60%) of 19

as white crystals, mp. 179.3-179.8 °C. ¹H NMR (300 MHz, CDCl₃)

δ 7.66 (d, J ) 8 Hz, 4 H, o-Ts), 7.39 (m, 2 H, o-Bz), 7.33 (d, J )

8 Hz, 4 H, m-Ts), 7.28 (m, 3 H, m,p-Bz), 5.37 (s, 2 H, CdCH₂),

3.85 (bs, 4 H, H2, H4), 3.46 (bs, 4 H, H8, H10), 3.18 (t, J ) 6 Hz,

7.33 (d, J ) 8 Hz, 4 H, m-Ts), 5.33 (s, 2 H, CdCH₂), 3.82 (s, 4 H,

H2, H4), 3.67 (m, 4 H, CH₂O), 3.14-3.27 (m, 12 H, H6, H8, H10,

H12, OCH₂CH₂N), 2.45 (s, 6 H, ArCH₃), 1.86 (m, 4 H, H7, H11).

¹³C NMR (75 MHz, CDCl₃) δ 165.2, 144.0, 141.4, 135.7, 130.1,

127.5, 117.5, 66.9, 52.1, 47.9, 47.7, 44.6, 26.0, 21.7. IR (KBr) 2977

(w), 2920 (w), 2861 (w), 1645 (s), 1598 (w) 1412 (m), 1340 (s),

1231 (m), 1157 (s), 1118 (s), 1099 (m), 894 (m), 815 (m), 785

(m), 755 (w), 662 (m), 550 (s). MS (FAB) m/z 605 (MH⁺). Anal.

Calcd for C₂₉H₄₀N₄O₆S₂‚0.25 H₂O: C, 57.17; H, 6.70; N, 9.20; S,

10.53. Found: C, 56.49; H, 6.76; N, 9.28; S, 10.85.

N,N′-Bis(methanesulfonyl)bis(3-aminopropyl)benzylamine Hy-

drochloride (23). A solution of 40 mL (59 g, 0.52 mol) of

methanesulfonyl chloride in 220 mL of CH₂Cl₂was stirred in a

flask immersed in a 23 °C water bath as a solution of triamine 3

(40 g, 0.18 mol) in 100 mL (78 g, 0.77 mol) of Et₃N was added

dropwise over a period of 3 h. Saturated aq NaCl (50 mL) was

added within an hour of the start of the addition, and the reaction

mixture was stirred for 16 h at room temperature. The organic layer

was extracted with 3 × 50 mL of saturated aqueous NaCl. The

resulting emulsion was broken by vacuum-filtration. The combined

aqueous solutions were extracted with 2 × 70 mL of CHCl₃. The

combined extracts were dried (Na₂SO₄) and concentrated by rotary

evaporation to give a thick, yellowish oil. A solution of 40 g (0.10

mol) of this crude product in 150 mL of CHCl₃was treated with

130 mL of 1 M HCl in ether to give 40 g (97%) of 23.

Recrystallization from hot methanol gave 25 g (64%) of white solid.

¹H NMR (300 MHz, CDCl₃) δ 11.45 (bs, 1 H, NH⁺), 7.66 (m, 2

H, o-Bn), 7.44 (m, 3 H, m,p-Bn), 4.04 (d, J ) 4.0 Hz, 2 H, CH₂Ph),

3.72 (t, J ) 6.2 Hz, 4 H, H1), 3.58 (m, 4 H, H3), 3.39 (s, CH₃),

3.04 (m, 2 H, SO₂NH), 2.19 (m, 4 H, H2). ¹³C NMR, APT (75

MHz, CDCl₃) δ 131.1 (CH), 129.7 (C), 129.2 (CH), 128.6 (CH),

55.6 (CH₂), 48.7 (CH₂), 45.0 (CH₂), 43.1 (CH₃), 23.5 (CH₂).

9-Benzyl-3-methylene-1,5-bis(methanesulfonyl)-1,5,9-triaza-

cyclododecane (MFS105). A mixture of NaH (0.4 g of a 60% (w/

w) slurry in mineral oil, 0.24 g NaH, 10 mmol, washed with hexane

under nitrogen) and 100 mL of anhydrous DMF was stirred at room

temperature as a solution of 1.0 g (2.4 mmol) of hydrochloride

salt 23 in 50 mL of anhydrous DMF was added. The resulting

mixture was stirred as a solution of 0.6 mL (0.65 g, 5.2 mmol) of

3-chloro-2-chloromethyl-1-propene in 28 mL of anhydrous DMF

was added over a period of 14 h by means of a syringe pump. The

reaction mixture was stirred for 12 h at room temperature. The

reaction mixture was allowed to cool, and the solvent was removed

by rotary evaporation using a hot water bath. The resulting solid

residue was treated as described for crude CADA, giving 0.85 g

(82%) of a solid. Flash chromatography of 0.44 g of this solid

yielded 0.11 g (21%) of MFS105 free base as an off-white solid.

¹H NMR (300 MHz, CDCl₃) δ 7.25 (m, 5 H, Bn), 5.37 (s, 2 H,

CdCH₂), 3.90 (s, 4 H, H2, H4), 3.46 (s, 2 H, CH₂Ph), 3.32 (t, J )

7.0 Hz, 4 H, H6, H12), 2.85 (s, 6 H, SO₂CH₃), 2.44 (t, J ) 6 Hz,

4 H, H8, H10), 1.83 (quint., J ) 6 Hz, 4 H, H7, H11). ¹³C NMR,

APT (75 MHz, CDCl₃) δ 139.6 (C), 129.2 (CH), 128.5 (CH), 127.3

(CH), 116.2 (CH₂), 60.1 (CH₂), 51.4 (CH₂), 50.4 (CH₂), 45.0 (CH₂),

37.8 (CH₃), 26.2 (CH₂). IR (KBr): 2931, 2805, 1452, 1327, 1150,

964, 794, 729. HCl Salt. A solution of 0.10 g (0.23 mmol) of the

free base in 5 mL of CH₂Cl₂and 40 mL of ether was stirred

vigorously at 0 °C as a cold solution of 1.0 M HCl in ether was

added dropwise. The solvents were removed in vacuo and the

residue was washed with 3 × 2 mL of cold ether. The ether was

carefully pipetted off and the residue was dried under vacuum for

12-48 h at room temperature, yielding 0.11 g (100%) of MFS105‚

HCl. A sample for microanalysis was dried in vacuo for 3 d at

room temperature. MS (FAB) m/z 430 (M - Cl). Anal. Calcd for

C₁₉H₃₁N₃O₄S₂HCl: C, 48.97; H, 6.92, N, 9.02. Found: C, 48.67;

H, 6.84, N, 6.84.

4 H, H6, H12), 2.44 (s, 6 H, ArCH₃), 1.96 (bs, 4 H, H7, H11). ¹³

C

NMR (75 MHz, CDCl₃) δ 172.6, 144.0, 141.2, 137.1, 135.8, 130.2,

129.6, 128.8, 127.5, 126.7, 117.7, 27.0, 21.7. IR (KBr) 3057 (w),

2978 (m), 2947 (m), 2922 (m), 1633 (s), 1599 (m), 1495 (m), 1344

(s), 1330 (s), 1161 (s), 1102 (s), 946 (m), 896 (m), 786 (s), 754

(m), 708 (s), 656 (s), 550 (s). MS (FAB) m/z 596 (MH⁺), 618

(MNa⁺). Anal. Calcd for C₃₁H₃₇N₃O₅S₂: C, 62.50; H, 6.26; N, 7.05;

S, 10.76. Found: C, 62.29; H, 6.32; N, 7.14; S, 11.10.

9-Isopropoxycarbonyl-3-methylene-1,5-di-p-toluenesulfonyl-

1,5,9-triazacyclododecane (20). A solution of 2.9 mL (2.9 mmol)

of a 1 M toluene solution of isopropyl chloroformate in 10 mL of

chloroform was added dropwise to a solution of 0.50 g (0.94 mmol)

of 94-129 and 0.80 mL (0.58 g, 5.7 mmol) of triethylamine in 10

mL of chloroform over 30 min at 0 °C. The reaction mixture was

warmed to room temperature and stirred for 16 h, then concentrated

by rotary evaporation. Column chromatography on silica gel, eluting

with ethyl acetate/hexane (60:40, v/v), and drying in vacuo gave

0.37 g (69%) of 20 as a white solid, mp 83-85 °C. ¹H NMR (300

MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz, 4 H, o-Ts), 7.33 (d, J ) 8 Hz,

4 H, m-Ts), 5.19 (s, 2 H, CdCH₂), 4.84 (m, 1 H, CHMe₂), 3.84 (s,

4 H, H2, H4), 3.32 (t, J ) 6 Hz, 4 H, H6, H12), 3.01 (m, 4 H, H8,

H10), 2.42 (s, 6 H, ArCH₃), 1.81 (m, 4 H, H7, H11), 1.18 (d, J )

6 Hz, 6 H, CHCH₃). ¹³C NMR (75 MHz, CDCl₃) δ 156.9, 143.8,

139.7, 136.2, 130.1, 127.5, 117.3, 68.9, 51.8, 51.7, 45.6, 28.7, 22.4,

21.7. IR (KBr) 2979 (m), 2871 (w), 1692 (s), 1598 (m), 1472 (m),

1420 (m), 1339 (s), 1162 (s), 1111 (m), 1093 (m), 1030 (m), 924

(m), 816 (m), 747 (m), 658 (s), 581 (s). MS (FAB) m/z 578 (MH⁺).

Anal. Calcd for C₂₈H₃₉N₃O₆S₂: C, 58.2; H, 6.8; N, 7.3. Found: C,

58.09; H, 6.86; N, 7.26.

9-(N,N-Dimethylcarbamoyl)-3-methylene-1,5-bis(p-toluene-

sulfonyl)-1,5,9-triazacyclododecane (21). A solution of 62 µL (72

mg, 0.67 mmol) of N,N-dimethylcarbamoyl chloride in 5 mL of

chloroform was added dropwise to a solution of 0.14 g (0.27 mmol)

of 94-129 and 0.22 mL (0.16 g, 1.6 mmol) of triethylamine in 5

mL of chloroform over 30 min at 0 °C. The reaction mixture was

warmed to room temperature and stirred for 18 h, then worked up

as described for 97-269. Recrystallization from methanol/

chloroform gave 98 mg (64%) of white crystalline 21, mp 229-

1

230 °C. H NMR (300 MHz, CDCl₃) δ 7.68 (d, J ) 8 Hz, 4 H,

o-Ts), 7.33 (d, J ) 8 Hz, 4 H, m-Ts), 5.31 (s, 2 H, CdCH₂), 3.84

(s, 4 H, H2, H4), 3.20 (m, 8 H, H6, H8, H10, H12), 2.75 (s, 6 H,

NCH₃), 2.44 (s, 6 H, ArCH₃), 1.83 (m, 4 H, H7, H11). ¹³C NMR

(75 MHz, CDCl₃) δ 164.9, 142.9, 140.2, 134.8, 129.1, 126.5, 116.1,

50.9, 46.4, 43.5, 37.8, 24.9, 20.7. IR (KBr) 3028 (w), 2947 (m),

2899 (m), 1631 (s), 1596 (m), 1495 (s), 1340 (s), 1320 (s), 1157

(s), 1120 (s), 1090 (s), 939 (s), 895 (s), 819 (s), 805 (s), 665 (s),

590 (s), 564 (s). MS (FAB) m/z 563 (MH⁺). Anal. Calcd for

C₂₇H₃₈N₄O₅S: C, 57.63; H, 6.81; N, 9.96; S, 11.39. Found: C,

57.99; H, 7.16; N, 10.34; S, 11.74.

9-(4-Morpholinocarbonyl)-3-methylene-1,5-bis(p-toluene-

sulfonyl)-1,5,9-triazacyclododecane (22). A solution of 70 µL (90

mg, 0.60 mmol) of 4-morpholinecarbonyl chloride in 5 mL of

chloroform was added dropwise to a solution of 0.11 g (0.21 mmol)

of 94-129 and 0.20 mL (0.15 g, 1.4 mmol) of triethylamine in 5

mL of chloroform over 30 min at 0 °C. The reaction mixture was

warmed to room temperature and stirred for 18 h, then worked up

as described for 97-269. Two recrystallizations from methanol/

water gave 92 mg (74%) of 22 as white crystals, mp 177.5-178.5

°C. ¹H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 8 Hz, 4 H, o-Ts),

N,N′-Bis(benzenesulfonyl)bis(3-aminopropyl)benzylamine (24).

Reaction of 25.4 g (0.12 mol) of triamine 3 and 40.2 g (0.23 mol)

of benzenesulfonyl chloride gave three phases, as described for the

synthesis of 94-127. The upper two layers were separated, diluted

with CHCl₃, and dried (MgSO₄). Filtration, concentration by rotary

evaporation and drying in vacuo gave 57 g (100%) of free base 24

1306 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

as a pale yellow oil. A solution of 60 mL of 2 N aq HCl (60 mL)

and 60 mL of saturated aqueous NaCl was stirred vigorously with

a solution of 57 g of crude 24 in 150 mL of CH₂Cl₂for 1 h. The

organic layer was separated, washed with saturated aqueous NaCl

(3 × 50 mL), and concentrated by rotary evaporation. The residue

was dissolved in 200 mL of boiling ethanol, and ethyl acetate (ca.

400 mL) was added to induce precipitation. Vacuum filtration gave

N, 6.82. Found: C, 52.46; H, 5.98; N, 6.92. MS (MALDI) m/z

560 (M-35, 40).

p-Butoxymethylbenzenesulfonyl Chloride. Sodium butoxide

was prepared by stirring 4.5 g (0.20 mol) of sodium metal with 70

mL of anhydrous butanol until H₂gas evolution stopped (Cau-

tion: flammable gas hazard). By means of a solid addition funnel,

13 g (49 mmol) of 4-bromomethylbenzenesulfonyl chloride⁴¹was

added to the stirred sodium butoxide solution in small portions.

The reaction mixture was heated to 80 °C for 4 h and cooled to

room temperature, then 50 mL water was added slowly. The organic

layer was concentrated by rotary evaporation to give 12 g (100%)

of sodium p-butoxymethylbenzenesulfonate. A mixture of 13 g of

the sodium salt, 120 mL of CHCl₃, 45 g (0.38 mol) of thionyl

chloride, and 0.5 mL of anhydrous DMF was heated under reflux

for 4 h. The solvents were removed by rotary evaporation, and the

residue was extracted with CHCl₃(5 × 50 mL). Evaporation of

the extract gave 7.25 g (52%) of the product as a dark brown liquid.

GC-MS m/z 190 (M - BuO, 100%), 192 (MH⁺+ 2 - BuO, 30%).

¹H NMR (300 MHz, CDCl₃) δ 8.00 (d, J ) 8.4 Hz, 2 H, o-ArSO₂),

7.60 (d, J ) 8.4 Hz, 2 H, m-ArSO₂), 4.62 (s, 2 H, ArCH₂O), 3.55

(m, 2 H, OCH₂Pr), 1.64 (m, 2 H, CH₂Et), 1.44 (m, 2 H, CH₂Me),

0.94 (m, 3 H, CH₃). ¹³C NMR, APT (75 MHz, CDCl₃) δ 147.6

(C), 143.1 (C), 128.0 (CH), 127.2 (CH), 71.6 (CH₂), 71.2 (CH₂),

31.9 (CH₂), 19.5 (CH₂), 14.1 (CH₃).

1

55.9 g (90%) of 24‚HCl as a white solid, mp 135-136 °C. H

NMR (300 MHz, DMSO-d₆) δ 11.0 (br, 1 H, NH⁺), 7.89 (t, J )

5.7 Hz, 2 H, SO₂NH), 7.79 (d, J ) 7.2 Hz, 4 H, o-Ph), 7.59 (m, 8

H, m,p-Ph, o-Bn), 7.41 (m, 3 H, m,p-Bn), 4.23 (d, J ) 4.2 Hz, 2

H, CH₂Ph), 2.93 (m, 4 H, H3), 2.74 (m, 4 H, H1), 1.88 (m, 4 H,

H2). ¹³C NMR (75 MHz, DMSO-d₆) δ 140.3, 132.6, 131.5, 129.8,

129.6, 129.4, 128.9, 126.6, 56.0, 49.4, 40.1, 23.3. IR (KBr) 3242

(br), 3073 (s), 2976 (m), 2855 (m), 2609 (s), 1470 (m), 1446 (s),

1330 (s), 1163 (s), 1092 (s), 740 (s), 689 (s). Anal. Calcd for

C₂₅H₃₁N₃S₂O₄‚HCl: C, 55.80; H, 5.99; N, 7.81; S, 11.92; Cl, 6.59.

Found: C, 55.47; H, 6.13; N, 7.63; S, 11.63; Cl, 6.92. A mixture

of 6.51 g (12.1 mmol) of 24‚HCL, 40 mL of CH₂Cl₂, 15 mL of 1

N aq NaOH, and 15 mL of saturated aqueous NaCl was stirred

vigorously for 30 min. The organic layer was dried (MgSO₄),

concentrated by rotary evaporation, and dried in vacuo (0.4 mm,

45 °C) for 24 h, yielding 5.96 g (98%) of 24 free base as a thick,

colorless oil. TLC (silica): R_f0.21, 1:1 (v/v) ethyl acetate:hexane.

¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J ) 7 Hz, 4 H, o-Ph), 7.51

(m, 6 H, m,p-Ph), 7.22 (m, 3 H, m,p-Bn), 7.16 (m, 2 H, o-Bn), 5.9

(br, 2 H, NH), 3.40 (s, 2 H, CH₂Ph), 2.92 (t, J ) 6.3 Hz, 4 H, H3),

2.38 (t, J ) 6.3 Hz, 4 H, H1), 1.62 (quint., J ) 6.3 Hz, 4 H, H2).

¹³C NMR (75 MHz, CDCl₃) δ 139.9, 138.2, 132.4, 129.0, 128.4,

127.2, 126.9, 58.7, 51.8, 42.2, 26.1. IR (NaCl) 3277 (br), 3061

(w), 1446 (s), 1325 (s), 1160 (s), 1093 (s).

N,N′-Bis(p-butoxymethylbenzenesulfonyl)bis(3-aminopropyl)-

benzylamine (27). A mixture of 2.0 g (7.6 mmol) of p-butoxy-

methylbenzenesulfonyl chloride, 0.9 g (4.1 mmol) of triamine 3,

30 mL of CHCl₃, and 10 mL of 2 M aq NaOH was stirred overnight.

The aqueous layer was extracted with CHCl₃(4 × 30 mL), and

the combined organic solutions were dried (Na₂SO₄) and concen-

trated by rotary evaporation. Flash column chromatography (1:1

to 2:1 EtOAc/hexane, 1% Et₃N) of a 4.0 g sample gave 3.18 g

N,N′-Bis(3-p-bromobenzenesulfonyl)bis(3-aminopropyl)ben-

zylamine (25). A mixture of 22.0 g (86.1 mmol) of p-bromoben-

zenesulfonyl chloride, 100 mL of CH₂Cl₂, and 100 mL of saturated

aqueous NaCl was stirred vigorously as a solution of 9.53 g (43.1

mmol) of triamine 3 in 58 mL of 1.5 N aq NaOH was added over

1.5 h, then the reaction mixture was stirred overnight at room

temperature. The organic layer was washed with 50 mL of saturated

aqueous NaCl, dried (MgSO₄), and concentrated by rotary evapora-

tion. The residue was dried in vacuo (1 mm) giving 24.4 g (98%)

of 25 as a white solid, mp 57-59 °C. ¹H NMR (300 MHz, CDCl₃)

δ 7.68 (d, J ) 9 Hz, 4 H, o-Bs), 7.63 (d, J ) 9 Hz, 4 H, m-Bs),

7.27 (m, 3 H, m,p-Bn), 7.19 (m, 2 H, o-Bn), 6.01 (s, 2 H, SO₂NH),

3.44 (s, 2H, CH₂Ph), 2.95 (t, J ) 6.4 Hz, 4 H, H3), 2.45 (t, J ) 6.4

Hz, 4 H, H1), 1.95 (quint., J ) 6.4 Hz, 4 H, H2). ¹³C NMR (75

MHz, CDCl₃) δ 139.0, 138.1, 132.3, 129.0, 128.6, 128.5, 127.4,

58.7, 52.0, 42.3, 26.1. IR (KBr) 3261 (br), 3087 (w), 2944 (w),

2867 (w), 1573 (m), 1469 (m), 1437 (m), 1389 (m), 1329 (s), 1165

(s), 1090 (s), 1068 (s), 1010 (s), 883 (m), 824 (s), 738 (s), 609 (s).

N,N′-Bis(p-methoxybenzenesulfonyl)bis(3-aminopropyl)ben-

zylamine Hydrochloride (26‚HCl). A solution of 18.7 g (90 mmol)

of p-methoxybenzenesulfonyl chloride in 40 mL of diethyl ether

was stirred rapidly as a cloudy solution of 10 g (45 mmol) of

triamine 3, 55 mL of 2 M aq NaOH, and 100 mL of saturated

aqueous NaCl was added slowly over 10 h. The reaction mixture

was stirred for 10 h at room temperature, producing three layers.

The two upper layers were separated and stirred vigorously with

80 mL of 2 M aq HCl and 100 mL of saturated aqueous NaCl for

5 h. The white precipitate was collected by filtration, washed with

water (3 × 20 mL) and diethyl ether (3 × 20 mL), dried in vacuo

and recrystallized from chloroform/hexane yielding 24.5 g (91%)

of 26‚HCl as a white solid, mp 118-120 °C. ¹H NMR (300 MHz,

CDCl₃) δ 7.80 (d, J ) 9 Hz, 4 H, o-ArSO₂), 7.56 (m, 3 H, m,p-

Bn), 7.44 (m, 2 H, o-Bn), 6.96 (d, J ) 9 Hz, 4 H, m-ArSO₂), 6.50

(bs, 2 H, SO₂NH), 4.23 (s, 2 H, CH₂Ph), 3.85 (s, 6 H, OCH₃), 3.17

(m, 4 H, H3), 2.98 (m, 4 H, H1), 2.16 (m, 4 H, H2). ¹³C NMR (75

MHz, CDCl₃) δ 163.1, 138.6, 132.4, 129.5, 129.3, 128.8, 127.6,

114.5, 59.2, 55.8, 52.4, 42.5, 26.6. IR (KBr): 3566 (br), 3330 (br),

3099 (br), 2843 (w), 1596 (s), 1577 (m), 1499 (m), 1324 (s), 1260

(s), 1157 (s), 1093 (m), 1029 (m), 927 (w), 830 (s), 804 (m) 704

(m). Anal. Calcd for C₂₇H₃₅N₃O₆S₂‚HCl‚H₂O: C, 52.63; H, 6.17;

1

(85%) of 27 as a pale-yellow oil. H NMR (300 MHz, CDCl₃) δ

7.79 (m, 4 H, o-ArSO₂), 7.46 (m, 4 H, m-ArSO₂), 7.24 (m, 3H,

m,p-Bn), 7.19 (m, 2 H, o-Bn), 5.88 (bs, 2 H, NH), 4.55 (s, 2 H,

ArCH₂O), 3.51 (t, J ) 6.6 Hz, 4 H, OCH₂Pr), 3.42 (s, 2 H, CH₂Ph),

2.92 (m, 4 H, H1), 2.40 (m, 4 H, H3), 1.62 (m, 8 H, H2, CH₂Et),

1.41 (sext., J ) 7.7 Hz, CH₂Me), 0.93 (t, J ) 7.3 Hz, 6 H, CH₃).

¹³C NMR, APT (75 MHz, CDCl₃) δ 144.0 (C), 139.0 (C), 138.4

(C), 129.2 (CH), 128.7 (CH), 127.8 (CH), 127.4 (CH), 127.3 (CH),

72.8 (CH₂), 71.0 (CH₂), 59.0 (CH₂), 52.2 (CH₂), 42.5 (CH₂), 32.0

(CH₂), 26.4 (CH₂), 19.6 (CH₂), 14.1 (CH₃). FT-IR (NaCl) 3281

(br, s), 3086, 3062, 3028, 2957 (s), 2869 (s), 1600, 1455 (s), 1408,

1328, 1158, 1091, 1018, 963, 816, 773, 683, 633. MS (FAB) m/z

674 (MH⁺).

N,N′-Bis(o-nitrobenzenesulfonyl)bis(3-aminopropyl)benzyl-

amine (28). Reaction of 24.3 g (0.11 mol) of triamine 3 and 50.0

g (22 mmol) of o-nitrobenzenesulfonyl chloride gave three phases,

as described for the synthesis of 94-127. The two upper layers

were diluted with CHCl₃, separated, and dried (MgSO₄). Filtration,

concentration by rotary evaporation and drying in vacuo gave crude

28 as a brown tar. A solution of the crude product in 300 mL of

CHCl₃was dried (MgSO₄) and concentrated by rotary evaporation.

The residue was dried (1 mm) to give 59 g (91%) of 28 as a

brownish yellow residue. A mixture of this residue, 250 mL of

CHCl₃, 60 mL of 2 N aq HCl, and 60 mL of saturated aqueous

NaCl was stirred vigorously at room temperature for 30 min. The

organic layer was concentrated by rotary evaporation. Attempted

recrystallization of the residue from acetone/ethyl acetate gave 28‚

HCl as an oil, which was dried in vacuo (1 mm). A mixture of this

oil, 300 mL of CHCl₃, 110 mL of 1 N aq NaOH and 220 mL of

saturated aqueous NaCl was shaken for 1 h in a tightly stoppered

flask. The organic layer was separated, dried (Na₂SO₄), and

concentrated by rotary evaporation to give a sample of 28‚HCl that

was used without further purification. ¹H NMR (300 MHz, CDCl₃)

δ 8.06 (m, 2 H, SO₂NH), 7.73 (m, 4 H, Ns), 7.70 (m, 4 H, Ns),

7.39 (m, 2 H, o-Bn), 7.26 (m, 3 H, m,p-Bn), 3.87 (s, 2 H, CH₂Ph),

3.11 (m, 4 H, H1), 2.81 (m, 4 H, H3), 1.95 (m, 4 H, H2). ¹³C

NMR (75 MHz, CDCl₃) δ 147.7, 133.5, 133.0, 132.7, 130.6, 130.1,

128.6, 128.4, 124.9, 57.5, 50.5, 41.5, 24.9. IR (NaCl) 3342 (br),

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1307

3095 (w), 3028 (w), 2953 (w), 2597 (w), 1539 (s), 1364 (m), 1341

(m), 1165 (s), 1125 (m), 853 (m), 782 (w).

oil, 0.55 g NaH, 23 mmol, washed with hexane under nitrogen).

The resulting clear solution was stirred as a solution of 1.44 g (11.5

mmol) of 3-chloro-2-chloromethyl-1-propene in 8 mL of anhydrous

DMF was added over 10 h, then the reaction mixture was stirred

at room temperature for 24 h. The solvent was removed by rotary

evaporation using a hot water bath. A solution of the residue in 50

mL of CHCl₃was washed with water (3 × 30 mL), saturated

aqueous NaCl (2 × 30 mL), dried (MgSO₄), and concentrated by

rotary evaporation. The resulting thick yellow oil was dissolved in

100 mL of 1:1 (v/v) ethyl acetate:hexane and filtered through 16 g

of basic alumina (Woelm Act 1, 80-200 mesh), washing the

alumina with an additional 50 mL of 1:1 ethyl acetate/hexane.

Concentration under vacuum gave 4.93 g (77%) of 95-211 as a

foam. A mixture of crude 95-211, 30 mL of CHCl₃, 10 mL of 2

N aq HCl, and 10 mL of saturated aqueous NaCl was stirred for

30 at room temperature. The organic layer was separated, washed

with 20 mL of saturated aqueous NaCl, and concentrated by rotary

evaporation. The residue was recrystallized from ethanol/ethyl

acetate, followed by acetone/ethyl acetate, giving 3.03 (45%) of

95-211‚HCl, mp 135-136 °C. A sample for elemental analysis

was dried (24 h, 78 °C, 0.3 mm). ¹H NMR (300 MHz, DMSO-d₆)

δ 11.6 (br, 1 H, NH⁺), 7.79 (d, J ) 7.8 Hz, 4 H, o-Ph), 7.75-7.64

(m, 8 H, m,p-Ph, o-Bn), 7.43 (m, 3 H, m,p-Bn), 5.37 (s, 2 H, Cd

CH₂), 4.30 (d, 2 H, CH₂Ph), 3.69 (s, 4 H, H2, H4), 3.09 (m, 8 H,

H6, H8, H10, H12), 1.95 (m, 4 H, H7, H11). ¹³C NMR (75 MHz,

DMSO-d₆) δ 141.5, 136.9, 133.4, 131.1, 130.4, 129.7, 129.4, 128.8,

127.3, 118.8, 57.1, 51.8, 48.2, 46.3, 20.2. IR (KBr) 3060 (w), 2928

(w), 2873 (w), 2445 (br), 1447 (s), 1335 (s), 1163 (s), 1090 (m),

931 (m), 737 (s), 696 (m). UV (CH₃OH): λ_max(logꢀ), 224 (4.2).

MS (FAB) m/z 554 (MH⁺). Anal. Calcd for C₂₉H₃₅N₃S₂O₄‚HCl:

C, 59.02; H, 6.15; N, 7.12. Found: C, 59.39; H, 6.28; N, 7.21.

N,N′-Bis(m-nitrobenzenesulfonyl)bis(3-aminopropyl)benzyl-

amine (29). A mixture of 25.0 g (0.11 mmol) of m-nitrobenzene-

sulfonyl chloride, 100 mL of CH₂Cl₂, and 120 mL of saturated

aqueous NaCl was stirred vigorously as a solution of 12.5 g (57

mmol) of triamine 3 in 80 mL of 1.5 N aq NaOH was added over

2 h, then the reaction mixture was stirred overnight at room

temperature. The organic layer was washed with 3 × 50 mL of

saturated aqueous NaCl, dried (MgSO₄), and concentrated by rotary

evaporation. Drying in vacuo (1 mm) gave 33 g (91%) of 29 as an

1

amber oil. H NMR (300 MHz, CDCl₃) δ 8.65 (d, J ) 2.0 Hz, 2

H, o-Ns), 8.43 (dd, J ) 8.3, 1.5 Hz, 2 H, p-Ns), 8.17 (dd, J ) 7.8,

1.0 Hz, 2 H, o′-Ns), 7.75 (t, J ) 8.3 Hz, 2 H, m-Ns), 7.27 (m, 3 H,

m,p-Bn), 7.20 (m, 2 H, o-Bn), 6.3 (br, 2 H, SO₂NH), 3.48 (s, 2 H,

CH₂Ph), 3.03 (t, J ) 6 Hz, 4 H, H3), 2.52 (t, J ) 6 Hz, 4 H, H1),

1.95 (quint., J ) 6 Hz, 4 H, H2). ¹³C NMR (75 MHz, CDCl₃) δ

148.3, 142.3, 137.8, 132.6, 130.5, 129.0, 128.5, 127.5, 126.9, 122.1,

58.8, 52.1, 42.4, 26.2. IR (NaCl) 3395 (br), 3088 (w), 3029 (w),

2951 (w), 2872 (w), 2825 (w), 1606 (w), 1534 (s), 1429 (m), 1353

(s), 1168 (s), 1127 (s), 1081 (m), 880 (m), 758 (m), 673 (m), 588

(w).

N,N′-Bis(p-nitrobenzenesulfonyl)bis(3-aminopropyl)benzyl-

amine (30). Reaction of 22.8 g (0.103 mol) of triamine 3 and 50.1

g (0.203 mol) of p-nitrobenzenesulfonyl chloride was conducted

as described for the synthesis of 94-127. Upon completion of the

addition of 3, the reaction mixture was stirred at room temperature

overnight. The resulting two-phase mixture was decanted from a

brown tar-like residue, then the ether layer was recombined with

the tar. The aqueous portion was extracted with 50 mL of CHCl₃.

The combined organic portions were concentrated by rotary

evaporation, providing crude 30 as a brown tar. A mixture of crude

30, 250 mL of CHCl₃, 60 mL of 2 N aq HCl, and 60 mL of

saturated aqueous NaCl was stirred vigorously for 1 h at room

temperature. The organic layer was separated and concentrated by

rotary evaporation. A mixture of the residue and 300 mL of acetone

was heated to boiling and filtered while hot. Precipitation was

induced by adding ethyl acetate to the boiling filtrate. Cooling to

room temperature and filtration gave 52.3 g (82%) of 30‚HCl as a

yellow solid, mp 200-205 °C (dec). A sample for microanalysis

was recrystallized from acetone and dried at 78 °C (0.2 mm, 12

h), giving an off-white solid, mp 232-233 °C (dec). ¹H NMR (300

MHz, DMSO-d₆) δ 10.9 (br, 1 H, NH⁺), 8.41 (d, J ) 8.7 Hz, 4 H,

m-Ns), 8.27 (t, 2 H, SO₂NH), 8.03 (d, J ) 8.7 Hz, 4 H, o-Ns),

7.58 (m, 3 H, m,p-Bn), 7.43 (m, 2 H, o-Bn), 4.24 (d, 2 H, CH₂Ph),

2.95 (m, 4 H, H3), 2.82 (m, 4 H, H1), 1.89 (m, 4 H, H2). ¹³C

NMR (75 MHz, DMSO-d₆) δ 149.7, 146.0, 131.4, 129.8, 129.5,

128.8, 128.2, 124.6, 56.0, 49.4, 40.1, 23.3. IR (KBr) 3436 (br),

3114 (w), 3074 (w), 2578 (br), 2504 (br), 1530 (s), 1352 (m), 1339

(m), 1307 (m), 1161 (s), 1093 (m), 855 (m), 746 (m), 683 (m),

609 (m). Anal. Calcd for C₂₅H₂₉N₅S₂O₈‚HCl: C, 47.81; H, 4.81;

N, 11.15; S, 10.21; Cl, 5.64. Found: C, 47.78; H, 5.01; N, 11.52;

S, 10.07. Free Base. A mixture of 10.34 g (16.5 mmol) of 30‚

HCl, 70 mL of CH₂Cl₂, 17 mL of 1 N aq NaOH, and 20 mL of

saturated aqueous NaCl was stirred vigorously for 3 h. The organic

layer was separated and washed with 50 mL of saturated aqueous

NaCl, dried (MgSO₄), and concentrated by rotary evaporation.

Drying under vacuum (0.4 mm, 24 h) gave 9.16 g (94%) of 30 as

a thick, golden brown oil. ¹H NMR (300 MHz, CDCl₃) δ 8.33 (d,

J ) 8.7 Hz, 4 H, m-Ns), 7.99 (d, J ) 8.7 Hz, 4 H, o-Ns), 7.27 (m,

3 H, m,p-Bn), 7.20 (m, 2 H, o-Bn), 6.3 (br, 2 H, SO₂NH), 3.45 (s,

2 H, CH₂Ph), 3.02 (t, J ) 6 Hz, 4 H, H3), 2.49 (t, J ) 6 Hz, 4 H,

H1), 1.73 (quint., J ) 6 Hz, 4 H, H2). ¹³C NMR (75 MHz, CDCl₃)

δ 150.1, 145.9, 137.8, 129.1, 128.7, 128.3, 127.6, 124.3, 58.9, 52.2,

45.5, 26.2. IR (NaCl) 3294 (br), 3105 (w), 3031 (w), 2951 (w),

2867 (w), 2828 (w), 1606 (w), 1529 (s), 1349 (s), 1309 (m), 1164

(s), 1093 (m), 911 (w), 854 (m), 736 (m), 685 (m).

9-Benzyl-3-methylene-1,5-bis(p-bromobenzenesulfonyl)-1,5,9-

triazacyclododecane (ASPB127). A mixture of 59.4 g (0.43 mol)

of K₂CO₃, 23.0 g (35 mmol) of 25, and 900 mL of anhydrous DMF

was stirred at 60 °C for 1 h. The reaction mixture was stirred at 60

°C as a solution of 5.0 g (40 mmol) of 3-chloro-2-chloromethyl-

1-propene in 10 mL of anhydrous DMF was added over 15 h by

means of a syringe pump. The reaction mixture was stirred for 1 h

at room temperature, then the solvent was removed by rotary

evaporation using a hot water bath. A solution of the residue in

250 mL of chloroform was washed with water (2 × 100 mL), 1 N

aq NaOH solution (2 × 100 mL), and saturated aqueous NaCl

solution (2 × 100 mL). The solution was dried (MgSO₄), filtered

and concentrated to dryness by rotary evaporation. The residue was

dried in vacuo (0.1 mm), yielding 17.5 g (70%) of crude ASPB127

as a yellow foam. A 1.60 g sample of crude ASPB127 was purified

by silica gel flash chromatography eluting with 95:5 (v/v) chloroform/

ethyl acetate, giving 0.83 g (36%) of ASPB127 as a white foam.

¹H NMR (300 MHz, CDCl₃) δ 7.67 (d, J ) 9 Hz, 4 H, o-Bs), 7.63

(d, J ) 9 Hz, 4 H, m-Bs), 7.25-7.21 (m, 3 H, m,p-Bn), 7.15-7.12

(m, 2 H, o-Bn), 5.21 (s, 2 H, CdCH₂), 3.85 (s, 4 H, H2, H4), 3.40

(s, 2 H, CH₂Ph), 3.14 (t, J ) 6.8 Hz, 4 H, H6, H12), 2.38 (t, J )

5.9 Hz, 4 H, H8, H10), 1.66 (quint., J ) 6 Hz, 4 H, H7, H11). ¹³

C

NMR (75 MHz, CDCl₃) δ 139.2, 138.1, 137.9, 132.5, 128.79,

128.76, 128.2, 127.7, 127.0, 116.4, 59.2, 51.1, 49.7, 44.2, 24.9.

HCl Salt. A solution of 0.83 g (1.2 mmol) of ASPB127 in 10 mL

of CHCl₃was stirred with 2 mL of 1 M HCl in ether for 2 h. Ethyl

acetate (20 mL) was added, and the resulting mixture was stored

at -25 °C overnight. A precipitate was collected by vacuum

filtration and washed with 10 mL of hexane, giving 0.84 g (97%)

of ASPB127‚HCl as a white solid, mp 175-176 °C. ¹H NMR (300

MHz, DMSO-d₆) δ 10.9 (s, 1 H, NH⁺), 7.88 (d, J ) 8.3 Hz, 4 H,

o-Bs), 7.73 (d, J ) 8.3 Hz, 4 H, m-Bs), 7.66 (m, 2 H, o-Bn), 7.46

(m, 3 H, m,p-Bn), 5.36 (s, 2 H, CdCH₂), 4.31 (d, 2 H, CH₂Ph),

3.70 (s, 4 H, H2, H4), 3.16-3.06 (m, 8 H, H6, H8, H10, H12),

1.86 (m, 4 H, H7, H11). ¹³C NMR (75 MHz, DMSO-d₆) δ 141.2,

136.2, 132.7, 131.1, 130.4, 129.4, 128.8, 127.5, 118.9, 57.1, 51.8,

48.0, 46.3, 20.1. IR (KBr) 3085 (w), 2976 (w), 2920 (w), 2380

(br), 1574 (m), 1471 (m), 1349 (s), 1163 (s), 1070 (m), 1008 (m),

899 (m), 746 (s), 607 (s). MS (FAB) m/z 710 (MH⁺, 13), 712

(M+3, 26), 714 (M+5, 16). Anal. Calcd for C₂₉H₃₃N₃S₂O₄Br₂‚

9-Benzyl-3-methylene-1,5-bis(benzenesulfonyl)-1,5,9-triaza-

cyclododecane Hydrochloride (95-211‚HCl). A solution of 5.78

g (11.5 mmol) of 24 in 220 mL of anhydrous DMF was added

slowly with stirring to NaH (0.92 g of a 60% (w/w) slurry in mineral

1308 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

HCl‚CHCl₃: C, 41.72; H, 4.09; N, 4.87; S, 7.41. Found: C, 41.78;

H, 4.14; N, 5.21; S, 7.73.

(v/v) chloroform/ethyl acetate. The combined filtrates were con-

centrated to dryness by rotary evaporation. A solution of the residue

in 25 mL of ethyl acetate was diluted with 12 mL of hexane, causing

a dark oil to separate. The cloudy yellow supernatant solution was

decanted and the process was repeated twice. The combined

supernatants were concentrated by rotary evaporation, and the

residue was dried (1 mm), yielding 6.26 g (55%) of a golden foam.

A solution of the crude AS123 in 30 mL of chloroform was stirred

at 0 °C as 15 mL of 1.0 M HCl in ether was added. The supernatant

liquid was decanted from the gummy residue, which was triturated

with 25 mL of acetone. The resulting precipitate was collected by

filtration and recrystallized from CHCl₃, giving 3.03 g (25%) of

AS123‚HCl, mp 214-215 °C (dec). ¹H NMR (300 MHz, DMSO-

d₆) δ 10.84 (br, 1 H, NH⁺), 8.03 (d, J ) 7.8 Hz, 4 H, Ns), 7.93 (t,

J ) 7.3 Hz, 2 H, Ns), 7.87 (t, J ) 7.3 Hz, 2 H, Ns), 7.62 (m, 2 H,

o-Bn), 7.44 (m, 3 H, m,p-Bn), 5.35 (s, 2 H, CdCH₂), 4.30 (d, J )

3.9 Hz, 2 H, CH₂Ph), 4.07 (d, J ) 17 Hz, 4 H, H2, H4), 3.98 (d,

J ) 17 Hz, 2 H, H2′, H4′), 3.48 (m, 4 H, H8, H10), 3.07 (m, 4 H,

H6, H12), 1.89 (m, 4 H, H7, H11). ¹³C NMR (75 MHz, CDCl₃) δ

147.9, 139.5, 134.9, 132.7. 131.3, 130.5, 130.2, 129.9, 129.4, 128.7,

124.6, 118.5, 57.6, 51.0, 47.1, 20.8. IR (KBr) 3093 (w), 3007 (w),

2952 (w), 2388 (br), 1594 (w), 1545 (s), 1459 (m), 1441 (m), 1361

(s), 1347 (s), 1163 (s), 1128 (s), 1061 (m), 1030 (m), 903 (m), 941

(m), 853 (s), 783 (s), 702 (s). Anal. Calcd for C₂₉H₃₃N₅S₂O₈‚HCl:

C, 51.21; H, 5.04; N, 10.30; S, 9.43. Found: C, 51.27; H, 5.15; N,

10.27; S, 9.66.

9-Benzyl-3-methylene-1,5-bis(4-methoxybenzenesulfonyl)-

1,5,9-triazacyclododecane (KKD023). A mixture of NaH (3.0 g

of a 60% (w/w) slurry in mineral oil, 1.8 g NaH, 75 mmol, washed

with hexane under nitrogen) and 500 mL of anhydrous DMF was

stirred at 75 °C as a solution of 15.0 g (25 mmol) of 26‚HCl in 60

mL of anhydrous DMF was added. A solution of 3.0 g (25 mmol)

of 3-chloro-2-chloromethyl-1-propene in 60 mL of anhydrous DMF

was added dropwise over a period of 36 h by means of a syringe

pump, then the reaction mixture was stirred at 60 °C for 12 h. The

reaction mixture was allowed to cool to room temperature, then

the solvent was removed on a rotary evaporator. A solution of the

residue in 200 mL of CHCl₃was washed with water (3 × 150

mL), then concentrated to dryness. Column chromatography on

silica gel, eluting with 9:1 CH₂Cl₂/hexane, gave 13.0 g (85%) of

1

KKD023 as a light yellow solid, mp 158-159 °C. H NMR (300

MHz, CDCl₃) δ 7.70 (d, J ) 9 Hz, 4 H, o-ArSO₂), 7.25 (m, 3 H,

m,p-Bn), 7.13 (m, 2 H, o-Bn), 6.98 (d, J ) 9 Hz, 4 H, m-ArSO₂),

5.23 (s, 2 H, CdCH₂), 3.88 (s, 6 H, OCH₃), 3.83 (s, 4 H, H2, H4),

3.39 (s, 2 H, CH₂Ph), 3.12 (t, J ) 7 Hz, 4 H, H6, H12), 2.36 (t, J

) 6 Hz, 4 H, H8, H10), 1.65 (quint., J ) 6 Hz, 4 H, H7, H11). ¹³

C

NMR (75 MHz, CDCl₃) δ 163.3, 139.7, 139.2, 131.1, 129.6, 129.1,

128.4, 127.2, 116.3, 114.6, 59.7, 55.9, 51.5, 50.3, 44.5, 25.4. IR

(KBr): 3100 (w), 2943 (w), 1595 (s), 1577 (s), 1499 (s), 1444

(m), 1346 (s), 1262 (s), 1158 (s), 1117 (m), 1093 (m), 1023 (m),

936 (m), 831 (m), 719 (m), 688 (m), 558 (s). Anal. Calcd for

C₃₁H₃₉N₃O₆S₂2H₂O: C, 56.38; H, 6.67 N, 6.46. Found: C, 56.23;

H, 6.55; N 6.45. MS (MALDI) m/z 613 (MH⁺).

9-Benzyl-3-methylene-1,5-bis(m-nitrobenzenesulfonyl)-1,5,9-

triazacyclododecane (AS121). A solution of 8.16 g (13.8 mmol)

of 29 in 320 mL of anhydrous DMF was added slowly with stirring

to NaH (1.29 g of a 60% (w/w) dispersion in mineral oil, 0.77 g

NaH, 32 mmol, washed with hexane under nitrogen). The resulting

brown solution was stirred at 45-50 °C and a solution of 1.90 g

(15.2 mmol) of 3-chloro-2-chloromethyl-1-propene in 20 mL of

anhydrous DMF was added over 12 h. The reaction mixture was

stirred under N₂for an additional 10 h, then the solvent was

removed by rotary evaporation using a 65 °C water bath. A solution

of the residue in 100 mL of CHCl₃was washed with water (3 ×

25 mL), 50 mL of saturated aqueous NaCl, dried (MgSO₄), and

concentrated by rotary evaporation. A solution of the resulting thick

brown oil in 15 mL of 9:1 (v/v) chloroform/ethyl acetate was filtered

through 30 g of flash silica gel, washing with 185 mL of 9:1 (v/v)

chloroform/ethyl acetate. The combined filtrates were concentrated

by rotary evaporation and dried (1 mm). The residue was recrystal-

lized from acetone, giving 2.26 g (25%) of AS121 as a pale yellow

solid, mp 180-181 °C. The mother liquor was diluted with 30 mL

of ethanol and cooled to -25 °C to induce precipitation. Filtration

and washing with 10 mL of ethanol gave 1.1 g (12%) of AS121 as

9-Benzyl-3-methylene-1,5-bis(p-butoxymethylbenzenesulfonyl)-

1,5,9-triazacyclododecane (MFS117). A mixture of 2.88 g (4.27

mmol) of 27, 40 mL of anhydrous DMF, and NaH (0.6 g of 60%

(w/w) slurry in mineral oil, 0.36 g NaH, 14.5 mmol, washed with

hexane under nitrogen) was stirred at room temperature as a solution

of 1.0 g (8.0 mmol) of 3-chloromethyl-2-chloro-1-propene in 32

mL of anhydrous DMF was added by means of a syringe pump

over a period of 10 h. The reaction mixture was stirred for 12 h at

room temperature, then the solvent was removed by rotary

evaporation (bath temp. 95 °C), giving 3.56 g of a yellow-brown,

viscous oil. Flash column chromatography (1:2 to 1:1 EtOAc/

hexane, (v/v)) of a 3.3 g sample gave 1.15 g (35%) of MFS117 as

a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.74 (d, J ) 8.1 Hz,

4 H, o-ArSO₂), 7.49 (d, J ) 8.1 Hz, 4 H, m-ArSO₂), 7.23 (m, 3 H,

m,p-Bn), 7.14 (d, J ) 7.3 Hz, 2 H, o-Bn), 5.22 (s, 2 H, CdCH₂),

4.57 (s, 4 H, ArCH₂O), 3.85 (s, 4 H, H2, H4), 3.52 (t, J ) 6.6 Hz,

4 H, OCH₂Pr), 3.39 (s, 2 H, CH₂Ph), 3.13 (d, J ) 6.2 Hz, 4 H, H8,

H10), 2.36 (d, J ) 6.0 Hz, 4 H, H6, H12), 1.63 (m, 8 H, H7, H11,

CH₂Et), 1.42 (sext., J ) 7.7 Hz, 4 H, CH₂Me), 0.91 (t, J ) 7.32

Hz, 6 H, CH₃). ¹³C NMR, APT (75 MHz, CDCl₃) δ 144.4 (C),

129.0 (CH), 127.9 (CH), 127.6 (CH), 72.1 (CH₂), 71.1 (CH₂), 59.5

(CH₂), 51.4 (CH₂), 50.1 (CH₂), 44.4 (CH₂), 32.1 (CH₂), 19.7 (CH₂),

14.1 (CH₃). FT-IR (NaCl): 3264 (br, s), 3085, 3028, 2940, 2809,

1675 (s), 1545 (s), 1476, 1374, 1320, 1288, 1163, 1134, 878, 777,

729, 698, 578. Anal. Calcd for C₃₉H₅₅N₃O₆S₂‚HCl: C, 61.44; H,

7.40; N, 5.51. Found: C, 61.05; H, 7.57; N, 5.47%. MS (FAB)

m/z 726 (MH⁺).

9-Benzyl-3-methylene-1,5-bis(o-nitrobenzenesulfonyl)-1,5,9-

triazacyclododecane (AS123). A solution of 10.5 g (17.7 mmol)

of 28 in 450 mL of anhydrous DMF was added slowly with stirring

to NaH (1.42 g of a 60% (w/w) dispersion in mineral oil, 0.85 g

NaH, 35 mmol, washed with hexane under nitrogen). The resulting

brown solution was stirred at 55 °C and a solution of 2.46 g (19.7

mmol) of 3-chloro-2-chloromethyl-1-propene in 20 mL of anhy-

drous DMF was added over 14 h. The reaction mixture was stirred

at room temperature under N₂for 6 h, then the solvent was removed

by rotary evaporation using a 68 °C water bath. A solution of the

residue in 100 mL of CHCl₃was washed with water (3 × 25 mL),

50 mL of saturated aqueous NaCl, dried (MgSO₄), and concentrated

by rotary evaporation. A solution of the oily residue in 30 mL of

95:5 (v/v) chloroform/ethyl acetate, was filtered through 45 g of

silica gel (60-200 µm), which was washed with 250 mL of 95:5

1

a yellow solid, mp 178-180 °C. H NMR (300 MHz, CDCl₃) δ

8.62 (d, J ) 2 Hz, 2 H, o-Ns), 8.46 (d, J ) 8.3 Hz, 2 H, p-Ns),

8.11 (d, J ) 7.8 Hz, 2 H, o′-Ns), 7.78 (dd, J ) 8.3, 7.8 Hz, 2 H,

m-Ns), 7.24 (m, 3 H, m,p-Bn), 7.14 (m, 2 H, o-Bn), 5.22 (s, 2 H,

CdCH₂), 3.92 (s, 4 H, H2, H4), 3.42 (s, 2 H, CH₂Ph), 3.21 (t, J )

6.6 Hz, 4 H, H6, H12), 2.41 (t, J ) 5.4 Hz, 4 H, H8, H10), 1.71

(quint., J ) 5.9 Hz, 4 H, H7, H11). ¹³C NMR (75 MHz, CDCl₃) δ

148.5, 141.0, 138.9, 137.6, 132.6, 130.6, 128.8, 128.2, 127.1, 122.4,

116.7, 59.1, 51.1, 49.6, 44.5, 25.1. IR (KBr) 3102 (w), 2993 (w),

2950 (w), 2920 (w), 2859 (w), 2809 (w), 1607 (m), 1530 (s), 1466

(m), 1452 (m), 1354 (s), 1329 (s), 1175 (s), 1167 (s), 1124 (m),

1073 (m), 1040 (m), 941 (s), 880 (s), 798 (s), 736 (m), 720 (s),

685 (s). AS121‚HCl. A solution of 0.80 g (1.2 mmol) of AS121 in

15 mL of CHCl₃was diluted slowly with 1.5 mL of 1.0 M HCl in

ether. The mixture was stirred for 15 min and stored overnight at

room temperature. Filtration and washing with 15 mL of CHCl₃

gave a solid that was recrystallized from acetone, giving 0.70 (86%)

1

of AS121‚HCl as a pale yellow solid, mp 168-170 °C. H NMR

(300 MHz, DMSO-d₆) δ 10.90 (br, 1 H, NH⁺), 8.57 (dd, J ) 8.3,

1.0 Hz, 2 H, p-Ns), 8.45 (s, 2 H, o-Ns), 8.25 (d, J ) 7.3 Hz, 2 H,

o′-Ns), 7.97 (dd, J ) 8.3, 7.8 Hz, 2 H, m-Ns), 7.66 (m, 2 H, o-Bn),

7.46 (m, 3 H, m,p-Bn), 5.40 (s, 2 H, CdCH₂), 4.33 (d, J ) 5.4 Hz,

2 H, CH₂Ph), 3.79 (s, 4 H, H2, H4), 3.24-3.10 (m, 8 H, H6, H8,

H10, H12), 1.94 (m, 4 H, H7, H11). ¹³C NMR (75 MHz, DMSO-

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1309

d₆) δ 148.2, 140.8, 138.6, 133.1, 131.7, 131.1, 130.3, 129.4, 128.8,

127.9, 122.1, 119.0, 57.2, 51.7, 46.3, 20.2. IR (KBr) 3088 (w),

2956 (w), 2871 (w), 2480 (br), 1607 (w), 1532 (s), 1458 (m), 1355

(s), 1175 (s), 1127 (m), 1086 (w), 1002 (w), 931 (m), 908 (m),

879 (s), 748 (s), 717 (s), 674 (s). Anal. Calcd for C₂₉H₃₃N₅S₂O₈‚

HCl: C, 51.21; H, 5.04; N, 10.30; S, 9.43; Cl, 5.21. Found: C,

52.24; H, 5.79; N, 9.15.

dropwise over a period 5 min, and the reaction mixture was stirred

for 20 min at -78 °C. Note: t-BuLi should not be necessary to

form MFS034. Ethyl chloroformate (0.56 g, 5.2 mmol) was added

and the reaction mixture was stirred for 2 h. Water (15 mL) was

added and the resulting mixture was extracted with CHCl₃(4 ×

25 mL). The organic layer was dried (Na₂SO₄) and concentrated

to dryness by rotary evaporation. Flash column chromatography

(1:2.5 to 1:1.6 (v/v) EtOAc/hexane) gave 26 mg of unreacted

ASPB127 and 41 mg (38%) of MFS034 as a white solid. ¹H NMR

(300 MHz, CDCl₃) δ 7.68 (m, 8 H, Bs), 5.20 (s, 2 H, CdCH₂),

4.50 (s, 4 H, CH₂Ph), 4.07 (q, J ) 7.2 Hz, 2 H, OCH₂), 3.87 (s, 4

H, H2, H4), 3.34 (t, J ) 6.7 Hz, 4 H, H6, H12 or H8, H10), 3.12

(m, 4 H, H8, H10 or H6, H12), 1.86 (m, 4 H, H7, H11), 1.21 (t, J

) 7.2 Hz, 3 H, CH₃). ¹³C NMR, APT (75 MHz, CDCl₃) δ 157.3

(C), 139.0 (C), 138.0 (C), 132.8 (CH₂), 128.9 (CH₂), 128.2 (C),

117.5 (CH₂), 61.6 (CH₂), 45.7 (CH₂), 45.5 (CH₂), 28.4 (CH₂), 14.9

(CH₃). IR (NaCl) 3089, 2980, 2870, 2253 (w), 1772 (w), 1692 (vs),

1571, 1470, 1389, 1342 (vs), 1163 (vs), 1068, 1009, 917, 795, 738

(s), 601. Anal. Calcd for C₂₅H₃₁Br₂N₃O₆S₂: C, 43.30; H, 4.51; N,

6.06. Found: C, 43.62; H, 4.49; N, 5.75. MS (FAB) m/z 694 (M+3).

3-Methylene-1,5-bis(4-methoxybenzenesulfonyl)-1,5,9-triaza-

cyclododecane (KKD025). A mixture of 9.5 g (16 mmol) of

KKD023, 2.5 g (17.6 mmol) of 1-chloroethyl chloroformate, and

50 mL of 1,2-dichloroethane was stirred and heated under reflux

for 2 h, cooled to room temperature, then concentrated to dryness

by rotary evaporation. A solution of the residue in 80 mL of

methanol was heated under reflux overnight, cooled to room

temperature, and filtered. The filtrate was concentrated to dryness

by rotary evaporation. A solution of the residue in 60 mL of CHCl₃

was stirred with 60 mL of 2 N aq NaOH for 4 h. The CHCl₃layer

was dried (Na₂SO₄) and concentrated by rotary evaporation. Column

chromatography on silica gel, eluting with 5:95 (v/v) methanol/

CH₂Cl₂gave 6.7 g (83%) of KKD025 as a white solid, mp 84-86

°C. ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J ) 9 Hz, 4 H,

o-ArSO₂), 7.00 (d, J ) 9 Hz, 4 H, m-ArSO₂), 5.04 (s, 2 H, CdCH₂),

3.89 (s, 6 H, OCH₃), 3.79 (s, 4 H, H2, H4), 3.18 (t, J ) 6 Hz, 4 H,

H6, H12), 2.62 (t, J ) 6 Hz, 4 H, H8, H10), 1.65 (m, 5 H, H7, H9,

H11). ¹³C NMR (75 MHz, CDCl₃) δ 163.2, 138.9, 131.0, 129.8,

115.5, 114.6, 55.8, 52.1, 44.8, 43.7, 28.3. IR (KBr): 3340 (br),

3098 (w), 2944 (w), 2840 (w), 1596 (s), 1497 (s), 1461 (m), 1334

(s), 1259 (s), 1157 (s), 1093 (m), 1025 (m), 915 (w), 835 (m), 806

(m), 690 (m), 599 (s). Anal. Calcd for C₂₄H₃₃N₃O₆S₂: C, 55.05;

H, 6.35; N, 8.02. Found: C, 54.85; H, 6.16; N 7.95. MS (MALDI)

m/z 524 (MH⁺).

9-Benzyl-3-methylene-1,5-bis(p-nitrobenzenesulfonyl)-1,5,9-

triazacyclododecane (AS114). A solution of 9.16 g (15.5 mmol)

of 30 in 275 mL of anhydrous DMF was added slowly with stirring

to NaH (1.24 g of a 60% (w/w) dispersion in mineral oil, 0.74 g

NaH, 31 mmol, washed with hexane under nitrogen). The resulting

brown solution was stirred at room temperature and a solution of

1.94 g (15.5 mmol) of 3-chloro-2-chloromethyl-1-propene in 20

mL of anhydrous DMF was added over 12 h. The reaction mixture

was stirred at room temperature for 24 h, then the solvent was

removed by rotary evaporation using a hot water bath. A solution

of the residue in 75 mL of CHCl₃was washed with water (3 × 25

mL), 50 mL of saturated aqueous NaCl, dried (MgSO₄), filtered

through 21 g of basic alumina (Woelm Act. 1, 80-200 mesh),

washing with 75 mL of CHCl₃. The combined filtrates were

concentrated by rotary evaporation. A mixture of crude AS114, 20

mL of CHCl₃, 20 mL of 2 N aq HCl, and 30 mL of saturated

aqueous NaCl was shaken vigorously for 20 min, then the organic

layer was separated and concentrated by rotary evaporation. The

resulting yellow solid was triturated with 40 mL of acetone. The

precipitate was collected by filtration, washed with acetone (2 ×

10 mL) and water (4 × 25 mL), then dried overnight (1 mm), giving

5.82 g (55%) of AS114‚HCl as a pale yellow solid, mp 198-200

°C. A mixture of AS114‚HCl (1.26 g), 20 mL of CH₂Cl₂, 2 mL of

1.5 N aq NaOH, and 10 mL of saturated aqueous NaCl was stirred

vigorously for 1 h. The organic layer was washed with 15 mL of

saturated aqueous NaCl and dried (MgSO₄), then concentrated by

rotary evaporation. The residue was purified by silica gel flash

chromatography, eluting with 95:5 (v/v) chloroform/ethyl acetate,

1

affording 0.76 g of AS114 as a pale yellow film. H NMR (300

MHz, CDCl₃) δ 8.39 (d, J ) 9 Hz, 4 H, m-Ns), 7.98 (d, J ) 9 Hz,

4 H, o-Ns), 7.27 (m, 3 H, m,p-Bn), 7.17 (m, 2 H, o-Bn), 5.22 (s,

2 H, CdCH₂), 3.93 (s, 4 H, H2, H4), 3.42 (s, 2 H, CH₂, CH₂Ph),

3.20 (t, J ) 6 Hz, 4 H, H6, H12), 2.40 (t, J ) 6 Hz, 4 H, H8,

H10), 1.69 (quint., J ) 6 Hz, 4 H, H7, H11). ¹³C NMR (75 MHz,

CDCl₃) δ 150.2, 144.5, 139.0, 137.6, 128.8, 128.4, 128.2, 127.1,

124.5, 116.6, 59.1, 51.1, 49.6, 44.4, 25.1. IR (KBr) 3105 (w), 3028

(w), 2936 (w), 2864 (w), 2807 (w), 1529 (s), 1458 (w), 1350 (s),

1309 (m), 1164 (s), 1090 (m), 1041 (w), 937 (w), 855 (m), 736

(m), 688 (m). AS114‚HCl. A solution of 0.70 g (1.2 mmol) of

AS114 in 15 mL of CHCl₃was stirred with 1.5 mL of 1.0 M HCl

in ether for 15 min at room temperature, then the mixture was stored

overnight at room temperature. A precipitate was collected by

filtration, washed with 15 mL of CHCl₃, and dissolved in 25 mL

of warm DMSO. The solution was stored overnight at room

temperature. The resulting precipitate was collected by filtration,

washed with 4 × 5 mL of water, and dried for 7 d at room

temperature (0.4 mm), yielding 0.50 g of AS114‚HCl as a white

9-(3-Methylbutyl)-3-methylene-1,5-bis(4-methoxybenzene-

sulfonyl)-1,5,9-triazacyclododecane (KKD027). A mixture of 0.59

g (1.1 mmol) of KKD025, 15 mL of acetonitrile, 0.10 g (0.66

mmol) of NaI, 0.18 g (1.7 mmol) of Na₂CO₃, and 0.22 g (1.7 mmol)

of 1-bromo-3-methylbutane was stirred and heated under reflux for

4 h. The reaction mixture was cooled and filtered, washing the solids

with 20 mL of acetonitrile. The combined filtrates were concentrated

by rotary evaporation. A solution of the resulting thick yellow oil

in 15 mL of CH₂Cl₂was stirred vigorously for 5 min with 10 mL

of saturated aqueous Na₂S₂O₃. The organic layer was washed with

saturated aqueous NaCl (2 × 10 mL). The combined aqueous layers

were extracted with CH₂Cl₂. The combined organic solutions were

dried (Na₂SO₄) and concentrated by rotary evaporation. Column

chromatography on silica gel, eluting with 6:4 (v/v) ethyl acetate/

CH₂Cl₂gave 0.38 g (58%) of KKD027 free base as a white solid,

which was converted to its HCl salt as described for CADA‚HCl,

1

solid, mp 200-202 °C. H NMR (300 MHz, DMSO-d₆) δ 10.89

(br, 1 H, NH⁺), 8.45 (d, J ) 8.3 Hz, 4 H, m-Ns), 8.08 (d, J ) 8.8

Hz, 4 H, o-Ns), 7.65 (m, 2 H, o-Bn), 7.46 (m, 3 H, m,p-Bn), 5.41

(s, 2 H, CdCH₂), 4.33 (d, J ) 4.9 Hz, 2 H, CH₂Ph), 3.78 (s, 4 H,

H2, H4), 3.25-3.07 (m, 8 H, H6, H8, H10, H12), 1.91 (m, 4 H,

H7, H11). ¹³C NMR (75 MHz, DMSO-d₆) δ 150.2, 142.5, 140.5,

131.0, 130.2, 129.5, 129.1, 129.0, 128.8, 124.8, 119.1, 57.3, 51.6,

47.8, 46.5 20.3. IR (KBr) 3106 (w), 3031 (w), 2979 (w), 2940 (w),

2872 (w), 2449 (br), 2404 (br), 1607 (w), 1530 (s), 1478 (m), 1459

(m), 1350 (s), 1313 (m), 1165 (s), 1109 (m), 1089 (m), 1005 (w),

937 (m), 902 (m), 857 (m), 742 (s), 687 (s). MS (FAB) m/z 644

(MH⁺). Anal. Calcd for C₂₉H₃₃N₅S₂O₈‚HCl: C, 51.21; H, 5.04; N,

10.30. Found: C, 49.20; H, 5.53; N, 8.89.

1

mp 133-135 °C. H NMR (300 MHz, CDCl₃) δ 7.72 (d, J ) 9

Hz, 4 H, o-ArSO₂), 6.99 (d, J ) 9 Hz, 4 H, m-ArSO₂), 5.13 (s, 2

H, CdCH₂), 3.88 (s, 6 H, OCH₃), 3.79 (s, 4 H, H2, H4), 3.13 (t,

J ) 7 Hz, 4 H, H6, H12), 2.33 (t, J ) 6 Hz, 4 H, H8, H10), 2.24

(t, J ) 7 Hz, 2 H, NCH₂iBu), 1.64 (quint., J ) 5 Hz, 4 H, H7,

H11), 1.5 (m, 1 H, CHMe₂), 1.17 (q, J ) 8 Hz, 2 H, CH₂iPr), 0.84

(d, J ) 7 Hz, 6 H, CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 162.8,

138.2, 130.3, 129.4, 128.8, 128.2, 116.1, 114.3, 55.6, 51.6, 51.2,

49.6, 44.0, 35.2, 26.2, 24.8, 22.6. IR (KBr) 3416 (br), 2957 (m),

2871 (w), 2398 (br), 1596 (s), 1577, 1498 (s), 1336 (s), 1306 (s),

1261 (s), 1156 (s), 1112 (m), 1091 (m), 1021 (m), 836 (m), 806

9-Ethoxycarbonyl-3-methylenebis(p-bromobenzenesulfonyl)-

1,5,9-triazacyclododecane (MFS034). A solution of 0.11 g (0.16

mmol) of ASPB127 in 20 mL of THF was stirred at -78 °C, 1.0

mL of 1.7 M t-BuLi in pentane (caution: pyrophoric) was added

1310 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4

Bell et al.

(m), 690 (m), 558 (s). Anal. Calcd for C₂₉H₄₃N₃O₆S₂‚HCl‚

0.5H₂O: C, 54.48; H, 7.03; N, 6.57. Found: C, 54.14; H, 6.30; N

6.54. MS (MALDI) m/z 594 (M - Cl).

2.85 (m, 4 H, H3), 2.38 (s, 3 H, ArCH₃), 2.27 (t, J ) 7 Hz, 4 H,

H1), 1.50 (quint., J ) 6 Hz, 4 H, H2). ¹³C NMR (75 MHz, CDCl₃)

δ 152.0, 143.3, 138.4, 137.2, 135.2, 130.4, 130.0, 129.8, 129.4,

129.2, 128.6, 128.4, 127.3, 127.2, 123.3, 119.2, 115.3, 58.7, 51.9,

45.5, 42.4, 26.3, 26.0, 21.6. MS (MALDI) m/z 609 (MH⁺). 35‚

HCl: IR (KBr) 3374 (w), 3095 (m), 2967 (m), 2464 (br), 1604

(m), 1454 (s), 1325 (m), 1147 (m), 1074 (m), 795 (m), 572 (s).

Anal. Calcd for C₃₂H₄₀N₄O₄S₂‚2HCl: C, 56.38; H, 6.21; N, 8.22.

Found: C, 55.99; H, 6.32; N, 7.91.

3-(2-Methyltetrahydropyrimidin-1-yl)propylamine (32). A

mixture of 22 g (0.17 mol) of bis(3-aminopropyl)amine and 800

mL of CHCl₃was stirred at 3 °C and 7.4 g (0.17 mol) of

acetaldehyde was added dropwise. The reaction mixture was stirred

for 5 min at this temperature, then the solvent was removed by

rotary evaporation. Drying (0.5 mm) and vacuum distillation (110

1

mm, 100 °C) gave 22 g (83%) of 32 as a colorless oil. H NMR

N-(5-Dimethylaminonaphthalene-1-sulfonyl)-N′-(p-toluene-

sulfonyl)bis(3-aminopropyl)cyclohexylmethylamine (36). A mix-

ture of 0.25 g (0.41 mmol) of 34, 50 mL of acetonitrile, 0.1 g (0.66

mmol) of sodium iodide, 0.40 g (3.8 mmol) of sodium carbonate,

and 0.38 g (2.1 mmol) of bromomethylcyclohexane was stirred and

heated under reflux for 4 h. The reaction mixture was cooled to

room temperature and filtered, washing with 50 mL of acetonitrile.

The combined filtrates were concentrated by rotary evaporation.

A solution of the resulting viscous oil in 50 mL of CH₂Cl₂was

stirred vigorously for 5 min with 58 mL of saturated aqueous

Na₂S₂O₃. The organic layer was washed with saturated aqueous

NaCl (2 × 70 mL). The combined aqueous layers were extracted

with CH₂Cl₂. The combined CH₂Cl₂solutions were dried (MgSO₄)

and concentrated by rotary evaporation. Column chromatography

on alumina, eluting with ethyl acetate/hexane, followed by drying

(65 °C, 0.5 mm, 3 d) gave 0.25 g (19%) of 36 as a yellow semisolid.

¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, J ) 9 Hz, 1 H, 2-Dn), 8.33

(d, J ) 9 Hz, 1 H, 4-Dn), 8.22 (d, J ) 9 Hz, 1 H, 8-Dn), 7.71 (d,

J ) 8 Hz, 2 H, o-Ts), 7.51 (m, 2 H, 3,7-Dn), 7.28 (d, J ) 8 Hz, 2

H, m-Ts), 7.18 (d, J ) 7 Hz, 1 H, 6-Dn), 5.81 (bs, 2 H, NH), 2.96

(m, 4 H, H3), 2.88 (s, 6 H, NCH₃), 2.30 (m, 4 H, H1), 2.01 (d, J

) 7 Hz, 2 H, CH₂), 1.59 (m, 10 H, CH₂), 1.30 (m, 1 H, CH), 1.13

(quint., J ) 7 Hz, 2 H, H2), 0.77 (quint., J ) 7 Hz, 2 H, H2′). IR

(NaCl) 3264 (br), 2918 (m), 2849 (w), 1664 (w), 1465 (m), 1318

(s), 1155 (s), 1086 (m), 913 (w), 795 (m), 642 (w). MS (MALDI)

m/z 615 (MH⁺).

9-Benzyl-1-(5-dimethylaminonaphthalene-1-sulfonyl)-3-meth-

ylene-5-(p-toluenesulfonyl)-1,5,9-triazacyclododecane (KKD015).

A solution of 0.5 g (0.8 mmol) of 35 in 5 mL of anhydrous DMF

was added to a stirred mixture of NaH (0.13 g of a 60% (w/w)

slurry in mineral oil, 78 mg of NaH, 3.3 mmol, washed with hexane

under nitrogen) and 40 mL of anhydrous DMF at 75 °C. A solution

of 0.13 g (0.93 mmol) of 3-chloro-2-chloromethyl-1-propene in 20

mL of anhydrous DMF was added over 6 h by means of a syringe

pump. The reaction mixture was stirred at 60 °C for 12 h, then

cooled to room temperature, and the solvent was removed by means

of a rotary evaporator. A solution of the residue in 75 mL of CHCl₃

was washed with water (3 × 50 mL), then concentrated to dryness

by rotary evaporation. Chromatography on silica gel, eluting with

2:3 (v/v) ethyl acetate/hexane and recrystallization from diethyl

ether/hexane gave 0.14 g (27%) of KKD015, mp 194-195 °C. ¹H

NMR (300 MHz, CDCl₃) δ 8.52 (d, J ) 8 Hz, 1 H, 2-Dn), 8.27 (d,

J ) 8 Hz, 1 H, 4-Dn), 8.21 (d, J ) 8 Hz, 1 H, 8-Dn), 7.64 (d, J )

8 Hz, 2 H, o-Ts), 7.53 (m, 2 H, H6, 3,7-Dn), 7.25 (m, 4 H, o,m-

Bn), 7.19 (m, 2 H, 6-Dn, p-Bn), 5.19 (m, 2 H, CdCH₂), 4.13 (s, 2

H, H2), 3.66 (s, 2 H, H4), 3.37 (s, 2 H, CH₂Ph), 3.32 (t, J ) 7 Hz,

2 H, H12), 2.99 (t, J ) 7 Hz, 2 H, H6), 2.88 (s, 6 H, NCH₃), 2.44

(s, 3 H, ArCH₃), 2.44 (t, J ) 7 Hz, 2 H, H10), 2.20 (t, J ) 7 Hz,

2 H, H8), 1.80 (quint., J ) 7 Hz, 2 H, H11), 1.47 (quint., J ) 7

Hz, 2 H, H7). ¹³C NMR (75 MHz, CDCl₃) δ 151.9, 143.7, 139.6,

138.6, 135.1, 134.7, 130.6, 130.3, 129.9, 128.9, 128.3, 127.6, 127.1,

123.3, 119.6, 116.7, 115.4, 59.3, 53.8, 50.4, 49.3, 48.5, 45.6, 45.3,

42.6, 25.9, 24.3, 21.7. IR (KBr) 3067 (w), 2945 (m), 2822 (m),

1577 (m), 1449 (m), 1309 (s), 1164 (s), 1092 (s), 941 (m), 779

(m), 679 (m), 550 (s). Anal. Calcd. for C₃₆H₄₄N₄O₄S₂: C, 65.43;

H, 6.71; N, 8.45. Found: C, 65.08; H, 6.53; N, 8.43. MS (MALDI)

m/z 661 (MH⁺).

(300 MHz, CDCl₃) δ 3.19 (q, J ) 6 Hz, 1 H, CHMe), 3.08 (m, 2

H, NCH₂), 2.72 (m, 4 H, NCH₂), 2.29 (m, 2 H, NCH₂), 1.63 (quint.,

J ) 7 Hz, 4 H, CCH₂C), 1.29 (bs, 3 H, NH, NH₂), 1.23 (d, J ) 6

Hz, 3 H, CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 72.4, 51.8, 50.5,

48.1, 45.1, 41.0, 40.7, 34.0, 30.6, 27.2, 20.6. IR (NaCl) 292 (br),

2931 (m), 1576 (s), 1473 (s), 1380 (m), 1315 (m), 1077 (w), 902

(w), 815 (w). MS (FAB) m/z 158 (MH⁺).

3-[2-Methyl-3-(p-toluenesulfonyl)tetrahydropyrimidin-1-yl]-

propylamine (33). A mixture of 1.14 g (7.3 mmol) of 32 and 25

mL of 1:1:2 (v/v/v) 2 M aq NaOH/THF/water was stirred at 0 °C

and a solution of 1.4 g (7.3 mmol) of p-toluenesulfonyl chloride in

20 mL of 1:1:2 (v/v/v) 2 aq M NaOH/THF/water was added in

one portion. The reaction mixture was stirred overnight at room

temperature, then it was saturated with NaCl. The organic layer

was dried (Na₂SO₄) and concentrated by rotary evaporation. Drying

(0.5 mm) gave 0.8 g (35%) of 33 as a semisolid oil. ¹H NMR (300

MHz, CDCl₃) δ 7.75 (d, J ) 8 Hz, 2 H, o-Ts), 7.30 (d, J ) 8 Hz,

2 H, m-Ts), 3.02 (m, 5 H, NCH₂), 2.17 (m, 2 H, NCH₂), 2.43 (s,

3 H, ArCH₃), 2.18 (m, 2 H, NCH₂), 1.63 (m, 2 H, CCH₂C), 1.55

(m, 2 H, CCH₂C), 1.23 (bs, 2 H, NH₂), 1.13 (d, J ) 6 Hz, 3 H,

CH₃). IR (KBr) 3285 (s), 3028 (s), 2788 (br), 1605 (s), 1435 (s),

1298 (s), 1159 (s), 913 (s), 715 (s), 561 (s). MS (FAB) m/z 312

(MH⁺).

N-(5-Dimethylaminonaphthalene-1-sulfonyl)-N′-(p-toluene-

sulfonyl)bis(3-aminopropyl)amine (34). A mixture of 5.96 g (19.2

mmol) of 33, 5.17 g (19.2 mmol) of dansyl chloride, 120 mL of

CH₂Cl₂, and 120 mL of saturated aqueous Na₂CO₃, was stirred for

18 h at room temperature. Sodium hydroxide (4.0 g, 0.1 mol) was

added to the reaction mixture and stirring was continued for 2 h.

The organic layer was evaporated to dryness. Two sequential

column chromatograms on silica gel, eluting with ethyl acetate,

then 1:9 (v/v) methanol/CHCl₃gave 5.0 g (50%) of 34, which was

1

used without further purification. H NMR (300 MHz, CDCl₃) δ

8.40 (d, J ) 8 Hz, 1 H, 2-Dn), 8.30 (d, J ) 8 Hz, 1 H, 4-Dn), 8.25

(d, J ) 8 Hz, 1 H, 8-Dn), 7.75 (d, J ) 8 Hz, 2 H, o-Ts), 7.51 (m,

2 H, 3,7-Dn), 7.29 (d, J ) 8 Hz, 2 H, m-Ts), 7.17 (d, J ) 7 Hz, 1

H, 6-Dn), 3.00 (m, 4 H, H3), 2.89 (s, 6 H, NCH₃), 2.58 (q, J ) 6

Hz, 4 H, H1), 2.41 (s, 3 H, ArCH₃), 1.62 (m, 5 H, CCH₂C, NH).

IR (NaCl) 3294 (m), 2937 (m), 2866 (m), 1573 (m), 1454 (m),

1321 (s), 1158 (s), 1092 (m), 791 (m). MS (FAB) m/z 519 (MH⁺).

N-(5-Dimethylaminonaphthalene-1-sulfonyl)-N′-(p-toluene-

sulfonyl)bis(3-aminopropyl)benzylamine (35). A mixture of 2.0

g (3.9 mmol) of 34, 35 mL of acetonitrile, 0.1 g (0.66 mmol) of

sodium iodide, 0.40 g (3.8 mmol) of sodium carbonate, and 0.49 g

(3.9 mmol) of benzyl chloride was stirred and heated under reflux

for 4 h. The reaction mixture was cooled to room temperature and

filtered, washing with 50 mL of acetonitrile. The combined filtrates

were concentrated by rotary evaporation. A solution of the resulting

viscous oil in 50 mL of CH₂Cl₂was stirred vigorously for 5 min

with 58 mL of saturated aqueous Na₂S₂O₃. The organic layer was

washed with saturated aqueous NaCl (2 × 70 mL). The combined

aqueous layers were extracted with CH₂Cl₂. The combined CH₂Cl₂

solutions were dried (MgSO₄) and concentrated by rotary evapora-

tion. Column chromatography on alumina, eluting with ethyl

acetate/hexane gave a yellow oil, which gradually solidified upon

1

drying at 65 °C (0.5 mm, 3 d) to give 1.19 g (50%) of 35. H

NMR (300 MHz, CDCl₃) δ 8.51 (d, J ) 8 Hz, 1 H, 2-Dn), 8.29 (d,

J ) 8 Hz, 1 H, 4-Dn), 8.19 (d, J ) 8 Hz, 1 H, 8-Dn), 7.67 (d, J )

8 Hz, 2 H, o-Ts), 7.48 (t, J ) 8 Hz, 2 H, 3,7-Dn), 7.22 (m, 5 H,

m-Ts, m,p-Bn), 7.13 (m, 3 H, 6-Dn, o-Bn), 5.99 (bs, 1 H, DnNH),

5.90 (bs, 1 H, TsNH), 3.32 (s, 2 H, CH₂Ph), 2.85 (s, 6 H, NCH₃),

9-Cyclohexylmethyl-1-(5-dimethylaminonaphthalene-1-sulfon-

yl)-3-methylene-5-(p-toluenesulfonyl)-1,5,9-triazacyclododecane

(KKD016). A solution of 0.25 g (0.41 mmol) of 36 in 5 mL of

anhydrous DMF was added to a stirred mixture of NaH (0.06 g of

a 60% (w/w) slurry in mineral oil, 36 mg of NaH, 1.6 mmol, washed

CD4 Down-Modulating CADA Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4 1311

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Taylor, R. M.; Eisenbarth, G. S. Nondepleting anti-CD4 monoclonal

antibody prevents diabetes and blocks induction of insulin auto-

antibodies following insulin peptide B:9-23 immunization in the NOD

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with hexane) and 40 mL of anhydrous DMF at 75 °C. A solution

of 0.05 g (0.41 mmol) of 3-chloro-2-chloromethyl-1-propene in 20

mL of anhydrous DMF was added over 6 h by means of a syringe

pump. The reaction mixture was stirred at 60 °C for 12 h and cooled

to room temperature, and the solvent was removed on a rotary

evaporator. A solution of the residue in 75 mL of CHCl₃was

washed with water (3 × 50 mL) and concentrated to dryness.

Chromatography on silica gel, eluting with 3:7 (v/v) ethyl acetate/

hexane gave 0.10 g (35%) of KKD016 as a viscous yellow oil. ¹H

NMR (300 MHz, CDCl₃) δ 8.54 (d, J ) 8 Hz, 1 H, 2-Dn), 8.32 (d,

J ) 8 Hz, 1 H, 4-Dn), 8.24 (d, J ) 8 Hz, 1 H, 8-Dn), 7.63 (d, J )

8 Hz, 2 H, o-Ts), 7.53 (m, 2 H, 3,7-Dn), 7.31 (d, J ) 8 Hz, 2 H,

m-Ts), 7.17 (d, J ) 7 Hz, 1 H, 6-Dn), 5.12 (m, 2 H, CdCH₂), 4.08

(s, 2 H, H2), 3.62 (s, 2 H, H4), 3.38 (t, J ) 7 Hz, 2 H, H12), 2.98

(t, J ) 7 Hz, 2 H, H6), 2.88 (s, 6 H, NCH₃), 2.43 (s, 3 H, ArCH₃),

2.31 (t, J ) 6 Hz, 2 H, H10), 2.16 (t, J ) 5 Hz, 2 H, H8), 1.95 (d,

J ) 9 Hz, 2 H, CH₂Cy), 1.63 (m, 8 H, H7, Cy), 1.13 (m, 3 H,

H11, Cy), 0.70 (quint., J ) 7 Hz, 2 H, Cy). MS (MALDI) m/z 666

(M⁺, 10). KKD016‚HCl: IR (KBr) 3419 (br), 2911 (s), 2839 (m),

2359 (br), 1594 (m), 1454 (s), 1309 (s), 1142 (s), 896 (m), 796 (s),

539 (s). Anal. Calcd for C₃₆H₅₀N₄O₄S₂‚2HCl‚3H₂O: C, 54.47; H,

7.31; N, 7.05. Found: C, 54.80; H, 6.89; N, 7.15.

Molecular Modeling. All molecular modeling calculations were

performed using the SYBYL program.⁴²Energy minimizations were

carried out using the Tripos force field,⁴³Gasteiger-Hu¨ckel charges,

and the Powel method, electrostatics included. The X-ray structure

of CADA was energy minimized, then modified to produce the

data set of 30 structures, each of which was also energy minimized.

The structures were aligned with CADA by minimizing the least-

squares sum of five deviations, consisting of the three ring nitrogens

and two sulfur atoms. Molecular surfaces were mapped using a

positively charged sp³carbon probe atom. Partial least squares (PLS)

analysis^44,45was used to derive the model, using CoMFA descriptors

as independent variables and pIC₅₀as the dependent variable. The

leave-one-out method⁴⁶was used for validation with no column

filtering. PLS analyses of CoMSIA indices^39,40were run indepen-

dently of other indices using the same settings as in the CoMFA

PLS. Color coded contour plots in Figure 4 were generated from a

CoMFA model produced from all activity data in Table 2 and

consist of std*coeff CoMFA steric and electrostatic contour plots

generated by SYBYL.

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Acknowledgment. We thank Youngmi Ahn for improving

the synthesis of CADA, Athanasios Glekas for initially preparing

compound 95-213, and Violeta Demillo for repeating the

1

synthesis of 26‚HCl and recording its H NMR spectrum. We

also thank the National Science Foundation for support of

molecular modeling facilities at UNR (grant no. MCB-9817605).

Supporting Information Available: Numbered thermal el-

lipsoid plots and X-ray crystallographic data for four compounds,

15, ASPB127, CADA, and KKD023. This material is available

free of charge via the Internet at http://pub.acs.org.

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JM0582524

Article Doi

Synthesis and structure-activity relationship studies of CD4 down-modulating cyclotriazadisulfonamide (CADA) analogues

DOI: 10.1021/jm0582524

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Full text of DOI:10.1021/jm0582524

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