The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs

Bioorganic & Medicinal Chemistry 21 (2013) 7309–7329

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry

journal homepage: www.elsevier.com/locate/bmc

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective

nicotinic acetylcholine receptor ligands. Part 2: Carboxamide

derivatives with different spacer motifs

Christoph Eibl ^a^,^b, Lenka Munoz , Isabelle Tomassoli , Clare Stokes , Roger L. Papke ,

Daniela Gündisch

a

a,c

b

d

a,b,

⇑

Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany

Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA

Department of Pharmacology, School of Medical Sciences, The University of Sydney, NSW 2006, Australia

b

c

d

Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USA

a r t i c l e i n f o

a b s t r a c t

Article history:

Available online 5 October 2013

3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have

been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated

between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispi-

Keywords:

dine carboxamides bearing spacer motifs often showed high afﬁnity in the low nanomolar range and

3

,7-Diazabicyclo[3.3.1]nonane

⁄

selectivity for the

a

4b2 nAChR. Compounds 15, 25, and 47 with K

i

values of about 1 nM displayed the

Bispidine

Nicotinic acetylcholine receptor

nAChR

Structure–activity relationship

Cytisine

⁄

highest afﬁnities for

a

4b2 nAChR. All evaluated compounds are partial agonists or antagonists at

⁄

a

4b2 , with reduced or no effects on

a

3b4 with the exception of compound 15 (agonist), and reduced

or no effect at a7 and muscle subtypes.

1

. Introduction

Di)azabicyclic templates dominate compound libraries for nic-

moiety and less often as carbonyl functionality or as heteroaryls.⁶^,⁷

The bulkiness of ring structures containing the potentially charged

nitrogen and moieties attached to the HBA system inﬂuence both

afﬁnity and functionality. The diazabicyclic scaffold 3,7-diazabicy-

clo[3.3.1]nonane (bispidine) originated from the natural product

(

1

8

otinic acetylcholine receptors (nAChRs). NAChRs are pentameric

cation channels found in the central and peripheral nervous sys-

tems, as well as in non-neuronal cells and serve as interesting tar-

gets especially for various brain diseases.²These (di)azabicyclic

templates display cationic/HB cores important for the interaction

with the receptors. An additional pharmacophoric point, a hydro-

gen bond acceptor (HBA) motif, is often introduced as a pyridine

and nAChR ligand cytisine 1 (Fig. 1). It is a privileged scaffold and

–5

6–15

has been used for the development of nAChR compounds.

In

our previous 3,7-diazabicyclo[3.3.1]nonane project, we explored

7

the inﬂuence of different non-heteroaryl based HBA systems. We

also reported that 3,7-diazabicyclo[3.3.1]nonane is active on nAC-

hRs and that some 3,7-diazabicyclo[3.3.1]nonane carboxamides

⁄

showed selectivity for the

a

4b2 nAChR. Herein, we extend the pre-

3 3

Abbreviations: BBB, blood–brain barrier; CD OD, tetradeuteromethanol; CDCl ,

deuterochloroform; CH

deuterium oxide; DCC, N,N -dicyclohexylcarbodiimide; DMAP, 4-(dimethyl-

2

Cl

2

, dichloromethane; CNS, central nervous system; D

2

O,

vious study by introducing spacer motifs like methylene, ethylene,

ethenylene, ethynylene or (hetero)aryls attached to the HBA system

to explore the chemical space for nAChRs further (Fig. 1). Diverse

substituents were connected to the spacer motifs.

0

amino)pyridine; DME, 1,2-dimethoxyethane; DMF, N,N-dimethylformamide; Et

diethyl ether; Et N, triethylamine; EtOAc, ethyl acetate; HBA, hydrogen bond

acceptor; HCl, hydrogen chloride; HEPES, 4-(2-hydroxyethyl)piperazine-1-ethane-

sulfonic acid; HSS, HEPES-buffered salt solution; K CO , potassium carbonate; KBr,

potassium bromide; KMnO , potassium permanganate; KOH, potassium hydroxide;

MeCN, acetonitrile; MeI, iodomethane; MeOH, methanol; MgSO , magnesium

sulfate; nAChR, nicotinic acetylcholine receptor; NaHCO sodium hydrogen

2

O,

3

2

3

4

3

,

carbonate; NaOH, sodium hydroxide; Pd/C, palladium on activated charcoal; PE,

petroleum ether; PEI, poly(ethyleneimine); Ro5, rule of ﬁve; THF, tetrahydrofuran;

TPSA, topological polar surface area; TRIS, tri(hydroxymethyl)aminomethane;

ZnBr

2

, zinc bromide.

Figure 1. Structures of (ꢀ)-cytisine 1, cytisine derivatives 4–7 and the development

of the 3,7-diazabicyclo[3.3.1]nonane based compounds 13–55 incorporating a

spacer motif, for example, compounds 30, 31, 36, and 37.

⇑

Corresponding author. Tel.: +1 808 933 2943; fax: +1 808 933 2974.

E-mail address: danielag@hawaii.edu (D. Gündisch).

0

http://dx.doi.org/10.1016/j.bmc.2013.09.060

7

310

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

Firstly, we synthesized and tested four cytisine derivatives

including the in vivo active 3-(pyridine-3-yl)-cytisine (3PC) 5 dis-

playing at least one rotatable bond and compared them with their

deprotection step. The coupling of aromatic or heteroaromatic moi-

eties to the cytisine backbone was achieved by using the Suzuki–

Miyaura reaction in a microwave synthesizer. The palladium cata-

analogously substituted 3,7-diazabicyclo[3.3.1]nonane carboxam-

lyst Pd(PPh

3, the appropriate boronic acid and an inorganic base in a mixture of

DME or DMF and H O. Microwave irradiation (30 W) at 80 °C was

3 4

) was added to a solution of 3-bromo-N-tboc-cytisine

ides to get insight into the inﬂuence of a spacer motif.¹

6–18

We

have recently shown that 3-(pyridine-3-yl)-cytisine (3PC) 5 serves

2

1

6–18

as an interesting lead for the development of antidepressants.

used for 30–90 min to synthesize the according N-tboc protected

Now, we want to ‘open’ the ‘chemical space’ of cytisine to have the

possibility to obtain compounds with better subtype selectivity

pattern than cytisine derivatives along with a much simpler syn-

thetic approach. Secondly, we prepared and tested a series of car-

boxamides bearing different spacer motifs providing additional

possible interaction points with nAChRs and their consequences

on afﬁnity and functionality for further proﬁling projects.

cytisine derivatives Boc-4–Boc-7. These products were puriﬁed

on preparative HPLC using a C18-RP column and a MeOH–H

2

O

gradient.

The N-tboc protection group of Boc-4–Boc-7 was directly re-

moved by using microwave irradiation (150 W) at 150 °C for

30 min in pure H O. The solvent of the ﬁnal cytisine products 4–

2

7 was removed by lyophilisation for at least 24 h.

The 3,7-diazabicyclo[3.3.1]nonane (bispidine) scaffold was syn-

thesized using the method described previously, where N-benzyl-

N -tboc-bispidinone 9 was obtained by a double Mannich reaction

2

. Results and discussion

.1. Chemistry

0

from commercially available tert-butyl 4-oxopiperidine carboxyl-

ate 8, benzylamine, and paraformaldehyde and reduced to the

0

7,13

key intermediate N-benzyl-N -tboc-bispidine 10.

The cleavage

Like previously described by us, (ꢀ)-cytisine was isolated from

_s_e_e_d_s_a_n_d_p_o_d_s_o_f_L_a_b_u_r_n_u_m_a_n_a_g_y_r_o_i_d_e_s_.1

6,17

0

of the N-benzyl protecting group from N-benzyl-N -tboc-bispidine

The dried and milled

1

5

1

0 was achieved by using palladium on activated charcoal (Pd/C)

% under a hydrogen atmosphere. The resulting N-tboc-bispidine

2 was now used as the starting material for all carboxamides

plant material was extracted with PE to remove lipids. Then (ꢀ)-

cytisine was extracted with a mixture of CH Cl :MeOH:NH

90:10:5) for 8 h. After ﬁltration and concentration of this solution,

it was extracted with HCl (1 N) and, subsequently, rendered alka-

line, and extracted with CH Cl until completion. The alkaloid 1

was ﬁnally puriﬁed by column chromatography on silica gel with

a mixture of CHCl and MeOH (6:1) or by preparative HPLC using

a C18-RP stationary phase and a MeOH–H O gradient.

The N-tboc protection group was introduced by adding di-tert-

butyl dicarbonate ((Boc)

O) to a solution of (ꢀ)-cytisine 1 and Na2-

CO in a mixture of CH Cl and H O. The solution was heated to re-

2

3

(

described.

In general, all N-tboc protected intermediates Boc-13–Boc-55

2

were puriﬁed by ﬂash chromatography on silica gel and analyzed

by LC–MS. When the purity was above 90–95% these intermediates

were N-tboc deprotected without further analysis. The N-tboc

deprotected ﬁnal compounds 13–55 were puriﬁed by ﬂash chro-

matography and have been analyzed in more details.

Using the method previously described, intermediates Boc-13–

Boc-28 were synthesized by using carbonyldiimidazole (CDI) as a

coupling reagent or via carboxylic acid chlorides/aminolysis or

3

2

3

2

ﬂux for 2 h and N-tboc-cytisine 2 was obtained in good yields after

extraction and recrystallization in PE. Alternatively, N-tboc-cyti-

0

7,13

via DCC (N,N -dicyclohexylcarbodiimide) coupling reaction

see Scheme 2).

After removal of the N-tboc protecting group ﬁnal compounds

sine 2 was synthesized by adding portions of (Boc)

of 1 and Na CO in a mixture of CH Cl and H

sine spot 1 has disappeared on TLC. After extracting the product 2

2

O to a solution

O until the (ꢀ)-cyti-

(

2

3

2

were often obtained as oils. For puriﬁcation purposes and to im-

prove stability, compounds 13–55 were transferred into their cor-

it was puriﬁed by preparative HPLC using a C18-RP column and a

MeOH–H

The reaction of N-tboc-cytisine 2 with N-bromosuccinimide

NBS) for 2 h under reﬂux in CH Cl afforded a mixture of isomeric

2

O gradient.

(

2

bromo-N-tboc-cytisine derivatives bearing the bromo substituents

in the 3 or the 5 position of the pyridone moiety. These isomers

could be separated by preparative HPLC using a C18-RP column

and a MeOH–H O gradient. Only 3-bromo-N-tboc-cytisine 3 was

2

used for this project (see Scheme 1).

The cytisine derivatives 4–7 were synthesized in a two-step

process incorporating a cross-coupling reaction and the N-tboc-

Scheme 2. Synthesis of bispidine derivatives. Reagents and conditions: (a) (CH

BnNH , AcOH, MeOH, [Ar] reﬂux, 6 h; (b) N (80%), NaOH, diethylene glycol,

25 °C, 2 h, then Dean Stark trap, 140 °C, 8 h; (c) Pd/C (5%), H (2–4 bar), MeOH, rt,

4–24 h; (d) CDI, THF, reﬂux, 2 h; (e) (i) MeI, MeCN, THF, rt, 24 h; (ii) R-COOH, Et N,

MeCN, rt, 12–120 h; (f) HCl/1,4-dioxane (4 M), rt, 4 h; (g) anhydr. ZnBr , CH Cl , rt,

Cl , 0 °C to

2 n

O) ,

2

2 4

H

1

2

Scheme 1. Synthesis of cytisine derivatives. Reagents and conditions: (a) (Boc)

2

O,

reﬂux, 2 h; (c) R-B(OH)

O [Ar], MW (30 W), 80 °C, 30–60 min; (d) H O,

3

Na

2

CO

3

,

CH

2

Cl ,

2

H

2

O, reﬂux, 2 h; (b) NBS, CH

2

Cl

2

,

2

,

2

Pd(PPh

3

)

4

, base, DME or DMF, H

2

12–120 h; (h) R-COCl, Et

rt, 12 h.

3

N, toluene, rt, 2 h; (j) R-COOH, DCC, DMAP, CH

2

MW (150 W), 150 °C, 30 min.

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7311

responding fumaric acid salts 13F–55F. Products 13F–55F have

been obtained in excellent purity (mostly >99%).

2.2.2. 3,7-Diazabicyclo[3.3.1]nonane based carboxamides with

methylene spacer

The introduction of the methylene spacer into compound 29

⁄

2

.2. Biological activity and SAR

(K

i

= 454 nM for

a

4b2 ) increased the afﬁnity for the

a4b2 subtype

by about eightfold (30; K

i

= 58 nM). Compound 30 showed also

Radioligand binding assays as previously described were per-

high subtype selectivity. The perﬂuorinated compound 34 failed

to interact with nAChRs tested. Other compounds bearing a meth-

ylene spacer (compounds 13, 31 and 35–38) between the amide

formed to determine the afﬁnities (K

i

values) of cytisine 1 (stan-

dard ligand and starting material), cytisine derivatives 4–7

19–21

(

Table 1) and the bispidine derivatives 13–55 (Table 2).

bond and the (hetero)aryl substituents also exhibited high afﬁnity

⁄

in the low nanomolar range for the

a

4b2 nAChR. Compound 35

2

.2.1. Cytisine derivatives in comparison with their analogously

substituted with a methylsulfonyl moiety in the para position of

⁄

substituted 3,7-diazabicyclo[3.3.1]nonane based carboxamides

In the past, we and several other research groups studied struc-

ture–activity relationships (SAR) around the intact cytisine tem-

plate to gain insights into nAChR afﬁnity and functional

the phenyl ring showed a K

i

value of 22.9 nM for the

3b4 nAChR. The 3-methyl-5-isoxaz-

a

4b2 sub-

⁄

type, and no afﬁnity for e.g.

a

i

olyl derivative 13 (K = 46.9 nM) bearing a substituent which can

be considered as a bioisosteric replacement of the phenyl ring dis-

1

,16,17,22

⁄

selectivity.

-Phenyl-cytisine 4 exhibited an afﬁnity for the

= 128 nM) what is about 1000 times lower than cytisine 1, but

played a similar K

i

value for

a

4b2 . For compounds 31 (3-pyridyl),

⁄

3

a

4b2 subtype

i

36 (4-pyridyl) and 37 (3,4-methylenedioxyphenyl) K values of

11.2 nM (31), 14.4 nM (36) and 13.2 nM (37), respectively, were

(K

i

with enhanced subtype selectivity. The introduction of a heteroaryl

obtained. These moieties have additional hydrogen bond acceptors

which might be beneﬁcial for increasing the afﬁnity for a4b2

nAChR further. Compound 38 with the bulkier 2-naphthyl moiety

⁄

substitutent provided compounds with high afﬁnity for

3PC): K = 0.91 nM; 6: K

as an additional HBA system enhancing the afﬁnity for

comparing with ligand 4, but decreasing the subtype selectivity for

e.g. 3b4 (5 (3PC): K = 119 nM; 6: K = 436 nM). Compound 7,

a

4b2 (5

(

i

= 3.9 nM). The pyridyl ring can function

⁄

a

4b2 when

exhibited a K value in the low nanomolar range (K = 10.2 nM)

i

for this receptor subtype. These results indicate that the introduc-

⁄

a

i

tion of a methylene spacer is tolerated by the

can increase the afﬁnity for this subtype.

a

4b2 subtype and

bearing an additional 3,4-methylendioxy substituent at the phenyl

⁄

ring, displayed similar afﬁnity for

nyl-cytisine 4 (K

a

4b2 (K

i

= 110 nM) like 3-phe-

i

= 128 nM) along with high subtype selectivity.

2.2.3. 3,7-Diazabicyclo[3.3.1]nonane based carboxamides with

an ethylene, oxymethylene, or cyclopropyl spacer

Compounds 30, 31, 36, and 37 (Table 2) can be directly com-

pared to cytisine derivatives 4–7. They can be seen as simpliﬁed

and more ﬂexible cytisine analogs, but lacking the pyridone ring

The homolog ethylene spacer in compound 32 did not change

⁄

the afﬁnity for

a

4b2 nAChR (K

i

= 52.5 nM) comparing with the

system of 1 (Table 1). Compounds 30 and 37 (K

i

= 57.6 and

methylene spacer compound 30 (Table 2). Compound 32 also dis-

⁄

1

3.2 nM, respectively) showed higher afﬁnity for the

nAChR than their more rigid cytisine analogs 4 and 7 (K

and 110 nM, respectively). In contrast, cytisine derivatives 5

a

4b2

played an afﬁnity for the

a

3b4 subtype (K

i

= 395.8 nM), but no

⁄

i

= 128

afﬁnity for the

a7

nAChR. The introduction of a 3-pyridyl ring

⁄

(compound 39) increased the afﬁnity for the

slightly (K

groups in the meta- and the para positions (compound 14) resulted

in a drop of afﬁnity for this receptor subtype (K = 232.6 nM). Com-

a

4b2 subtype only

and 6 (K

i

= 0.91 and 3.9 nM) bearing a pyridine substituent dis-

i

= 39 nM), whereas the introduction of three methoxy

⁄

played slightly higher afﬁnity for the

a4b2 nAChR than their

more ﬂexible bispidine analogs 31 and 36 (K

i

= 11.2 and

i

1

4.4 nM, respectively). 3,7-Diazabicyclo[3.3.1]nonane based car-

pound 33, bearing a 2-chloro aryl moiety and an oxymethylene

⁄

boxamides can therefore provide easier synthetically accessible

nAChR ligands with high

selectivity.

spacer displayed lower afﬁnity for the

a4b2 subtype (K

i

= 548 nM)

⁄

a

4b2 afﬁnity and enhanced subtype

compared to compound 32. This shows, that either a small electron

withdrawing group in the ortho position of the aromatic ring or a

Table 1

Afﬁnities (K

i

values) and calculated physicochemical parameters (logP, TPSA, logBB) of (ꢀ)-cytisine 1 and cytisine derivatives 4–7

⁄

ClogP^a

logBB^b

Structure

a4b2

a3b4

a

7

(

a1)

2

b1

c

d

Mol. weight

TPSA

K

i

[nM]

K

i

[nM]

K

i

[nM]

i

K [nM]

1^c

4^c

5^c

6^c

7^c

0.122

18

261

1300

190.24

266.34

267.14

310.35

0.17

2.27

1.03

0.78

2.31

32.34

45.23

50.80

ꢀ0.25

ꢀ0.01

ꢀ0.23

ꢀ0.28

ꢀ0.03

128

>10,000

119

>10,000

1,100

>10,000

>5000

0.91

3.9

436

>10,000

110

>10,000

a

b

c

logP values have been calculated using the ACD/Labs Algorithm (ACD).

logBB was calculated from logP derived from using the ACD/Labs Algorithm (ACD).

Data from Refs. 16–20.

7

312

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

Table 2

Afﬁnities (K

i

values ± SEM) and calculated physicochemical parameters (logP, TPSA, logBB) of the bispidine carboxamide derivatives 13–55

⁄

ClogP^a

logBB^b

Compd

R =

a

4b2

a

3b4

[nM]

a

7

(

a

i

1)

2

b1

c

d

Mol. weight

TPSA

K

i

[nM]

K

i

K

i

[nM]

K [nM]

2

9

0

453.6 ± 14.8

57.6 ± 15.4

>5000

n. d.

>10,000

n. d.

230.31

244.33

0.56

1.57

32.34

ꢀ0.09

3

0.18

3

4

>5,000

n.d.

334.28

1.75

32.34

0.25

3

5

3

22.9 ± 0.9

46.9 ± 7.2

>5000

>1000

>5000

>1000

>5000

n. d.

322.42

249.31

ꢀ0.15

ꢀ0.11

74.86

58.37

ꢀ0.10

ꢀ0.03

1

3

1

6

11.2 ± 1.5

14.4 ± 2.0

>1000

>5000

245.32

0.08

45.23

ꢀ0.01

3

7

8

13.2 ± 1.2

10.2 ± 2.1

>1000

>5000

288.34

294.39

1.43

2.80

50.80

32.34

ꢀ0.13

ꢀ0.19

3

2

9

52.5 ± 0.7

39 ± 3.4

395.8

>10,000

>5000

n. d.

258.36

259.35

2.08

0.59

32.34

45.23

0.04

3

>5000

ꢀ0.10

1

4

232.6

>5000

>10,000

n. d.

348.44

1.52

60.03

ꢀ0.08

33

15

16

548.0 ± 66.0

1.2 ± 0.4

>5000

81.1

>5000

>10,000

>5000

n. d.

294.78

270.37

256.34

1.75

1.73

1.87

41.57

32.34

ꢀ0.23

ꢀ0.13

ꢀ0.24

55.1 ± 12.5

>5000

>10,000

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7313

Table 2 (continued)

Compd R =

⁄

ClogP^a

logBB^b

a

4b2

a

3b4

a

7

(

a

i

1)

2

b1

c

d

Mol. weight

286.37

TPSA

K

i

[nM]

K

i

[nM]

K

i

[nM]

K [nM]

17

18

19

20

171.8 ± 39.7

23.7 ± 3.2

24.6 ± 4.2

38.9 ± 4.4

n. d.

>10,000

n. d.

1.87

41.57

ꢀ0.21

0.06

n. d.

>10,000

n. d.

290.79

335.24

301.34

2.47

2.70

1.77

32.34

81.17

n. d.

0.01

>1000

>10,000

ꢀ0.51

4

0

1

20.7 ± 2.4

39.6 ± 5.4

>5000

>10,000

274.33

286.37

1.87

1.81

32.34

41.57

ꢀ0.03

ꢀ0.23

2

n. d.

22

23

24

41

287.5 ± 25.7

96.9 ± 20.5

57.1 ± 12.3

32.59

>1000

2000

n.d.

>1000

>5000

n.d.

246.30

262.37

257.33

1.49

1.68

1.66

0.62

45.48

60.58

45.23

ꢀ0.07

ꢀ0.32

0.33

>10,000

>1000

n.d.

>1000

>5000

ꢀ0.23

2

5

6

1.03

>1000

>10,000

>1000

>5000

257.33

300.35

0.37

1.99

45.23

50.80

ꢀ0.27

ꢀ0.15

2

36.9 ± 8.0

(

continued on next page)

7

314

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

Table 2 (continued)

Compd R =

⁄

ClogP^a

3.10

logBB^b

ꢀ0.11

ꢀ0.27

a

4b2

a

3b4

[nM]

a

7

(

a

i

1)

2

b1c

d

Mol. weight

306.40

TPSA

32.34

K

i

[nM]

K

i

K

i

[nM]

K [nM]

2

7

2

296.6 ± 50.7

10.9 ± 3.4

>5000

>1000

>5000

>1000

4

254.33

2.41

4

3

241.9

>1000

>5000

284.35

2.33

41.57

ꢀ0.23

4

5

6.3 ± 1.1

7.8 ± 2.0

>1000

>5000

284.35

2.33

41.57

ꢀ0.23

4

46

47

48

2.1 ± 0.8

0.991 ± 0.02

10.9 ± 2.1

>1,000

>1000

>5000

314.38

318.80

268.35

2.15

2.87

50.80

41.57

32.34

ꢀ0.24

ꢀ0.19

ꢀ0.03

4

9

7.1 ± 2.4

>1000

>5000

272.32

2.46

32.34

ꢀ0.17

50

51

28

52

3.1 ± 1.0

46.0 ± 7.5

39.9 ± 7.1

25.0 ± 5.5

>1000

298.34

304.39

306.40

307.39

2.27

3.64

2.21

0.90

50.80

32.34

45.23

ꢀ0.14

ꢀ0.09

ꢀ0.65

ꢀ0.85

>1000

>5000

⁄

c

⁄c

1089.5 ± 290.5

>1000

>5000

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7315

Table 2 (continued)

Compd R =

⁄

ClogP^a

logBB^b

a

4b2

a

3b4

a

7

(

a

i

1)

2

b1c

d

Mol. weight

307.39

TPSA

K

i

[nM]

K

i

[nM]

K

i

[nM]

K [nM]

53

54

55

7.1 ± 1.3

>1000

n.d.

>1000

n.d.

>5000

n.d.

0.83

45.23

ꢀ0.86

ꢀ0.29

ꢀ0.34

5.6 ± 0.9

296.37

314.41

0.33

1.58

49.64

73.47

>1000

Values are generated from 2–10 independent experiments; n. d. = not determined.

a

logP values have been calculated using the ACD/Labs Algorithm.

logBB was calculated from logP derived from using the ACD/Labs Algorithm (ACD).

Radioligand binding was increased.

b

c

⁄

heteroatom in the spacer motif can decrease afﬁnity for

a4b2

a 4-pyridyl moiety (25), the afﬁnity increased for the

type (41: K = 32.6 nM; 25: 1.03 nM). The K

a

4b2 sub-

nAChR. In contrast, compound 15, bearing a cyclopropyl ring with

i

values of the 3-pyridyl

a trans substitution pattern as a spacer motif displayed high afﬁn-

compound 41 and its less rigid counterpart (compound 39, K

i

= 39 -

⁄

ity for the

type (K

a

4b2 nAChR (K

i

= 1.2 nM), but also for the

a

3b4 sub-

nM) are very similar for

a4b2 , indicating that both spacer motifs

i

= 81.1 nM). The rigidity of the cyclopropyl spacer could

allow similar orientation in the binding pocket. When the simple

phenyl moiety of compound 16 was extended by a fused 3,4-meth-

⁄

be beneﬁcial for high afﬁnity for the

a

4b2 nAChR subtype, but dif-

ferent trans and cis arrangements needs to be explored in the fu-

ylendioxy moiety (compound 26), a K

i

value of 36.9 nM was ob-

⁄

ture to evaluate the possibility to reduce

a3b4 interaction and

tained for the

a

4b2 nAChR subtype. The extension to a 1-

⁄

maintain

a4b2 activity.

naphthyl ring system (compound 27), however, decreased the

⁄

afﬁnity for the

a

4b2 subtype (K

i

= 296.6 nM).

2

.2.4. 3,7-Diazabicyclo[3.3.1]nonane based carboxamides with

an ethenylene spacer

2.2.5. 3,7-Diazabicyclo[3.3.1]nonane based carboxamides with

an ethynylene spacer

Bispidine derivative 16, with a cinnamic acid coupled to the

⁄

bispidine backbone, showed afﬁnity in the nanomolar range

Compound 42 displayed a 5-times higher afﬁnity for the

a4b2

⁄

(K

i

= 55.1 nM) for

a

4b2 nAChR, but lacked afﬁnity for any of the

nAChR subtype (K = 10.9 nM) than its more ﬂexible analogs 32 and

i

other nAChR subtypes tested. This spacer motif exhibited more

rigidity compared to its more ﬂexible ethylene spacer (compound

16. The introduction of an electron donating methoxy group (com-

⁄

pound 43) caused a drop in afﬁnity for

a4b2 (K

i

= 241.9 nM). A

3

2). The K

i

values of both compounds (32 vs. 16) are almost iden-

similar observation was made for compound 17, which means that

ortho substitutions are less tolerated by the receptor. Small elec-

tical (K = 55.1 vs. 52.5 nM, respectively). The introduction of an

i

electron donating methoxy substituent into the ortho position of

tron donating or withdrawing groups at meta and/or para positions

⁄

the phenyl ring (compound 17) showed lower afﬁnity for the

(compounds 44-50) increased the afﬁnity for the

a

4b2 subtype

⁄

a

4b2 subtype (K

i

= 171.8 nM) compared to its unsubstituted cin-

(up to about 11 fold). For example, a methoxy group in the meta

or para position increased the afﬁnity slightly (44: K = 6.3 nM;

45: K = 7.8 nM) and a di-substitution (compound 46) resulted in

an even higher afﬁnity for the

namic acid derivative 16. However, when small electron withdraw-

ing groups were introduced in the meta (chloro: 18, bromo: 19,

i

⁄

nitro: 20) or para position (ﬂuoro: 40), compounds with higher

i

a4b2 subtype (K = 2.1 nM). The

⁄

afﬁnity for the

a

4b2 subtype (18: K

i

= 23.7 nM; 19: K

i

= 24.6 nM;

combination of a 3-chloro/4-methoxy substitution (compound

2

0: K

i

= 38.9 nM; 40: K

i

= 20.7 nM) were obtained. Also, compound

47) resulted in a compound with the highest afﬁnity in this com-

2

1 with an electron donating methoxy group in the para position

pound library (K

group displayed the same afﬁnity (K = 10.9 nM) for the a4b2

i

= 0.991 nM). Compound 48, bearing a 4-methyl

⁄

displayed a slightly higher afﬁnity (K

i

= 39.6 nM) for the

a

4b2 sub-

type compared to compound 16. So, small electron withdrawing

nAChR subtype as the unsubstituted compound 42. 3-Fluoro sub-

groups in the meta or para position increase the afﬁnity for the

stitution (compound 49) also provided a ligand with high afﬁnity

⁄

a4b2 subtype and it seems that the position of the small electron

for

a

4b2 (K

i

value of 7.1 nM). The afﬁnity of compound 50 (3,4-

= 3.13 nM) is similar to its ring open

= 2.1 nM), and both compounds pos-

withdrawing or donating substituent might be more important

methylendioxy substituent; K

3,4-dimethoxy analog 46 (K

i

than its electronic properties.

i

⁄

The afﬁnity for the

a

4b2 nAChR subtype was decreased when

sess about a 10-fold higher afﬁnity than its analog bearing a vinyl

the phenyl ring of compound 16 was replaced by smaller ﬁve-

membered, aromatic rings systems, such as furanyl (compound

spacer (26). A 1-naphthyl moiety (compound 51) decreased afﬁnity

⁄

for the

a

4b2 subtype (K

i

= 46 nM) compared to compound 42. A

2

2) or thiophenyl (compounds 23 and 24). K

87.5 nM for the 2-furanyl (22), 96.9 nM for the 2-thiophenyl

i

values were

similar observation has been made with compounds 27 versus

16. In summary, bispidine compounds bearing an ethynylene

(

23), and 57.1 nM for the 3-thiophenyl derivative (24). When the

spacer moiety along with substitutions in the meta- and/or para

⁄

phenyl ring of compound 16 was replaced by a 3-pyridyl (41) or

position are well tolerated by the

a

4b2 nAChR subtype.

7

316

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

2

.2.6. 3,7-Diazabicyclo[3.3.1]nonane based carboxamides with

1

μM applied alone

an (hetero)aryl spacer

As previously reported, the biphenyl derivative 28 has a K

i

value

⁄

0.06

of 39.9 nM for

a4b2 nAChR, and about 1,100 nM for the

a3b4 sub-

7

type. In line with the observations for compounds 31 and 36 versus

3

0, 39 versus 32, and 41 and 25 versus 16, the replacement of the

0

.04

.02

.00

phenyl moiety by 3- or 4-pyridyls increased the afﬁnity for the

a

4

⁄

4b2 nAChR subtype (3-pyridyl-phenyl derivative 52: K

i

= 25 nM;

-pyridyl-phenyl derivative 53: K

i

= 7.1 nM). Additionally, the

replacement of the phenyl ring by an imidazolyl ring (compound

⁄

5

4) also increased afﬁnity for the

a

4b2 subtype (K

i

= 5.6 nM). The

⁄

phenyl group is tolerated as a spacer motif for a4b2 nAChRs. Com-

pound 55, where a 4-pyridyl substituent was connected via a thia-

zole spacer with the bispidine amide backbone, did not show any

afﬁnity for nAChRs. Similar observations have been made on the

previous set of bispidine compounds, when heteroatoms in close

30

35 13 31 36 37 32 16 21 41 25 26 52 53 54

compounds

7

10 μM applied alone

proximity to the HBA system caused a dramatic drop in afﬁnity.

In summary, various spacer moieties like methylene, ethylene,

ethenylene, ethynylene or phenyl, between the HBA motif and

0

.4

α4β2*

⁄

(

hetero)aryl moieties are tolerated by the

a4b2 nAChR subtype,

α3β4*

α7

even with high afﬁnity and subtype selectivity.

Most compounds showed partial agonism/antagonism in initial

characterization assays using previously described electrophysiolog-

ical experiments with diverse nAChRs expressed in Xenopus oocytes

0.3

α1β1εδ

0.2

0.1

0.0

7

,23–25

(

Fig. 2).

Compounds 15, 35, 46, 47, 50, 52, 53, and 54 produced

⁄

the strongest antagonistic effects for

a4b2 receptors. Compound 35

was further evaluated and recently discovered as an in vivo active,

2

6

highly selective agent with antidepressive effect in a mouse model.

Compound 15wasthe mostpotent agonistat

⁄

a3b4 inthiscompound

3

0 35 31 36 37 38 32 39 15 16 18 40 21 24 41 25 26 42 46 47 50 52 53 54

series. No strong effects were observed for 7 subtype. Compound 46

a

had some antagonistic effect at the muscle subtype. In general, spacer

compounds

motifs lead to compounds with partial agonist/antagonist proﬁles

⁄

with the strongest effects observed for

a

4b2 nAChRs. In contrast,

1

μM co-applied with ACh

the cyclopropyl spacer (trans form) produced compound 15 with an

α4β2*

α3β4*

α7

⁄

0

.5

0.0

0.5

additional

a

3b4 agonistic proﬁle.

2

.3. Physicochemical properties and drug-likeness

α1β1εδ

Physicochemical properties and druglikeness parameters ClogP,

TPSA, and logBB were calculated using ACD/ADME Suite 5.0 (ACD/

Labs) software. Most compounds are in the range for CNS druglike-

r

ness parameter values (M : 250 and 350; ClogP: between 1 and 3;

PSA <75). Additional parameters important for CNS compounds

have been calculated (Table 3; Supplementary data) for those com-

⁄

27

pounds showing nanomolar afﬁnity for

i

a4b2 (K < 1,000 nM).

-

Most active compounds showed ‘‘good’’ values (see Table 3; Sup-

plementary data). There were no correlations between afﬁnity

and ClogP or TPSA values or rotatable bonds. Most compounds

have 2–3 rotatable bonds due to their spacer motif which had an

inﬂuence on their functionality like stated above. For the likelihood

of blood brain barrier (BBB) penetration, logBB values were calcu-

lated from logP and TPSA values where logBB values below ꢀ0.5

would reﬂect very poor or no BBB penetration and >0.7 very high

penetrants. 3,7-Diazabicyclo[3.3.1]nonane carboxamides bearing

the ethenylene or ethynylene spacer could function as Michael

acceptors, properties which should be avoided for potential drug

candidates for chronic treatment. Results derived from these com-

pounds serve as a basis for further compound proﬁling projects and

therefore an important part in this early SAR study.

3

0 35 13 31 36 37 38 32 39 15 16 18 40 21 24 41 25 26 42 46 47 50 52 53 54

compounds

Figure 2. Responses of oocytes expressing diverse nAChR subtypes to 1 or 10 lM of

selected compounds (numbering are following the sequence in the table) relative to

ACh control responses. Responses of oocytes expressing diverse nAChRs to

compounds co-applied at 1 lM with ACh compared to responses to ACh alone.

Bars above zero indicate additive effects; bars below zero indicate reduced

responses.

Selected compounds were screened for agonist and antagonist

functionality. Most compounds displayed

ity regarding their afﬁnities measured.

⁄

a

4b2 subtype selectiv-

Cytisine derivatives 4–7 were compared with the four analo-

gously substituted bispidine derivatives 30, 31, 36, and 37. Their

3

. Conclusions

⁄

afﬁnities for the

that the impact of ﬂexibility/rigidity on

a

4b2 nAChR were in the same range. It seems

⁄

a4b2 afﬁnity is of minor

In summary, we synthesized and evaluated a small set of cyti-

importance. The introduction of an additional hydrogen bond

sine (4–7) derivatives and a series of 3,7-diazabicyclo[3.3.1]nonane

carboxamide (13–55) for their afﬁnities at various nAChRs.

acceptor (HBA) motif, for example, pyridyl groups, increased the

⁄

afﬁnity for the

a

4b2 subtype in both sets of derivatives.

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7317

The incorporation of spacer moieties like methylene, ethylene,

ethenylene, ethynylene or phenyl at the 3,7-diazabicy-

(30 mg, 0.027 mmol) the reaction vessel was sealed with a septum

and placed into the microwave cavity. Microwave irradiation of

30 W was used and the temperature ramped from rt to 80 °C. Once

80 °C was reached the reaction mixture was held for 30–90 min.

before the mixture was allowed to cool to rt. The reaction vessel

was opened and the solvents were evaporated under reduced pres-

sure. The brown residue was extracted on a C-18 SPE column elut-

clo[3.3.1]nonane carboxamide template increased the afﬁnity for

⁄

the

a

4b2 nAChR. Heteroaryl substituents with HBA functionality

⁄

increased the afﬁnity for

a4b2 nAChR further.

Compounds 15, 25, and 47 with K

i

values of about 1 nM showed

⁄

the highest afﬁnities for

a4b2 nAChR.

From the electrophysiology point of view, all evaluated com-

2

ing with a mixture of MeOH/H O 70:30 or 60:40 v/v and the

aqueous solution was concentrated under reduced pressure, subse-

quently. The residue was puriﬁed on a preparative HPLC system

⁄

pounds displayed partial agonism or antagonism at

a4b2 , reduced

⁄

or no effects on

a

3b4 with the exception of compound 15 (ago-

nist), and reduced or no effect at

a7 and muscle type.

2

using RP C-18 silica gel and appropriate MeOH/H O gradients.

The chromatograms were scanned at 254 nm and the appropriate

fractions were collected. The fractions containing the desired prod-

ucts were concentrated under reduced pressure on a rotary

evaporator.

4

. Experimental section

All reagents and solvents were obtained from various suppliers

ABCR, Acros, Aldrich, Alfa Aesar, Fluka, Merck or Sigma) and used

(

without further puriﬁcation unless otherwise noted. Dichloro-

methane was freshly distilled from calcium hydride. Methanol

was treated with sodium, distilled afterwards and stored under

nitrogen. Sodium wires were used to dry diethyl ether, petroleum

ether, tetrahydrofuran, and toluene. Water was taken from a water

puriﬁcation system PureLab Plus UV (ELGA Labwater) or Direct-

Q™ 5 (Millipore). Amines were puriﬁed prior to use with a Kugel-

rohr distillation apparatus (Büchi). Reactions were monitored by

thin-layer chromatography (TLC) using aluminum sheets coated

with silica gel 60 F254 (Merck). Compounds were visualized using

4.2. General procedure B: cleavage of the N-tboc protecting

group from N-tboc protected cytisine derivatives

The concentrated aqueous solution of the N-tboc protected cyti-

sine derivative (approx. 70 mL) was put into a 80 mL microwave

glass tube, sealed and placed into the microwave cavity. Micro-

wave irradiation of 150 W was used and the temperature ramped

from rt to 150 °C. Once 150 °C was reached the reaction mixture

was held for 30 min. before the mixture was allowed to cool to

rt. The reaction vessel was opened and the solvent was evaporated

by lyophilization for at least 24 h.

UV light (254 or 365 nm) and using a KMnO

4

solution (1% in

water). Column chromatography was carried out on silica gel

(

0.035–0.060 mm) using different mixtures of CH

2

Cl

2

with MeOH

4.3. Isolation of (1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methano-8H-

pyrido[1,2-a][1,5]diazocin-8-one [(ꢀ)-cytisine] (1)

40:1, 20:1 or 9:1) or of PE with EtOAc (4:1 or 3:1) as mobile

1

13

phases. H NMR spectra (400 or 500 MHz) and C NMR spectra

100 or 125 MHz) were recorded on an Avance 400 or on an Avance

00 NMR spectrometer (Bruker). All NMR spectra were recorded at

(

5

Seeds and pods of Laburnum anagyroides watereri were collected

in the Cologne-Bonn area (Germany) in the months September and

October. The plant material was air-dried at least for 3 months and

ground to a powder consistence. The plant material was extracted

with CH Cl /MeOH/aq NH (10:4:1) through homogenization by

rt. Chemical shifts (d) are given in parts per million (ppm) relative

to the remaining protons of the deuterated solvents used as inter-

nal standard. Coupling constants J are given in Hertz (Hz) and spin

multiplicities are given as s (singlet), d (doublet), dd (doublet of

doublets), t (triplet), q (quartet), m (multiplet) and br (broad). Mass

spectra were recorded on an API 2000 mass spectrometer with an

electron spray ionization source (Applied Biosystems) coupled to

an Agilent 1100 HPLC system (LC/ESI-MS) or on a Varian 500-MS

mass spectrometer (ESI-MS). The purity of the compounds was

determined by LC/ESI-MS or a Shimadzu Prominence HPLC system

at an appropriate wavelength. HRMS runs were performed on Agi-

lent Technologies 6530 Accurate-Mass Q-TOF LC/MS. All com-

pounds proved to possess P95% purity. Melting points were

determined in open capillary tubes with a melting point apparatus

2

3

Ultra-turrax for 8 h. The evaporated solvents were replaced, ex-

actly the same amounts of each solvent were added to the homog-

enate during the extraction. The homogenate was centrifuged

(2000 ꢁ min, 40 min) and the supernatant collected. The dark

green solution was concentrated under reduced pressure to the ﬁ-

nal volume of 500 ml and extracted with 1 M HCl (3 ꢁ 100 ml). The

aqueous acid solution was rendered alkaline with 26% NH OH (pH

4

11–12) and the free base extracted with CH Cl (10 ꢁ 100 ml). The

2

organic layers were collected and the solvent evaporated in vacuo.

The dark green/brownish residue was puriﬁed by column chroma-

tography on silica gel column with CHCl /MeOH (6:1). The alkaloid

3

(

Weiss–Gallenkamp) or with a Melting Point B-540 (Büchi) and are

uncorrected. Infrared spectroscopy was performed with a Tensor-

7 FTIR infrared spectrometer (Bruker Optic) using KBr pellet or

with a Nicolet iS10 (Thermo Scientiﬁc). Elemental microanalyses

C, H, N) were performed with a VarioEL apparatus (Elementar

1 was recrystallized from perchloroethylene or directly used in the

next step (synthesis of N-tboc-cytisine 2). Isolated yields ranged

from 0.11 to 0.48% of 1 calculated from the dry weight; mp 155–

2

1

156 °C. H NMR (500 MHz, CDCl ) d 1.65 (br s, 2H), 2.03 (br s,

3

(

1H), 2.62 (br s, 1H), 2.70–2.75 (m, 4H), 3.57 (dd, J = 15.7, 6.6 Hz,

Analysensysteme) or a Costech elemental combustion apparatus

and the determined values are generally within ±0.4% of the theo-

retical values. Hydrogen for hydrogenations was produced by a Ho-

gen GC hydrogen generator (Proton Energy Systems) or by a 60H

hydrogen generator (Parker, domnick hunter). Lyophilizations

were performed with an Alpha 1-4 LSC freeze dryer (Martin Christ).

1H), 3.77 (d, J = 15.4 Hz, 1H), 5.77 (d, J = 6.9 Hz, 1H), 6.17 (d,

J = 9.1 Hz, 1H), 7.05 (dd, J = 9.1, 6.9 Hz, 1H). C NMR (125 MHz,

1

3

CDCl ) d 25.6, 27.0, 34.9, 49.1, 52.3, 53.3, 104.2, 115.7, 138.1,

3

+

150.7, 162.8. LC/ESI-MS: positive mode m/z = 190.9 ([M+H] ). Pur-

ity (>99.9%). IR (KBr, cm ) 3316, 3282, 3084, 3032, 1650, 1541,

1443, 1141, 821, 737. Anal. (C₁₁H₁₄N O 0.25H O) C, H, N.

ꢀ

1

⁄

2

4

3

.1. General procedure A: suzuki cross-coupling reaction with

-bromo-N-tboc-cytisine

4.4. 8-Oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methano-pyrido[1,2-

a][1,5]diazocine-3-carboxylic acid tert-butyl ester [N-tboc-

cytisine] (2)

3

-Bromo-N-tboc-cytisine (100 mg, 0.27 mmol), the appropriate

boronic acid (0.41 mmol), a base (0.6 mmol), DME (3 mL) and H

2

O

Cytisine

1 (500 mg, 2.63 mmol), di-tert-butyl dicarbonate

(

1 mL) were added into a 10 mL microwave glass tube. The solution

(688 mg, 3.15 mmol, 1.2 equiv) and Na CO (334 mg, 3.15 mmol,

2

3

was washed with argon for 10 min. After the addition of Pd(PPh

3

)

4

2 2 2

1.2 equiv) were stirred in 25 ml CH Cl and 6 ml H O at 60 °C for

7

318

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

1

2

h. The reaction mixture was allowed to cool to rt and 10 ml of

concentrated NaCl solution was added. The organic layer was dried

over MgSO and the solvent was evaporated. Product 2 was recrys-

tallized from PE and obtained as an off-white crystalline powder

79.8–81.6 °C. H NMR (500 MHz, CDCl

3

) d 1.96 (br s, 2H), 2.36 (br

s, 1H), 2.95 (br s, 1H), 2.99–3.03 (m, 2H), 3.06 (dd, J = 12.0,

2.2 Hz, 1H), 3.11 (d, J = 12 Hz, 1H), 3.94 (dd, J = 15.6, 6.9 Hz, 1H),

4.16 (d, J = 15.6 Hz, 1H), 6.11 (d, J = 7.3 Hz, 1H), 7.29 (ddd, J = 7.9,

4.7, 0.9 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 8.16 (ddd, J = 7.9, 2.2,

1.6 Hz, 1H), 8.49 (dd, J = 4.7, 1.6 Hz, 1H), 8.78 (d, J = 1.6 Hz, 1H).

C NMR (125 MHz, CDCl

105.0, 122.8, 123.9, 133.2, 136.1, 137.2, 148.2, 149.1, 151.5,

161.9. HRMS (EI) calcd for C16 O 267.1371, found 267.1376.

4

1

(

590–690 mg, 77–90%); mp 149–150 °C. H NMR (500 MHz, CDCl

3

)

d 1.30 (s, 9H), 1.87 (m, 1H), 1.93 (m, 1H), 2.38 (br s, 1H), 2.94–3.05

1

3

(

m, 3H), 3.79 (dd, J = 15.7, 6.6 Hz, 1H), 4.00–4.19 (m olv, 2H), 4.14

d, J = 15.4 Hz, 1H), 6.03 (br s, 1H), 6.41 (d, J = 9.1 Hz, 1H), 7.24 (dd,

3

) d 26.2, 27.8, 35.7, 50.3, 53.0, 53.9,

1

3

J = 9.1, 6.3 Hz, 1H). C NMR (125 MHz, CDCl

3

) d 26.1, 27.5, 28.0,

17 3

H N

3

1

4.8, 48.9, 50.5, 51.6, 80.3, 105.8, 117.1, 138.9, 148.7, 154.5,

+

63.4. LC/ESI-MS: positive mode m/z = 291.3 ([M+H] ). Purity

4.8. 9-Pyridin-4-yl-1,2,3,4,5,6-hexahydro-1,5-methano-

pyridino[1,2-a]diazocin-8-one) [3-(pyridin-4 -yl)cytisine] (6)

ꢀ1

0

(

>99.9%). IR (KBr, cm ) 3217, 3099, 1687, 1654, 1465, 1445,

1

421, 1364, 818, 760, 572. Anal. (C16

22 2 3

H N O ) C, H, N.

The Suzuki reaction was performed according to general proce-

4

.5. 9-Bromo-8-oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methano-

dure A with 3-bromo-N-tboc-cytisine 3 (100 mg, 0.27 mmol), 4-

pyrido[1,2-a][1,5]diazocine-3-carboxylic acid tert-butyl ester

pyridineboronic acid (49 mg, 0.41 mmol),

0.6 mmol), Pd(PPh (30 mg, 0.027 mmol), DME and H

reaction time was 90 min. For the SPE puriﬁcation a mixture of

MeOH/H O 60:40 v/v (100 mL) was used. After the HPLC puriﬁca-

K

3

PO

4

(126 mg,

[

3-bromo-N-tboc-cytisine] (3)

3

)

4

2

O. The

N-tboc-cytisine 2 (1 g, 3.44 mmol) and N-bromosuccinimide

2

(

6

613 mg, 3.44 mmol, 1 equiv) were stirred in 30 ml CH

0 °C for 2 h. The reaction mixture was allowed to cool to rt and

the solvent was evaporated in vacuo. The oily residue was dis-

solved in 150 ml MeOH/H O (60:40) and the two isomers were

2

Cl

2

at

tion, general procedure B was used for the N-tboc deprotection. Fi-

nal product 6 was obtained as a yellow solid (45 mg, 62%). mp

1

n.d. °C. H NMR (500 MHz, CDCl

3

) d 1.96 (br s, 2H), 2.36 (br s,

2

1H), 2.94 (br s, 1H), 3.00 (ddd, J = 12.3, 2.5, 1.2 Hz, 1H), 3.04 (d,

J = 12.3 Hz, 1H), 3.07 (dd, J = 12.3, 2.5 Hz, 1H), 3.11 (dd, J = 12.3,

2.5 Hz, 1H), 3.95 (dd, J = 15.8, 6.6 Hz, 1H), 4.16 (d, J = 15.8 Hz,

1H), 6.13 (d, J = 7.4 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.67 (dd,

separated and puriﬁed by preparative HPLC. Product 3 was ob-

tained in 38–52% yield as a white crystalline powder; mp 131 °C.

1

3

H NMR (500 MHz, CDCl ) d 1.30 (s, 9H), 1.94 (t, J = 13.2 Hz, 2H),

.40 (br s, 1H), 2.99-3.06 (m, 3H), 3.85 (dd, J = 15.5, 6.3 Hz, 1H),

13

2

4

7

2

1

J = 6.1, 1.6 Hz, 2H), 8.57 (dd, J = 6.1, 1.6 Hz, 2H).

(125 MHz, CDCl ) d 26.2, 27.8, 35.8, 50.3, 53.0, 53.9, 104.9, 122.8,

123.9, 137.8, 144.9, 149.6, 152.6, 161.5. HRMS (EI) calcd for

O 267.1371, found 267.1379.

C NMR

.06-4.35 (m ovl, 2H), 4.23 (d, J = 15.8 Hz, 1H), 5.96 (br s, 1H),

3

.64 (dd, J = 7.6 Hz, 1H). ¹³C NMR (125 MHz, CDCl

) d 26.0, 27.4,

3

8.0, 34.7, 49.2, 50.2, 51.4, 80.6, 105.7, 112.5, 140.8, 148.5, 154.4,

16 17 3

C H N

+

59.4. LC/ESI-MS: positive mode m/z = 369.0 and 371.0 ([M+H] ).

ꢀ1

Purity (>99.9%). IR (KBr, cm ) 3092, 2974, 1692, 1648, 1587,

1

N.

4.9. 9-(Benzo[1,3]dioxol-5-yl)-1,2,3,4,5,6-hexahydro-1,5-

⁄

0

423, 1365, 1237, 1129, 760. Anal. (C16

H21BrN

2

O

3

0.25H

2

O) C, H,

methano-pyridino[1,2-a]diazocin-8-one) [3-(3 ,4 -

methylenedioxyphenyl)cytisine] (7)

4

.6. 9-Phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyridino[1,2-

The Suzuki reaction was performed according to general pro-

a]diazocin-8-one [3-phenyl-cytisine] (4)

cedure A with 3-bromo-N-tboc-cytisine 3 (100 mg, 0.27 mmol),

3

,4-methylenedioxyphenylboronic acid (68 mg, 0.41 mmol), Na2-

CO (64 mg, 0.6 mmol), Pd(PPh (30 mg, 0.027 mmol), DME

and H O. The reaction time was 30 min. For the SPE puriﬁcation

a mixture of MeOH/H O 70:30 v/v (100 mL) was used. After the

The Suzuki reaction was performed according to general proce-

dure A with 3-bromo-N-tboc-cytisine 3 (100 mg, 0.27 mmol),

3

3 4

)

2

phenylboronic acid (50 mg, 0.41 mmol), Na

.6 mmol), Pd(PPh (30 mg, 0.027 mmol), DME and H

reaction time was 30 min. For the SPE puriﬁcation a mixture of

MeOH/H O 70:30 v/v (100 mL) was used. After the HPLC puriﬁca-

2

CO

3

(64 mg,

2

0

3

)

4

2

O. The

HPLC puriﬁcation, general procedure B was used for the N-tboc

deprotection. Final product 7 was obtained as an off-white solid

1

2

(30 mg, 36%). mp 259.1–261.6 °C. H NMR (500 MHz, CDCl

3

) d

tion, general procedure B was used for the N-tboc deprotection. Fi-

1.95 (br s, 2H), 2.34 (br s, 1H), 2.90 (br s, 1H), 3.00 (br d,

J = 12.0 Hz, 2H), 3.06 (dd, J = 12.0, 2.2 Hz, 1H), 3.11 (d,

J = 12.0 Hz, 1H), 3.93 (dd, J = 15.7, 6.6 Hz, 1H), 4.16 (d,

J = 15.7 Hz, 1H), 5.94 (br s, 2H), 6.05 (d, J = 7.3 Hz, 1H), 6.81 (d,

J = 8.2 Hz, 1H), 7.12 (dd, J = 8.2, 1.6 Hz, 1H), 7.26 (d, J = 1.6 Hz,

1H), 7.38 (d, J = 7.3 Hz, 1H). C NMR (125 MHz, CDCl ) d 26.4,

3

27.9, 35.7, 50.2, 53.0, 54.0, 100.9, 104.9, 108.0, 109.4, 122.1,

127.1, 131.4, 136.4, 146.8, 147.3, 149.9, 162.1. HRMS (EI) calcd

nal product 4 was obtained as a white solid (42 mg, 58%). mp

1

39.8–140.6 °C. H NMR (500 MHz, CDCl

3

) d 1.96 (br s, 2H), 2.34

(

br s, 1H), 2.91 (br s, 1H), 3.02 (br d, J = 12.3 Hz, 2H), 3.07 (dd,

J = 12.3, 2.2 Hz, 1H), 4.19 (d, J = 15.5 Hz, 1H), 6.09 (d, J = 7.2 Hz,

H), 7.29 (tt, J = 7.2, 1.3 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.46 (d,

1

3

1

13

J = 7.2 Hz, 1H), 7.69 (dt, J = 7.2, 1.3 Hz, 2H). C NMR (125 MHz,

CDCl ) d 26.3, 27.9, 35.7, 50.2, 53.0, 54.0, 105.0, 127.2, 127.4,

28.0, 128.6, 137.0, 137.4, 150.3, 162.1. HRMS (EI) calcd for

O 266.1419, found 266.1426.

3

1

C

for C18

18 2 3

H N O 310.1317, found 310.1324.

17

18 2

H N

4

.10. General procedure C: synthesis of N-tboc protected

4

.7. 9-Pyridin-3-yl-1,2,3,4,5,6-hexahydro-1,5-methano-

bispidinecarboxamides

0

pyridino[1,2-a]diazocin-8-one [3-(pyridin-3 -yl)cytisine] (5)

Methyl iodide (570 mg, 4 mmol) was added to a stirred solution

of 12 (320 mg, 1 mmol) dissolved in dry MeCN (2 mL) and dry THF

(2 mL) at rt. The volatiles were removed under reduced pressure

The Suzuki reaction was performed according to general proce-

dure A with 3-bromo-N-tboc-cytisine 3 (100 mg, 0.27 mmol), 3-

pyridineboronic acid (49 mg, 0.41 mmol),

.6 mmol), Pd(PPh (30 mg, 0.027 mmol), DME and H

reaction time was 60 min. For the SPE puriﬁcation a mixture of

MeOH/H O 60:40 v/v (100 mL) was used. After the HPLC puriﬁca-

K

3

PO

4

(126 mg,

3

after 24 h, the residue was dissolved in dry MeCN (4 mL), and Et N

0

3

)

4

2

O. The

(101 mg, 1 mmol) and the appropriate carboxylic acid (1 mmol)

were added. The solution was allowed to stir at rt for 12–120 h be-

fore the volatiles were removed under reduced pressure. The residue

2

tion, general procedure B was used for the N-tboc deprotection.

Final product 5 was obtained as a yellow solid (48 mg, 66%). mp

was puriﬁed by ﬂash chromatography (silica gel, mixtures of CH

and MeOH—40:1, 20:1 or 9:1).

2 2

Cl

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7319

4

.11. General procedure D: synthesis of N-tboc protected

fumaric acid was dissolved in isopropanol (3 mL) and also heated

bispidinecarboxamides

to 70–80 °C. The two solutions were combined and allowed to cool

2

to rt. Dry Et O (10 mL) were added and the mixture was kept at 4–

The appropriate carboxyl chloride (1 mmol), either neat or dis-

solved in dry toluene (1–2 mL), was added dropwise to a stirred

8 °C overnight. The solid was ﬁltered off, washed with dry Et

(3 ꢁ 5 mL), dissolved in water (20–30 mL), and freeze-dried.

2

O

solution of N-tboc-bispidine 11 (230 mg, 1 mmol) and Et

101 mg, 1 mmol) in dry toluene (5 mL) at rt. The volatiles were re-

moved under reduced pressure after 2 h and the residue was puri-

3

N

(

4.17. (1R,5S)-tert-Butyl 7-benzyl-9-oxo-3,7-

diazabicyclo[3.3.1]nonane-3-carboxylate (9)

ﬁed by ﬂash chromatography (silica gel, mixtures of CH

MeOH—40:1, 20:1 or 9:1).

2 2

Cl and

Compound 9 was obtained following the synthetic procedures

published previously. A solution of tert-butyl 4-oxopiperidine-1-

7

4

.12. General procedure E: synthesis of N-tboc protected

carboxylate 8 (10.0 g, 50.2 mmol), acetic acid (2.9 mL, 50.9 mmol),

and benzylamine (5.5 mL, 50.4 mmol) in methanol (40 mL) was

added dropwise to a stirred suspension of paraformaldehyde

(3.32 g, 110.6 mmol). The resulting mixture was heated under reﬂux

for 1 h before another portion of paraformaldehyde (3.32 g,

110.6 mmol) was added. This mixture was heated at reﬂux for addi-

tional 5 h before the reaction was allowed to cool to rt and the sol-

vent was evaporated under reduced pressure. The residue was

bispidinecarboxamides

Theappropriate carboxylic acid (1 mmol) and N-tboc-bispidine 11

248 mg, 1.1 mmol)weredissolvedindry CH Cl (5 mL) and cooled to

°C. DMAP (6.1 mg, 0.05 mmol) and DCC (206 mg, 1 mmol) were

added and the mixture was allowed to warm up and stirat rt. The pre-

cipitatewas ﬁltered offafter12 h and washed with cold CH Cl (2 mL)

(

0

2

The solvent of the ﬁltratewas evaporatedunder reducedpressureand

the residue was puriﬁedbyﬂashchromatography (silica gel, mixtures

dissolved in Et

(1 M, 2 ꢁ 80 mL). The combined aqueous layers were extracted with

Et

O (3 ꢁ 50 mL). The combined organic layers were dried with

MgSO , ﬁltered, and the solvent was evaporated under reducedpres-

2

O (150 mL) and washed with aqueous KOH solution

2

of CH Cl

2

and MeOH—40:1. 20:1 or 9:1).

2

4

.13. General procedure F: cleavage of the N-tboc protecting

sure. Flash column chromatography (silica gel, PE:EtOAc 3:1) of the

group from N-tboc protected bispidine derivatives

residue afforded a white solid 9 (13.0 g, 78%) after extensive evapo-

1

ration of the solvents; mp 83 °C. H NMR (500 MHz, CDCl

3

) d 1.53 (s,

HCl in 1,4-dioxane (4 M, 4-5 mL) was added to a stirred solution

of the N-tboc protected bispidine derivative (0.2–1.0 mmol), dis-

solved in 4–5 mL of 1,4-dioxane, and the mixture was allowed to stir

at rt for 2–12 h. The volatiles were removed under reduced pressure

and before the residue was dissolved in KOH solution (0.25 M,

9H), 2.42 (br m, 2H), 2.70 (br m, 2H), 3.17 (br m, 2H), 3.27 (br d,

J = 12.5 Hz, 1H), 3.35 (br d, J = 12.5 Hz, 1H), 3.52 (br m, 2H), 4.41

(br d, J = 12.9 Hz, 1H), 4.57 (br d, J = 12.9 Hz, 1H), 7.24–7.38 (m,

1

3

5H). C NMR (125 MHz, CDCl ) d 28.7, 47.7, 50.0, 50.6, 58.8, 59.1,

62.0, 80.2, 127.4, 128.5, 128.9, 137.5, 154.9, 213.6. LC/ESI-MS: posi-

+

ꢀ1

2

0 mL) and extracted with of CH

organic layers were washed with saturated NaHCO

10 mL), water (10 mL), dried with MgSO and ﬁltered. The product

was obtained after evaporating the solvent under reduced pressure.

2

Cl

2

(3–5 ꢁ 20 mL). The combined

tive mode m/z = 331.3 ([M+H] ). Purity (>98.5%). IR (KBr, cm

1731, 1695. Anal. (C19 ) C, H, N.

)

3

solution

26 2 3

H N O

(

4

4.18. (1R,5S)-tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-

3

-carboxylate (10)

4

.14. General procedure G: cleavage of the N-tboc protecting

group from N-tboc protected bispidine derivatives

A solution of 9 (18.9 g, 57.2 mmol), NaOH (10.0 g, 250 mmol),

and hydrazine hydrate (80%, 10.0 mL, 160 mmol) in 150 mL of

diethylene glycol was heated at 125 °C under reﬂux conditions.

After 2 h the reﬂux condenser was exchanged for a Dean–Stark

apparatus and the mixture was heated at 140 °C for additional

8 h. After cooling to rt 250 mL of water were added and the result-

ing mixture was extracted with toluene (4 ꢁ 150 mL). The com-

The N-tboc protected bispidine derivative (0.2–1.0 mmol) was

dissolved in dry CH Cl (5 mL), anhydrous ZnBr (2–3 equiv) was

2 2 2

added, and the mixture was allowed to stir at rt for 12–120 h. After

the removal of the volatiles under reduced pressure the residue

was dissolved in KOH solution (0.25 M, 20 mL) and extracted with

CH

with saturated NaHCO

MgSO , and ﬁltered. The product was obtained after evaporating

the solvent under reduced pressure.

2

Cl

2

(5 ꢁ 20 mL). The combined organic layers were washed

bined organic layers were washed with saturated NaHCO

3

solution (10 mL), water (10 mL), dried over

solution (1 ꢁ 30 mL), water (2 ꢁ 30 mL), dried with MgSO

4

and ﬁl-

4

tered. The solvent was evaporated under reduced pressure and the

residue was puriﬁed by ﬂash chromatography (silica gel, PE:EtOAc

1

4

:1) to afford 10 as a white solid (13.2 g, 73%); mp 66 °C. H NMR

4

.15. General procedure H: formation of fumaric acid salts of

3

(500 MHz, CDCl ) d 1.52 (s, 9H), 1.61 (m, 1H), 1.66 (m, 1H), 1.79 (br

bispidine derivatives

s, 1H), 1.87 (br s, 1H), 2.16 (br d, J = 10.9 Hz, 1H), 2.22 (br d,

J = 10.9 Hz, 1H), 2.89 (br d, J = 10.8 Hz, 1H), 2.99 (br d, J = 10.9 Hz,

1H), 3.05 (ddd, J = 13.1, 3.9, 1.7 Hz, 1H), 3.10 (ddd, J = 13.1, 3.9,

1.7 Hz, 1H), 3.30 (d, J = 13.5 Hz, 1H), 3.44 (d, J = 13.5 Hz, 1H), 3.99

(br d, J = 13.1 Hz, 1H), 4.16 (br d, J = 13.1 Hz, 1H), 7.19-7.34 (m,

2

The amine (0.2–1.0 mmol) was dissolved in a mixture of Et O

and MeOH (9:1, 2–5 mL). A saturated solution of fumaric acid in

the same mixture of solvents was added dropwise to a stirred solu-

tion of the amine until no further precipitation was observed. The

solution was kept at 4–8 °C overnight before the precipitate was

ﬁltered off and washed with the same mixture of solvents (2 ꢁ

1

3

5H). C NMR (125 MHz, CDCl ) d 28.9, 29.2, 31.3, 47.7, 48.6,

58.9, 59.2, 63.7, 78.9, 126.8, 128.2, 128.7, 139.1, 155.2. LC/ESI-

+

MS: positive mode m/z = 317.1 ([M+H] ). Purity (>99.5%). IR (KBr,

ꢀ1

5

3

mL) and dry Et

0 mL), and freeze-dried.

2

O (5 mL). The solid was dissolved in water (20–

28 2 2

cm ) 1681. Anal. (C19H N O ) C, H, N.

4

.19. (1R,5S)-tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-

4

.16. General procedure I: formation of fumaric acid salts of

carboxylate fumaric acid salt (11F)

bispidine derivatives

2

00 mg of Pd/C (5%) was added to a solution of 10 (1.5 g,

The amine (0.2–1.0 mmol) was dissolved in isopropanol (3–

mL), ﬁltered, and heated to 70–80 °C. The same molar amount of

4.74 mmol) in MeOH (7 mL) and the mixture was allowed to react

under an atmosphere of hydrogen (10 psi) at rt for 4 h. After the

5

7

320

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

mixture was ﬁltered and washed thoroughly with MeOH the sol-

vent was evaporated under reduced pressure. The product was ob-

tained as a clear oil (1.05 g, 4.64 mmol) in 98% yield. The free

amine 10 was used for further syntheses. General procedure H

was used to transfer this clear oil 10 (161 mg, 0.71 mmol) into a

the solvents a clear oil (375 mg, 84%) was obtained. The N-tboc

protection group of this oil (270 mg, 0.60 mmol) was cleaved using

the general procedure F for 12 h and an off-white solid 14 (192 mg,

92%) was obtained after extraction. This solid 14 (96 mg,

0.28 mmol) was transferred to its fumaric acid salt 14F by using

the general procedure I with fumaric acid (32 mg, 0.28 mmol).

Compound 14F (96 mg, 73%) was obtained as a white solid in

white solid, its fumaric acid salt 10F (200 mg, 82%); mp 170 °C

1

(

dec). H NMR (500 MHz, D

2

O) d 1.47 (s, 9H), 1.86 (br d,

1

J = 13.5 Hz, 1H), 1.96 (br d, J = 13.5 Hz, 1H), 2.25 (br s, 2H), 3.17

56% yield over three steps; mp 124–126 °C (dec). H NMR

(

br d, J = 13.2 Hz, 2H), 3.31 (br d, J = 13.2 Hz, 2H), 3.48 (br d,

2

(500 MHz, D O) d 1.83 (br d, J = 13.5 Hz, 1H), 1.95 (br d,

1

3

J = 13.2 Hz, 2H), 4.05 (br d, J = 13.2 Hz, 2H), 6.80 (s, 2.0H).

NMR (125 MHz, MeOD) d 28.2, 30.3, 30.5, 50.7, 50.9, 85.3, 137.6,

1

ity (>99.9%). IR (KBr, cm ) 3438, 1691, 1657, 985. Anal. (C12

O

C

J = 13.4 Hz, 1H), 2.21 (br s, 1H), 2.29 (br s, 1H), 2.71 (br m, 1H),

2.84-3.01 (br m, 5H), 3.29 (br m, 2H), 3.42 (br m, 2H), 3.76 (s,

3H), 3.85 (s, 6H), 4.01 (br d, J = 13.2 Hz, 1H), 4.39 (br d,

+

61.0, 174.4. LC/ESI-MS: positive mode m/z = 226.9 ([M+H] ). Pur-

ꢀ1

13

H

22

N

2-

J = 13.9 Hz, 1H), 6.63 (s, 2H), 6.67 (s, 2.0H). C NMR (125 MHz,

⁄

2

1.0C H

4 4

O

4

0.1H

2

O) C, H, N.

D

2

O) d 28.0, 28.4, 30.2, 34.1, 37.9, 48.8, 50.1, 50.5, 52.2, 58.9,

6

3.8, 108.9, 137.5, 138.1, 140.7, 155.3, 174.4, 180.0. LC/ESI-MS: po-

+

ꢀ1

4

.20. (1R,5S)-tert-Butyl 7-(1H-imidazole-1-carbonyl)-3,7-

sitive mode m/z = 349.1 ([M+H] ). Purity (>99.9%). IR (KBr, cm )

3440, 1707, 1641, 973. Anal. (C19

H, N.

⁄ ⁄

28 2 4 4 4 4 2

H N O 1.0C H O 0.75H O) C,

diazabicyclo[3.3.1]nonan-3-carboxylate (12)

N-tboc-bispidine 11 (1.5 g, 6.63 mmol) was dissolved in dry THF

(

20 mL) and CDI (1.18 g, 7.29 mmol) was added. The solution was

4.23. (1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl((1R,2R)-2-

reﬂuxed for 2 h before the solvent was evaporated under reduced

pressure. The residue was puriﬁed by ﬂash chromatography (silica

phenylcyclopropyl)methanone fumaric acid salt (15F)

gel, mixture of CH

2

Cl

2

and MeOH—20:1). Evaporation of the sol-

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-2-phenylcyclopropane-1-carboxylic

acid (162 mg, 1 mmol) for 48 h. A mixture of CH Cl and MeOH

2 2

vents afforded a white solid 12 (1.98 g, 6.2 mmol, 93%); mp

1

2

7

4

43 °C (dec). H NMR (500 MHz, CDCl

3

) d 1.43 (s, 9H), 1.87 (s,

H), 1.96 (br s, 2H), 3.01 (br m, 1H), 3.09 (br m, 1H), 3.26 (br s,

(20:1) was used for the chromatographic puriﬁcation. After re-

moval of the solvents a clear oil (326 mg, 88%) was obtained. The

N-tboc protection group of this oil (250 mg, 0.67 mmol) was

cleaved using the general procedure F for 12 h and a clear oil 15

(177 mg, 97%) was obtained after extraction. This oil 15 (67 mg,

0.25 mmol) was transferred to its fumaric acid salt 15F by using

the general procedure I with fumaric acid (29 mg, 0.25 mmol).

Compound 15F (28 mg, 28%) was obtained as a white solid in

H), 3.97 (br s, 1H), 4.25 (br m, 3H), 7.07 (s, 1H), 7.33 (s, 1H),

1

3

.89 (s, 1H). C NMR (125 MHz, CDCl

3

) d 27.8, 28.5, 31.2, 47.4,

8.8, 50.2, 51.8, 80.3, 118.0, 129.4, 137.0, 151.8, 155.0. LC/ESI-

+

MS: positive mode m/z = 321.1 ([M+H] ), negative mode m/

-

ꢀ1

z = 319.9 ([M – H] ). Purity (>99.8%). IR (KBr, cm ) 1675. Anal.

) C, H, N.

16 24 4 3

(C H N O

1

4

.21. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-(3-

24% yield over three steps; mp 101–102 °C (dec). H NMR

methylisoxazol-5-yl)ethanone fumaric acid salt (13F)

(500 MHz, D

.03 (br m, 2H), 2.23–2.60 (br m, 4H), 3.11 (br d, J = 14.0 Hz, 1H),

3.28–3.58 (br m, 5H), 4.26–4.43 (br m, 2H), 6.67 (s, 1.6H), 7.19–

2

O) d (rotamers present) 1.41–1.73 (br m, 2H), 1.90–

2

The N-tboc protected compound was obtained by using the gen-

eral procedure C with 3-methyl-5-isoxazoleacetic acid (141 mg,

1

3

2

7.45 (m, 5H). C NMR (125 MHz, D O) d (rotamers present) 17.6,

1

mmol) for 48 h. A mixture of CH

2

Cl

2

and MeOH (20:1) was used

27.3, 28.1, 28.4, 28.6, 30.3, 49.5, 50.3, 50.6, 52.3, 128.9, 129.6,

for the chromatographic puriﬁcation. After removal of the solvents

a yellowish oil (234 mg, 67%) was obtained. The N-tboc protection

group of this oil (180 mg, 0.52 mmol) was cleaved using the gen-

131.7, 137.6, 143.3, 174.5, 179.2. LC/ESI-MS: positive mode m/

+

ꢀ1

z = 271.3 ([M+H] ). Purity (>99.7%). IR (KBr, cm ) 3433, 3028,

⁄ ⁄

22 2 4 4 4 2

H N O 0.8C H O 1.25H O)

1705, 1637, 1459, 983, 972. Anal. (C17

C, H, N.

eral procedure G with anhydrous ZnBr

2

(348 mg, 1.55 mmol) for

7

2 h and an off-white solid 13 (126 mg, 98%) was obtained after

extraction. This solid 13 (74 mg, 0.30 mmol) was transferred to

its fumaric acid salt 13F by using the general procedure I with fu-

maric acid (34 mg, 0.30 mmol). Compound 13F (79 mg, 71%) was

4.24. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

phenylprop-2-en-1-one fumaric acid salt (16F)

obtained as a white solid in 46% yield over three steps; mp 168–

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-3-phenylacrylic acid (148 mg, 1 mmol)

1

69 °C (dec). H NMR (500 MHz, D

2

O) d 1.96 (br m, 1H), 2.02 (br

m, 1H), 2.29 (s, 3H), 2.35 (br s, 2H), 3.13 (br d, J = 13.9 Hz, 1H),

.30-3.40 (br m, 2H), 3.46 (br d, J = 13.2 Hz, 1H), 3.53 (br d,

J = 13.3 Hz, 2H), 4.05 (br d, J = 17.0 Hz, 1H), 4.13 (br d, J = 16.7 Hz,

2 2

for 48 h. A mixture of CH Cl and MeOH (20:1) was used for the

3

chromatographic puriﬁcation. After removal of the solvents a

white solid (256 mg, 72%) was obtained. The N-tboc protection

group of this solid (240 mg, 0.67 mmol) was cleaved using the gen-

1

3

2

H), 4.39 (br d, J = 13.9 Hz, 1H), 6.26 (s, 1H), 6.69 (s, 2.0H).

C

NMR (125 MHz, D

2

O) d 13.3, 28.0, 28.4, 30.1, 35.3, 49.1, 50.2,

2

eral procedure G with anhydrous ZnBr (303 mg, 1.35 mmol) for

5

0.5, 52.4, 108.1, 137.6, 164.7, 168.7, 174.4, 174.5. LC/ESI-MS: po-

72 h and a white solid 16 (150 mg, 87%) was obtained after extrac-

tion. This solid 16 (73 mg, 0.28 mmol) was transferred to its fuma-

ric acid salt 16F by using the general procedure I with fumaric acid

(33 mg, 0.28 mmol). Compound 16F (40 mg, 37%) was obtained as

+

ꢀ1

sitive mode m/z = 250.4 ([M+H] ). Purity (>99.5%). IR (KBr, cm

3

O) C, H, N.

)

⁄ ⁄

19 3 2 4 4 4

H N O 1.0C H O 0.6H2-

474, 3139, 1704, 1657, 970. Anal. (C13

a white solid in 23% yield over three steps; mp 155–159 °C (dec).

1

4

.22. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(3,4,5-

2

H NMR (500 MHz, D O) d 2.02 (br m,2H), 2.38 (br s, 2H), 3.20

trimethoxyphenyl)propan-1-one fumaric acid salt (14F)

(br d, J = 13.7 Hz, 1H), 3.32–3.42 (br m, 2H), 3.46–3.59 (br m,

H), 4.38 (br d, J = 12.7 Hz, 1H), 4.49 (br d, J = 13.8 Hz, 1H), 6.68

(s, 1.8H), 7.16 (d, J = 15.6 Hz, 1H), 7.49 (m, 3H), 7.59 (d,

3

The N-tboc protected compound was obtained by using the gen-

eral procedure C with 3-(3,4,5-trimethoxyphenyl)propionic acid

1

3

2

J = 15.6 Hz, 1H), 7.68 (m, 2H). C NMR (125 MHz, D O) d 28.2,

(

140 mg, 1 mmol) for 48 h. A mixture of CH

2

Cl

2

and MeOH (20:1)

28.5, 30.3, 49.4, 50.3, 50.6, 52.4, 120.5, 130.9, 132.0, 133.3, 137.5,

was used for the chromatographic puriﬁcation. After removal of

137.6, 146.5, 173.9, 174.5. LC/ESI-MS: positive mode m/z = 257.4

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7321

+

ꢀ1

(

1

[M+H] ). Purity (>99.8%). IR (KBr, cm ) 3433, 3059, 1650, 1616,

using the general procedure G with anhydrous ZnBr

2

(442 mg,

⁄

451, 975. Anal. (C16

H

20

N

2

O 0.9C H

4 4

O

4

1.2H

2

O) C, H, N.

1.96 mmol) for 48 h and a white solid 19 (206 mg, 94%) was ob-

tained after extraction. This solid 19 (132 mg, 0.39 mmol) was

transferred to its fumaric acid salt 19F by using the general proce-

dure I with fumaric acid (46 mg, 0.39 mmol). Compound 19F

4

.25. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(2-

methoxyphenyl)prop-2-en-1-one fumaric acid salt (17F)

(

97 mg, 55%) was obtained as a white solid in 40% yield over three

1

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-3-(2-methoxyphenyl)acrylic acid

2

steps; mp 142–144 °C (dec). H NMR (500 MHz, D O) d 2.00 (br m,

2H), 2.37 (br s, 2H), 3.18 (br d, J = 12.5 Hz, 1H), 3.30-3.41 (br m,

2H), 3.45-3.58 (br m, 3H), 4.31 (br d, J = 12.3 Hz, 1H), 4.46 (br d,

J = 13.1 Hz, 1H), 6.64 (s, 1.7H), 7.09 (d, J = 15.6 Hz, 1H), 7.34 (m,

1H), 7.45 (d, J = 15.6 Hz, 1H), 7.57 (m, 1H), 7.80 (m, 1H). ¹³C NMR

(

2 2

178 mg, 1 mmol) for 24 h. A mixture of CH Cl and MeOH (20:1)

was used for the chromatographic puriﬁcation. After removal of

the solvents a clear oil (335 mg, 87%) was obtained. The N-tboc

protection group of this oil (275 mg, 0.71 mmol) was cleaved using

(125 MHz, D

2

O) d 28.2, 28.5, 30.3, 49.4, 50.2, 50.5, 52.4, 121.7,

the general procedure

G

with anhydrous ZnBr

2

(481 mg,

125.2, 129.7, 133.3, 133.5, 135.7, 137.5, 139.6, 144.8, 173.4,

ꢀ1

2

.13 mmol) for 48 h and a white solid 17 (192 mg, 94%) was ob-

174.5. IR (KBr, cm ) 3423, 3054, 1703, 1649, 1474, 971. Anal. (C16-

⁄ ⁄

2 4 4 4 2

H19BrN O 0.85C H O 0.9H O) C, H, N.

tained after extraction. This solid 17 (142 mg, 0.50 mmol) was

transferred to its fumaric acid salt 17F by using the general proce-

dure I with fumaric acid (58 mg, 0.50 mmol). Compound 17F

4.28. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(3-

(

149 mg, 72%) was obtained as a white solid in 59% yield over three

nitrophenyl)prop-2-en-1-one fumaric acid salt (20F)

1

steps; mp 141-144 °C (dec). H NMR (500 MHz, D

1

3

2

O) d 1.97 (br m,

H), 2.03 (br m, 1H), 2.36 (br s, 2H), 3.17 (br d, J = 12.9 Hz, 1H),

.31-3.40 (br m, 2H), 3.47-3.58 (br m, 3H), 3.92 (s, 3H), 4.33 (br

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-3-(3-nitrophenyl)acrylic acid (193 mg,

d, J = 12.8 Hz, 1H), 4.48 (br d, J = 13.4 Hz, 1H), 6.66 (s, 2.0H), 7.07

dd, J = 7.7, 7.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.14 (d,

J = 15.7 Hz, 1H), 7.46 (m, 1H), 7.64 (dd, J = 7.7, 1.6 Hz, 1H), 7.83

2 2

1 mmol) for 24 h. A mixture of CH Cl and MeOH (20:1) was used

(

for the chromatographic puriﬁcation. After removal of the solvents

a yellow solid (294 mg, 73%) was obtained. The N-tboc protection

group of this solid (230 mg, 0.57 mmol) was cleaved using the gen-

1

3

(

4

1

d, J = 15.7 Hz, 1H). C NMR (125 MHz, D

2

O) d 28.2, 28.5, 30.3,

9.4, 50.3, 50.6, 52.4, 58.7, 115.0, 120.9, 124.1, 126.2, 131.5,

34.8, 137.5, 141.5, 160.6, 174.1, 174.4. LC/ESI-MS: positive mode

2

eral procedure G with anhydrous ZnBr (387 mg, 1.72 mmol) for

48 h and a yellow solid 20 (170 mg, 98%) was obtained after

extraction. This solid 20 (120 mg, 0.40 mmol) was transferred to

its fumaric acid salt 20F by using the general procedure I with fu-

maric acid (46 mg, 0.40 mmol). Compound 20F (97 mg, 57%) was

+

ꢀ1

m/z = 287.1 ([M+H] ). Purity (>99.8%). IR (KBr, cm ) 3432, 3044,

1

⁄ ⁄

22 2 2 4 4 4 2

H N O 1.0C H O 0.75H O) C,

705, 1645, 1462, 976. Anal. (C17

H, N.

obtained as a yellow solid in 41% yield over three steps; mp

1

4

.26. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(3-

184–187 °C (dec). H NMR (500 MHz, D

2

O) d 2.03 (br m, 2H),

chlorophenyl)prop-2-en-1-one fumaric acid salt (18F)

2.40 (br s, 2H), 3.22 (br d, J = 14.0 Hz, 1H), 3.32-3.43 (br m, 2H),

.47–3.62 (br m, 3H), 4.38 (br d, J = 13.2 Hz, 1H), 4.50 (br d,

3

The N-tboc protected compound was obtained by using the gen-

J = 13.7 Hz, 1H), 6.64 (s, 1.7H), 7.27 (d, J = 15.6 Hz, 1H), 7.58 (d,

J = 15.6 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H),

8.24 (ddd, J = 8.3, 2.3, 0.9 Hz, 1H), 8.45 (t, J = 1.9 Hz, 1H). ¹³C NMR

eral procedure

C

with trans-3-(3-chlorophenyl)acrylic acid

Cl and MeOH (20:1)

(

182 mg, 1 mmol) for 24 h. A mixture of CH

2

was used for the chromatographic puriﬁcation. After removal of

the solvents a white solid (287 mg, 73%) was obtained. The N-tboc

protection group of this solid (225 mg, 0.58 mmol) was cleaved

2

(125 MHz, D O) d 28.2, 28.5, 30.3, 49.4, 50.2, 50.5, 52.4, 123.2,

125.3, 127.4, 133.0, 137.2, 137.6, 139.1, 143.8, 151.1, 173.1,

+

174.5. LC/ESI-MS: positive mode m/z = 302.0 ([M+H] ). Purity

ꢀ1

using the general procedure G with anhydrous ZnBr

2

(389 mg,

(>99.8%). IR (KBr, cm ) 3423, 3082, 1702, 1652, 1529, 1443, 983,

⁄ ⁄

19 3 3 4 4 4 2

974. Anal. (C16H N O 0.85C H O 1.5H O) C, H, N.

1

.73 mmol) for 48 h and a white solid 18 (160 mg, 96%) was ob-

tained after extraction. This solid 18 (103 mg, 0.35 mmol) was

transferred to its fumaric acid salt 18F by using the general proce-

dure I with fumaric acid (41 mg, 0.35 mmol). Compound 18F

4.29. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(4-

methoxyphenyl)prop-2-en-1-one fumaric acid salt (21F)

(

88 mg, 62%) was obtained as a white solid in 43% yield over three

1

steps; mp 141–144 °C (dec). H NMR (500 MHz, D

H), 2.04 (br m, 1H), 2.37 (br s, 2H), 3.18 (br d, J = 13.7 Hz, 1H), 3.36

br m, 2H), 3.52 (br m, 3H), 4.33 (br d, J = 12.9 Hz, 1H), 4.47 (br d,

J = 13.9 Hz, 1H), 6.65 (s, 1.58H), 7.11 (d, J = 15.6 Hz, 1H), 7.39–7.46

2

O) d 1.99 (br m,

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-3-(4-methoxyphenyl)acrylic acid

(178 mg, 1 mmol) for 24 h. A mixture of CH Cl and MeOH (20:1)

2 2

1

(

was used for the chromatographic puriﬁcation. After removal of

the solvents a white solid (249 mg, 64%) was obtained. The N-tboc

protection group of this solid (240 mg, 0.62 mmol) was cleaved

1

3

(

m, 2H), 7.48 (d, J = 15.6 Hz, 1H), 7.54 (m, 1H), 7.66 (m, 1H).

C

2

NMR (125 MHz, D O) d 28.2, 28.5, 30.3, 49.4, 50.2, 50.5, 52.4,

1

21.7, 129.3, 130.4, 132.8, 133.3, 137.1, 137.6, 139.4, 144.9,

2

using the general procedure G with anhydrous ZnBr (418 mg,

+

73.4, 174.4. LC/ESI-MS: positive mode m/z = 291.4 ([M+H] ). Pur-

1.86 mmol) for 24 h and a white solid 21 (175 mg, 98%) was ob-

tained after extraction. This solid 21 (175 mg, 0.61 mmol) was

transferred to its fumaric acid salt 21F by using the general proce-

dure I with fumaric acid (71 mg, 0.61 mmol). Compound 21F

ꢀ1

ity (>99.8%). IR (KBr, cm ) 3427, 3058, 1702, 1649, 1475, 971.

Anal. (C16

⁄ ⁄

2 4 4 4 2

H19ClN O 0.79C H O 1.15H O) C, H, N.

4

.27. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(3-

(194 mg, 76%) was obtained as a white solid in 48% yield over three

1

bromophenyl)prop-2-en-1-one fumaric acid salt (19F)

steps; mp 169–170 °C (dec). H NMR (500 MHz, D

2

O) d 2.00 (br m,

2

H), 2.36 (br s, 2H), 3.12–3.19 (br m, 1H), 3.31–3.40 (br m, 2H),

The N-tboc protected compound was obtained by using the gen-

3.45–3.58 (br m, 3H), 3.87 (s, 3H), 4.35 (br d, J = 12.0 Hz, 1H),

4.47 (br d, J = 13.5 Hz, 1H), 6.65 (s, 2.0H), 6.99 (d, J = 15.5 Hz, 1H),

7.03 (ddd, J = 8.8, 3.0, 2.0 Hz, 2H), 7.53 (d, J = 15.5 Hz, 1H), 7.62

(ddd, J = 8.7, 2.9, 1.9 Hz, 2H). C NMR (125 MHz, D O) d 28.2,

2

28.5, 30.3, 49.4, 50.3, 50.6, 52.3, 58.3, 117.4, 117.9, 130.5, 132.8,

eral procedure

178 mg, 1 mmol) for 24 h. A mixture of CH

C

with trans-3-(3-bromophenyl)acrylic acid

Cl and MeOH (20:1)

(

2

1

3

was used for the chromatographic puriﬁcation. After removal of

the solvents a white solid (337 mg, 77%) was obtained. The N-tboc

protection group of this solid (285 mg, 0.65 mmol) was cleaved

137.6, 146.3, 163.6, 174.0, 174.5. LC/ESI-MS: positive mode m/

7

322

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

+

ꢀ1

z = 287.4 ([M+H] ). Purity (>99.8%). IR (KBr, cm ) 3427, 3032,

1

H, N.

salt 24F by using the general procedure I with fumaric acid (56 mg,

0.48 mmol). Compound 24F (129 mg, 70%) was obtained as a white

solid in 58% yield over three steps; mp 155–159 °C (dec). H NMR

⁄ ⁄

22 2 2 4 4 4 2

H N O 1.0C H O 0.75H O) C,

737, 1650, 1604, 979. Anal. (C17

1

(

2

500 MHz, D O) d 1.97 (br m, 1H), 2.02 (br m, 1H), 2.36 (br s, 2H),

4

.30. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

3.17 (br d, J = 12.2 Hz, 1H), 3.30–3.40 (br m, 2H), 3.45–3.58 (br m,

3H), 4.34 (br d, J = 12.5 Hz, 1H), 4.47 (br d, J = 13.3 Hz, 1H), 6.66 (s,

(

furan-2-yl)prop-2-en-1-one fumaric acid salt (22F)

1

.8H), 6.97 (d, J = 15.4 Hz, 1H), 7.47 (dd, J = 5.1, 1.1 Hz, 1H), 7.52

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-3-(furan-2-yl)acrylic acid (138 mg,

mmol) for 72 h. A mixture of CH Cl and MeOH (40:1) was used

for the chromatographic puriﬁcation. After removal of the solvents

an orange solid (176 mg, 51%) was obtained. The N-tboc protection

group of this solid (175 mg, 0.51 mmol) was cleaved using the gen-

(dd, J = 5.1, 3.0 Hz, 1H), 7.59 (d, J = 15.4 Hz, 1H), 7.74 (dd, J = 2.8,

1.1 Hz, 1H). C NMR (125 MHz, D O) d 28.2, 28.5, 30.3, 49.4,

2

1

3

1

2

50.3, 50.6, 52.3, 119.6, 128.0, 130.5, 131.8, 137.5, 140.4, 140.5,

+

174.1, 174.4. LC/ESI-MS: positive mode m/z = 263.4 ([M+H] ). Pur-

ꢀ1

ity (>99.8%). IR (KBr, cm ) 3428, 3087, 1705, 1647, 1594, 973.

⁄

Anal. (C14H N OS 0.9C H O 0.9H O) C, H, N.

18 2 4 4 4 2

eral procedure G with anhydrous ZnBr

2

(341 mg, 1.52 mmol) for

1

2 h and an orange oil 22 (84 mg, 68%) was obtained after extrac-

4.33. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

tion. This oil 22 (84 mg, 0.34 mmol) was transferred to its fumaric

acid salt 22F by using the general procedure I with fumaric acid

(pyridin-4-yl)prop-2-en-1-one fumaric acid salt (25F)

(

40 mg, 0.34 mmol). Compound 22F (65 mg, 51%) was obtained

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-3-(pyridin-4-yl)acrylic acid (149 mg,

1 mmol) for 24 h. A mixture of CH Cl and MeOH (9:1) was used

2 2

for the chromatographic puriﬁcation. After removal of the solvents

a white solid (243 mg, 68%) was obtained. The N-tboc protection

group of this solid (185 mg, 0.52 mmol) was cleaved using the gen-

as an orange solid in 18% yield over three steps; mp 142–144 °C

1

(

dec). H NMR (500 MHz, D

2

O) d 2.00 (br m, 1H), 2.09 (br m, 1H),

.32 (br s, 2H), 3.30-3.40 (br m, 4H), 3.51 (br s, 2H), 4.48 (br s,

H), 6.58 (dd, J = 3.4, 1.7 Hz, 1H), 6.72 (s, 2.0H), 6.77 (d,

2

J = 3.4 Hz, 1H), 7.05 (d, J = 15.2 Hz, 1H), 7.45 (d, J = 15.2 Hz, 1H),

7

4

.65 (d, J = 1.7 Hz, 1H). ¹³C NMR (125 MHz, D

9.0, 113.7, 115.8, 116.5, 131.4, 136.5, 146.3, 153.2, 171.1, 171.7.

O) d 27.7, 29.5,

2

eral procedure G with anhydrous ZnBr (350 mg, 1.55 mmol) for

48 h and an off-whiteoil 25 (116 mg, 87%) was obtained after extrac-

tion. This oil 25 (63 mg, 0.24 mmol) was transferred to its fumaric

acid salt 25F by using the general procedure I with fumaric acid

(28 mg, 0.24 mmol). Compound 25F (70 mg, 72%) was obtained as

+

LC/ESI-MS: positive mode m/z = 247.4 ([M+H] ). Purity (>99%). IR

ꢀ1

(

KBr, cm ) 3426, 3095, 1679, 1648, 1608, 984, 968. Anal. (C14H

18-

⁄ ⁄

2 2 4 4 4 2

O 1.0C H O 0.75H O) C, H, N.

N

a white solid in 43% yield over three steps; mp 155–159 °C (dec).

1

4

.31. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

2

H NMR (500 MHz, D O) d 2.02 (br m, 2H), 2.38 (br s, 1H), 2.40 (br

(

thiophen-2-yl)prop-2-en-1-one fumaric acid salt (23F)

s, 1H), 3.24 (br d, J = 14.7 Hz, 1H), 3.33–3.41 (br m, 2H), 3.49 (br d,

J = 13.3 Hz, 1H), 3.54–3.62 (br m, 2H), 4.33 (br d, J = 13.2 Hz, 1H),

4.48 (br d, J = 13.9 Hz, 1H), 6.58 (s, 2.0H), 7.56 (s, 2H), 8.02 (d,

J = 6.7 Hz, 1H); 8.70 (d, J = 6.2 Hz, 1H). C NMR (125 MHz, D O) d

2

28.1, 28.4, 30.2, 49.4, 50.1, 50.4, 52.5, 127.3, 130.4, 138.0, 140.4,

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-3-(thiophen-2-yl)acrylic acid (154 mg,

mmol) for 24 h. A mixture of CH Cl and MeOH (20:1) was used

1

3

1

2

for the chromatographic puriﬁcation. After removal of the solvents

a clear oil (220 mg, 61%) was obtained. The N-tboc protection

group of this oil (170 mg, 0.47 mmol) was cleaved using the gen-

146.6, 152.7, 172.2, 176.2. LC/ESI-MS: positive mode m/z = 258.4

+

ꢀ1

([M+H] ). Purity (>99.9%). IR (KBr, cm ) 3427, 3038, 1699, 1653,

⁄ ⁄

19 3 4 4 4 2

1602, 982. Anal. (C15H N O 1.0C H O 1.25H O) C, H, N.

eral procedure G with anhydrous ZnBr

2

(317 mg, 1.41 mmol) for

4

8 h and a clear oil 23 (122 mg, 99%) was obtained after extraction.

4.34. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-one fumaric acid salt

(26F)

This oil 23 (44 mg, 0.17 mmol) was transferred to its fumaric acid

salt 23F by using the general procedure I with fumaric acid (19 mg,

0

.17 mmol). Compound 23F (24 mg, 37%) was obtained as an off-

white solid in 22% yield over three steps; mp 173–178 °C (dec).

H NMR (500 MHz, D O) d 1.87–2.06 (br m, 2H), 2.33–2.48 (br m,

2

The N-tboc protected compound was obtained by using the gen-

eral procedure C with trans-3-(benzo[d][1,3]dioxol-5-yl)acrylic

1

2

3

H), 3.13–3.24 (br m, 1H), 3.30–3.58 (br m, 5H), 4.30–4.52 (br m,

H), 6.67 (s, 2.0H), 6.91 (d, J = 15.2 Hz, 1H), 7.15 (dd, J = 5.1,

.6 Hz, 1H), 7.42 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 5.1, 1H), 7.75 (d,

2 2

acid (192 mg, 1 mmol) for 72 h. A mixture of CH Cl and MeOH

(40:1) was used for the chromatographic puriﬁcation. After re-

moval of the solvents a white solid (284 mg, 71%) was obtained.

The N-tboc protection group of this solid (235 mg, 0.59 mmol)

was cleaved using the general procedure F for 2 h and an off-white

solid 26 (128 mg, 73%) was obtained after extraction. This solid 26

(128 mg, 0.43 mmol) was transferred to its fumaric acid salt 26F by

1

3

J = 15.2, 1H). C NMR (125 MHz, D

2

O) d 28.2, 28.5, 30.3, 49.4,

5

1

0.3, 50.6, 52.3, 118.6, 131.4, 132.0, 134.5, 137.6, 139.5, 142.4,

73.5, 174.5. LC/ESI-MS: positive mode m/z = 263.4 ([M+H] ). Pur-

+

ꢀ1

ity (>99.8%). IR (KBr, cm ) 3441, 3074, 1700, 1638, 1600, 968.

Anal. (C14

⁄

H

18

N

2

OS 1.0C

4 4

H O

4

0.6H

2

O) C, H, N.

using the general procedure

.43 mmol). Compound 26F (106 mg, 58%) was obtained as an

off-white solid in 30% yield over three steps; mp 147–148 °C

I with fumaric acid (49 mg,

0

4

.32. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

1

(

thiophen-3-yl)prop-2-en-1-one fumaric acid salt (24F)

(dec). H NMR (500 MHz, D

2

O) d 1.97 (br m, 1H), 2.03 (br m, 1H),

2

.37 (s, 2H), 3.16 (br d, J = 12.2 Hz, 1H), 3.31–3.41 (br m, 2H),

The N-tboc protected compound was obtained by using the gen-

3.44–3.58 (br m, 3H), 4.34 (br d, J = 11.6 Hz, 1H), 4.46 (br d,

J = 13.2, 1H), 6.02 (s, 2H), 6.65 (s, 2.0H), 6.91 (d, J = 8.0 Hz, 1H),

6.94 (d, J = 15.3 Hz, 1H), 7.12 (dd, J = 8.1, 1.6 Hz, 1H), 7.19 (d,

J = 1.6 Hz, 1H), 7.47 (d, J = 15.4 Hz, 1H). C NMR (125 MHz, D O)

2

d 28.1, 28.5, 30.3, 49.4, 50.3, 50.6, 52.3, 104.6, 109.3, 111.6,

eral procedure C with trans-3-(thiophen-3-yl)acrylic acid (154 mg,

mmol) for 24 h. A mixture of CH Cl and MeOH (20:1) was used

1

2

1

3

for the chromatographic puriﬁcation. After removal of the solvents

a white solid (312 mg, 86%) was obtained. The N-tboc protection

group of this solid (240 mg, 0.66 mmol) was cleaved using the gen-

118.0, 127.6, 131.9, 137.5, 146.5, 150.8, 152.0, 173.9, 174.3. LC/

+

eral procedure G with anhydrous ZnBr

8 h and a clear oil 24 (168 mg, 97%) was obtained after extraction.

This oil 24 (126 mg, 0.48 mmol) was transferred to its fumaric acid

2

(447 mg, 1.98 mmol) for

ESI-MS: positive mode m/z = 301.4 ([M+H] ). Purity (>99.5%). IR

ꢀ1

4

(KBr, cm ) 3434, 3054, 1706, 1646, 1607, 1448, 976. Anal. (C17H

20-

⁄ ⁄

2 3 4 4 4 2

N O 1.0C H O 0.75H O) C, H, N.

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7323

4

.35. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

29F (46 mg, 44%) was obtained as a white solid in 42% yield over

1

(

naphthalen-1-yl)prop-2-en-1-one fumaric acid salt (27F)

three steps; mp 162–165 °C (dec). H NMR (500 MHz, D

.99 (br m, 1H), 2.07 (br m, 1H), 2.27 (br s, 2H), 3.35-3.37 (br m,

2H), 3.37-3.40 (br m, 2H), 3.46 (br d, J = 13.1 Hz, 1H), 3.98 (br m,

2

O) d

1

The N-tboc protected compound was obtained by using the gen-

13

eral procedure

C

with trans-3-(naphthalene-1-yl)acrylic acid

Cl and MeOH (20:1)

1H), 4.56 (br s, 1H), 6.73 (s, 1.8H), 7.53 (m, 5H).

(125 MHz, D O) d 27.3, 29.1, 48.3, 48.5, 128.3, 129.7, 131.2,

136.2, 136.8, 171.3, 175.4. LC/ESI-MS: positive mode m/z = 231.4

C NMR

(

198 mg, 1 mmol) for 48 h. A mixture of CH

2

was used for the chromatographic puriﬁcation. After removal of

the solvents a white solid (344 mg, 85%) was obtained. The N-tboc

protection group of this solid (270 mg, 0.66 mmol) was cleaved

+

ꢀ1

([M+H] ). Purity (>99.9%). IR (KBr, cm ) 3420, 1701, 1613, 987,

⁄ ⁄

18 2 4 4 4 2

969. Anal. (C14H N O 0.9C H O 1.5H O) C, H, N.

using the general procedure G with anhydrous ZnBr

2

(449 mg,

1

.99 mmol) for 72 h and an off-white solid 27 (196 mg, 96%) was

4.38. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-

obtained after extraction. This solid 27 (119 mg, 0.39 mmol) was

transferred to its fumaric acid salt 27F by using the general proce-

dure I with fumaric acid (45 mg, 0.39 mmol). Compound 27F

phenylethanone fumaric acid salt (30F)

The N-tboc protected compound was obtained by using the gen-

(

103 mg, 61%) was obtained as a white solid in 50% yield over three

eral procedure D with phenylacetyl chloride (155 mg, 1 mmol). A

mixture of CH Cl and MeOH (20:1) was used for the chromato-

2 2

1

steps; mp 171–174 °C (dec). H NMR (500 MHz, D

2

O) d 1.86 (br d,

J = 13.3 Hz, 1H), 1.97 (br d, J = 13.4 Hz, 1H), 2.21 (br s, 1H), 2.32 (br

s, 1H), 3.03 (br d, J = 13.0 Hz, 1H), 3.20 (br d, J = 12.3 Hz, 1H), 3.30

graphic puriﬁcation. After removal of the solvents a white solid

(343 mg, 98%) was obtained. The N-tboc protection group of this

solid (310 mg, 0.90 mmol) was cleaved using the general proce-

dure F for 12 h and an off white solid 30 (210 mg, 97%) was ob-

tained after extraction. This solid 30 (180 mg, 0.74 mmol) was

transferred to its fumaric acid salt 30F by using the general proce-

dure H. Compound 30F (158 mg, 66%) was obtained as a white so-

(

br d, J = 13.0 Hz, 2H), 3.44 (br d, J = 13.4 Hz, 2H), 4.15 (br d,

J = 12.3 Hz, 1H), 4.41 (br d, J = 13.4 Hz, 1H), 6.61 (s, 1.9H), 6.96 (d,

J = 15.3 Hz, 1H), 7.50 (dd, J = 7.8, 7.7 Hz, 1H), 7.56 (m, 2H), 7.74

(

d, J = 7.2 Hz, 1H), 7.91 (dd, J = 7.7, 6.7 Hz, 2H), 8.13 (d, J = 8.2 Hz,

1

2

1

H), 8.21 (d, J = 15.3 Hz, 1H). ¹³C NMR (125 MHz, D

2

O) d 28.1,

1

8.4, 30.2, 49.3, 50.2, 50.5, 52.2, 122.8, 126.0, 127.9, 128.6, 129.3,

30.0, 131.6, 133.3, 133.8, 134.5, 136.2, 137.5, 143.0, 173.4,

lid in 62% yield over three steps; mp 145–147 °C (dec). H NMR

(500 MHz, D O) d 1.91 (br m, 1H), 1.97 (br m, 1H), 2.27 (br s,

2

+

74.3. LC/ESI-MS: positive mode m/z = 307.5 ([M+H] ). Purity

1H), 2.32 (br s, 1H), 2.78 (br d, J = 13.4 Hz, 1H), 3.27–3.33 (br m,

3H), 3.39 (br d, J = 12.9 Hz, 1H), 3.45 (br d, J = 13.2 Hz, 1H), 3.85–

3.97 (br m, 2H), 4.17 (br d, J = 13.2 Hz, 1H), 4.40 (br d, J = 13.7 Hz,

ꢀ1

(

>99.9%). IR (KBr, cm ) 3433, 3048, 1701, 1643, 1601, 1458, 970.

⁄

Anal. (C20

H

22

N

2

O 0.95C

4 4

H O

4

2

1.1H O) C, H, N.

1

3

1

2

H), 6.69 (s, 0.9H), 7.27–7.45 (m, 5H). C NMR (125 MHz, D O) d

4

.36. (1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl(biphenyl-4-

28.0, 28.3, 30.2, 43.5, 49.1, 50.2, 50.6, 52.5, 130.2, 131.9, 132.1,

yl)methanone fumaric acid salt (28F)

137.3, 138.0, 176.5, 178.8. LC/ESI-MS: positive mode m/z = 245.4

+

ꢀ1

(

[M+H] ). Purity (>99%). IR (KBr, cm ) 3443, 3031, 1696, 1640,

⁄

The N-tboc protected compound was obtained by using the gen-

1457, 984, 969. Anal. (C15

20

H N

O 0.45C H

2 4 4

O

4

2

1.5H O) C, H, N.

eral procedure C with 4-biphenylcarboxylic acid (198 mg, 1 mmol)

for 12 h. A mixture of CH

2

Cl

2

and MeOH (40:1) was used for the

4.39. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-(pyridine-

chromatographic puriﬁcation. After removal of the solvents a clear

oil (293 mg, 72%) was obtained. The N-tboc protection group of this

oil (250 mg, 0.61 mmol) was cleaved using the general procedure F

for 12 h and a clear oil 28 (141 mg, 75%) was obtained after extrac-

tion. This oil 28 (60 mg, 0.20 mmol) was transferred to its fumaric

acid salt 28F by using the general procedure I with fumaric acid

3-yl)ethanone fumaric acid salt (31F)

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 2-(pyridine-3-yl)acetic acid (137 mg, 1 mmol)

for 12 h. A mixture of CH Cl and MeOH (20:1) was used for the chro-

2 2

matographic puriﬁcation. After removal of the solvents a white solid

(262 mg, 76%) was obtained. The N-tboc protection group of this so-

lid (222 mg, 0.64 mmol) was cleaved using the general procedure F

for 2 h and a clear oil 31 (143 mg, 90%) was obtained after extraction.

This oil 31 (143 mg, 0.58 mmol) was transferred to its fumaric acid

salt 31F by using the general procedure I with fumaric acid

(67 mg, 0.58 mmol). Compound 31F (96 mg, 47%) was obtained as

(

23 mg, 0.20 mmol). Compound 28F (54 mg, 63%) was obtained

as a white solid in 34% yield over three steps; mp 148–150 °C

1

(

2

(

4

dec). H NMR (500 MHz, D

.43 (br s, 1H), 3.30–3.41 (br m, 3H), 3.42–3.54 (br m, 3H), 3.91

br m, 1H), 4.53 (br m, 1H), 6.67 (s, 2.0H), 7.48 (m, 1H), 7.56 (m,

2

O) d 1.99 (br m, 2H), 2.20 (br s, 1H),

1

3

H), 7.74 (d, J = 7.9 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H). C NMR

O) d 28.0, 28.5, 30.3, 49.4, 49.6, 50.6, 54.8, 129.9,

(

125 MHz, D

2

a white solid in 32% yield over three steps; mp 166–168 °C (dec).

1

30.0, 130.5, 131.2, 132.1, 136.2, 137.6, 142.4, 145.5, 174.6,

2

H NMR (400 MHz, D O) d 1.97 (br d, J = 13.6 Hz, 1H), 2.03 (br d,

+

77.8. LC/ESI-MS: positive mode m/z = 307.5 ([M+H] ). Purity

J = 13.3 Hz, 1H), 2.36 (br s, 2H), 3.14 (br d, J = 13.5 Hz, 1H), 3.30–

3.42 (br m, 2H), 3.46 (br d, J = 13.0 Hz, 1H), 3.53–3.64 (br m, 2H),

4.04 (br d, J = 18.1 Hz, 1H), 4.19 (br d, J = 12.2 Hz, 1H), 4.22 (br d,

J = 17.1 Hz, 1H), 4.38 (br d, J = 13.9 Hz, 1H), 6.55 (s, 1.84H), 7.91

(dd, J = 7.9, 5.8 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.61 (s, 1H), 8.67 (d,

ꢀ1

(

>99.9%). IR (KBr, cm ) 3427, 1705, 1624, 982, 970. Anal. (C20H

22-

⁄ ⁄

2 4 4 4 2

O 1.0C H O 0.9H O) C, H, N.

N

4

.37. (1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-

1

3

yl(phenyl)methanone fumaric acid salt (29F)

J = 5.3 Hz, 1H). C NMR (100 MHz, D

2

O) d 25.8, 26.2, 27.9, 37.9,

4

7.0, 48.0, 48.2, 49.8, 126.9, 135.3, 142.1, 144.4, 147.0, 174.2,

+

The N-tboc protected compound was obtained by using the gen-

eral procedure D with benzoyl chloride (141 mg, 1 mmol). A mix-

174.3. ESI-MS: positive mode m/z = 246.3 ([M+H] ). Purity

(>99.9%). IR (cm ) 2926, 2859, 1699, 1640, 1219, 1106, 970, 639.

Anal. (C14H N O 1.0C H O 0.4H O) C, H, N.

ꢀ1

⁄

ture of CH

2

Cl

2

and MeOH (20:1) was used for the

19 3 4 4 4 2

chromatographic puriﬁcation. After removal of the solvents a

white solid (325 mg, 97%) was obtained. The N-tboc protection

group of this solid (200 mg, 0.61 mmol) was cleaved using the gen-

eral procedure F for 12 h and an off white solid 29 (138 mg, 99%)

was obtained after extraction. This solid 29 (67 mg, 0.29 mmol)

was transferred to its fumaric acid salt 29F by using the general

procedure I with fumaric acid (34 mg, 0.29 mmol). Compound

4.40. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

phenylpropan-1-one fumaric acid salt (32F)

The N-tboc protected compound was obtained by using the gen-

eral procedure D with 3-phenylpropionic acid chloride (169 mg,

1 mmol). A mixture of CH Cl and MeOH (20:1) was used for the

2 2

7

324

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

chromatographic puriﬁcation. After removal of the solvents a

white solid (355 mg, 97%) was obtained. The N-tboc protection

group of this solid (340 mg, 0.95 mmol) was cleaved using the gen-

eral procedure F for 12 h and a clear oil 32 (235 mg, 96%) was ob-

tained after extraction. This oil 32 (103 mg, 0.40 mmol) was

transferred to its fumaric acid salt 32F by using the general proce-

dure I with fumaric acid (46 mg, 0.40 mmol). Compound 32F

50.7, 136.4, 172.5, 173.7. LC/ESI-MS: positive mode m/z = 335.2

+

([M+H] ). HRMS (EI) calcd for C15

H

15

F

5

N

2

O 335.1177, found

ꢀ1

335.1186. Purity (>99%). IR (cm ) 1669, 1657, 1506, 1410, 1222,

⁄ ⁄

1004, 974, 642. Anal. (C15H F N O 1.0C H O 0.4H O) C, H, N.

15 5 2 4 4 4 2

4.43. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-(4-

(methylsulfonyl)phenyl)ethanone fumaric acid salt (35F)

(

115 mg, 75%) was obtained as a white solid in 70% yield over three

1

steps; mp 153–156 °C (dec). H NMR (500 MHz, D

2

O) d 1.86 (br m,

The N-tboc protected compound was obtained by using the gen-

1

2

3

H), 1.94 (br m, 1H), 2.22 (br s, 1H), 2.29 (br s, 1H), 2.78 (br m, 1H),

.88 (br m, 1H), 2.90–2.96 (br m, 1H), 2.99 (br d, J = 14.0 Hz, 1H),

.14 (br d, J = 13.7 Hz, 1H), 3.27 (br m, 2H), 3.39 (br m, 2H), 4.02

eral procedure

(214 mg, 1 mmol) for 12 h. A mixture of CH

E

with 4-(methylsulfonyl)phenylacetic acid

Cl and MeOH (40:1)

2

was used for the chromatographic puriﬁcation. After removal of

the solvents a white solid (296 mg, 70%) was obtained. The N-tboc

protection group of this solid (246 mg, 0.58 mmol) was cleaved

using the general procedure F for 2 h and a white solid 35

(147 mg, 78%) was obtained after extraction. This solid 35

(147 mg, 0.46 mmol) was transferred to its fumaric acid salt 35F

by using the general procedure I with fumaric acid (53 mg,

(

br d, J = 13.5 Hz, 1H), 4.37 (br d, J = 14.1 Hz, 1H), 6.69 (s, 2.0H),

7

3

1

.30 (m, 3H), 7.38 (m, 2H). ¹³C NMR (125 MHz, D

2

O) d 28.0, 28.3,

0.1, 33.6, 37.9, 48.8, 50.2, 50.6, 52.2, 129.4, 131.4, 131.7, 137.5,

43.7, 174.4, 180.2. LC/ESI-MS: positive mode m/z = 259.5

+

ꢀ1

(

[M+H] ). Purity (>99.8%). IR (KBr, cm ) 3433, 3054, 1701, 1645,

⁄ ⁄

22 2 4 4 4 2

H N O 1.0C H O 0.5H O) C, H, N.

1

454, 984. Anal. (C16

0

.46 mmol). Compound 35F (121 mg, 61%) was obtained as a white

1

4

.41. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-(2-

solid in 33% yield over three steps; mp 188–191 °C (dec). H NMR

(400 MHz, D O) d 1.93 (br d, J = 13.5 Hz, 1H), 2.01 (br d, J = 13.6 Hz,

H), 2.33 (br s, 2H), 3.11 (br d, J = 13.2 Hz, 1H), 3.27 (s, 3H), 3.29–

chlorophenoxy)ethanone fumaric acid salt (33F)

2

1

The N-tboc protected compound was obtained by using the gen-

3.39 (br m, 2H), 3.42–3.57 (br m, 3H), 4.03 (s, 2H), 4.16 (br d,

eral procedure C with (2-chlorophenoxy)acetic acid (187 mg,

J = 13.2 Hz, 1H), 4.39 (br d, J = 13.9 Hz, 1H), 6.68 (s, 1.90H), 7.51

1

3

1

mmol) for 24 h. A mixture of CH

2

Cl

2

and MeOH (20:1) was used

(d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H). C NMR (100 MHz,

O) d 25.8, 26.2, 27.9, 41.0, 44.0, 46.9, 48.0, 48.3, 50.1, 128.0,

131.5, 135.4, 138.1, 142.4, 172.1, 175.5. ESI-MS: positive mode

for the chromatographic puriﬁcation. After removal of the solvents

a clear oil (186 mg, 47%) was obtained. The N-tboc protection

group of this oil (130 mg, 0.33 mmol) was cleaved using the gen-

eral procedure F for 12 h and a white solid 33 (95 mg, 98%) was ob-

tained after extraction. This solid 33 (46 mg, 0.16 mmol) was

transferred to its fumaric acid salt 33F by using the general proce-

dure I with fumaric acid (18 mg, 0.16 mmol). Compound 33F

D

2

+

m/z = 323.3 ([M+H] ). HRMS (EI) calcd for C16

H

22

N

2

O

3

S 323.1424,

ꢀ1

found 323.1416. Purity (>99.9%). IR (cm ) 2930, 2857, 2720,

2626, 1652, 1582, 1253, 1144, 962, 751, 634. Anal. (C16

⁄

-

22

H N

2

O

3

S

⁄

1.0C H

4 4

O

4

0.7H

2

O) C, H, N.

(

40 mg, 62%) was obtained as a white solid in 29% yield over three

4.44. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-(pyridine-

4-yl)ethanone fumaric acid salt (36F)

1

steps; mp 145–149 °C (dec). H NMR (500 MHz, D

H), 2.34 (br s, 1H), 2.37 (br s, 1H), 3.18 (br d, J = 13.4 Hz, 1H), 3.35

br m, 2H), 3.49 (br d, J = 13.1 Hz, 1H), 3.59 (br m, 2H), 4.00 (br d,

J = 13.2 Hz, 1H), 4.38 (br d, J = 13.9 Hz, 1H), 4.85 (br d, J = 14.3 Hz,

H), 5.15 (br d, J = 14.6 Hz, 1H), 6.68 (s, 1.8H), 7.07 (m, 2H), 7.33

m, 1H), 7.50 (dd, J = 8.2, 1.3 Hz, 1H). ¹³C NMR (125 MHz, D

O) d

2

O) d 2.02 (br m,

2

(

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 2-(pyridine-4-yl)acetic acid (137 mg, 1 mmol)

for 12 h. A mixture of CH Cl and MeOH (20:1) was used for the chro-

2 2

matographic puriﬁcation. After removal of the solvents a white solid

(276 mg, 80%) was obtained. The N-tboc protection group of this so-

lid (220 mg, 0.64 mmol) was cleaved using the general procedure F

for 2 h and a clear oil 36 (128 mg, 82%) was obtained after extraction.

This oil 36 (128 mg, 0.52 mmol) was transferred to its fumaric acid

salt 36F by using the general procedure I with fumaric acid

(61 mg, 0.52 mmol). Compound 36F (157 mg, 74%) was obtained

1

(

2

1

2

8.0, 28.2, 30.2, 49.0, 50.2, 50.5, 51.2, 70.1, 117.2, 124.7, 125.8,

31.2, 133.3, 137.5, 155.5, 174.2, 176.4. LC/ESI-MS: positive mode

+

ꢀ1

m/z = 295.1 ([M+H] ). Purity (>97%). IR (KBr, cm ) 3441, 3065,

1

⁄ ⁄

2 2 4 4 4 2

H19ClN O 0.9C H O 0.8H O) C, H, N.

662, 1457, 970. Anal. (C15

4

.42. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-(2,3,4,5,6-

pentaﬂuorophenyl)ethanone fumaric acid salt (34F)

as a white solid in 48% yield over three steps; mp 174–175 °C

1

(

dec). H NMR (400 MHz, D

2

O) d 1.97 (br d, J = 13.6 Hz, 1H), 2.03

The N-tboc protected compound was obtained by using the gen-

(br d, J = 13.4 Hz, 1H), 2.37 (br s, 2H), 3.14 (br d, J = 13.5 Hz, 1H),

3.30–3.42 (br m, 2H), 3.47 (br d, J = 13.2 Hz, 1H), 3.54–3.63 (br m,

2H), 4.15 (br d, J = 12.6 Hz, 1H), 4.19–4.32 (m, 2H, exchangeable),

4.38 (br d, J = 13.9 Hz, 1H), 6.62 (s, 2.80H), 7.93 (d, J = 6.3 Hz, 2H),

eral procedure

226 mg, 1 mmol) for 12 h. A mixture of CH

E

with 2,3,4,5,6-pentaﬂuorophenylacetic acid

Cl and MeOH (20:1)

(

2

was used for the chromatographic puriﬁcation. After removal of

the solvents a white solid (370 mg, 85%) was obtained. The N-tboc

protection group of this solid (200 mg, 0.46 mmol) was cleaved

using the general procedure F for 4 h and a white solid 34

1

3

2

8.72 (d, J = 6.3 Hz, 2H). C NMR (100 MHz, D O) d 25.8, 26.2, 27.8,

40.8, 46.9, 48.0, 48.2, 49.9, 129.5, 135.6, 141.5, 157.0, 173.08,

+

173.14. ESI-MS: positive mode m/z = 246.3 ([M+H] ). HRMS (EI)

(

149 mg, 97%) was obtained after extraction. This solid 34

145 mg, 0.43 mmol) was transferred to its fumaric acid salt 34F

calcd for C14

H

19

N

3

O 246.1601, found 246.1591. Purity (>99.9%). IR

ꢀ1

(cm ) 2971, 2848, 1671, 1568, 1404, 1271, 976, 784, 631, 590. Anal.

⁄

by using the general procedure I with fumaric acid (50 mg,

.43 mmol). Compound 34F (149 mg, 79%) was obtained as a white

(C14H N O 1.0C H O 1.3H O) C, H, N.

19 3 4 4 4 2

0

1

solid in 65% yield over three steps; mp 176–180 °C (dec). H NMR

400 MHz, DMSO-d ) d 1.78 (br d, J = 13.6 Hz, 1H), 1.84 (br d,

4.45. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-

(benzo[d][1,3]dioxol-5-yl)ethanone fumaric acid salt (37F)

(

6

J = 13.8 Hz, 1H), 2.17 (br s, 1H), 2.20 (br s, 1H), 2.96 (br d,

J = 13.2 Hz, 1H), 3.15 (br m, 2H), 3.26 (br d, J = 13.1 Hz, 1H), 3.39

The N-tboc protected compound was obtained by using the gen-

(

br d, J = 13.0 Hz, 1H), 3.46 (br d, J = 12.7 Hz, 1H), 3.74 (br d,

eral procedure E with 2-(benzo[d][1,3]dioxol-5-yl)acetic acid

J = 17.3 Hz, 1H), 3.96 (br d, J = 16.4 Hz, 1H), 4.00 (br d, J = 11.7 Hz,

2 2

(180 mg, 1 mmol) for 12 h. A mixture of CH Cl and MeOH (40:1)

was used for the chromatographic puriﬁcation. After removal of

13

1

H), 4.17 (br d, J = 13.9 Hz, 1H), 6.48 (s, 1.80H).

C NMR

(

100 MHz, DMSO-d ) d 26.5, 27.0, 28.6, 29.5, 47.9, 48.8, 49.1,

6

the solvents a white solid (248 mg, 64%) was obtained. The N-tboc

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7325

protection group of this solid (207 mg, 0.53 mmol) was cleaved

using the general procedure F for 2 h and a white solid 37

27.7, 34.2, 46.6, 48.0, 48.3, 49.6, 127.5, 135.6, 139.7, 141.7, 142.3,

147.5, 173.1, 176.3. ESI-MS: positive mode m/z = 260.3 ([M+H] ).

+

(

152 mg, 99%) was obtained after extraction. This solid 37

152 mg, 0.53 mmol) was transferred to its fumaric acid salt 37F

HRMS (EI) calcd for C15

(>99.9%). IR (cm ) 2949, 2852, 1731, 1642, 1562, 1312, 1180,

985, 787, 641. Anal. (C15H N O 1.4C H O 1.0H O) C, H, N.

H

21

N

3

O 260.1757, found 260.1751. Purity

ꢀ1

⁄ ⁄

by using the general procedure I with fumaric acid (61 mg,

.53 mmol). Compound 37F (76 mg, 37%) was obtained as a white

21 3 4 4 4 2

0

1

solid in 23% yield over three steps; mp 179–185 °C (dec). H NMR

400 MHz, D O) d 1.91 (br d, J = 13.2 Hz, 1H), 1.98 (br d, J = 13.4 Hz,

H), 2.29 (br s, 1H), 2.31 (br s, 1H), 3.08 (br d, J = 13.5 Hz, 1H), 3.26-

.50 (br m, 5H), 3.81 (m, 2H), 4.15 (br d, J = 13.0 Hz, 1H), 4.39 (br d,

4.48. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(4-

ﬂuorophenyl)prop-2-en-1-one fumaric acid salt (40F)

(

1

3

2

The N-tboc protected compound was obtained by using the gen-

eral procedure E with trans-3-(4-ﬂuorophenyl)acrylic acid (166 mg,

1 mmol) for 12 h. A mixture of CH Cl and MeOH (40:1) was used for

2 2

the chromatographic puriﬁcation. After removal of the solvents a

white solid (242 mg, 65%) was obtained. The N-tboc protection

group of this solid (210 mg, 0.56 mmol) was cleaved using the gen-

eral procedure F for 2 h and a clear oil 40 (149 mg, 97%) was obtained

after extraction. This oil 40 (149 mg, 0.54 mmol) was transferred to

its fumaric acid salt 40F by using the general procedure I with fuma-

ric acid (63 mg, 0.54 mmol). Compound 40F (151 mg, 71%) was ob-

J = 13.7 Hz, 1H), 5.97 (s, 2H), 6.67 (s, 1.75H), 6.74 (d, J = 8.0 Hz, 1H),

6

2

1

.80 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H). ¹³C NMR (100 MHz, D

2

O) d

5.8, 26.3, 27.9, 40.8, 46.9, 48.0, 48.4, 50.2, 101.8, 109.3, 110.4,

23.2, 128.7, 135.5, 146.8, 148.1, 172.2, 176.6. ESI-MS: positive

+

mode m/z = 289.3 ([M+H] ). HRMS (EI) calcd for C16

20

H N

2

O

3

ꢀ1

2

1

H

89.1547, found 289.1550. Purity (>97%). IR (cm ) 2869, 1698,

659, 1596, 1443, 1398, 1253, 1213, 1192, 1034, 787. Anal. (C16-

⁄ ⁄

2 3 4 4 4 2

N O 1.1C H O 0.4H O) C, H, N.

20

4

.46. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-

tained as a white solid in 45% yield over three steps; mp 199–201 °C

1

(

naphthalene-2-yl)ethanone fumaric acid salt (38F)

(dec). H NMR (400 MHz, DMSO-d

6

) d 1.76 (br d, J = 12.5 Hz, 1H),

1

.87 (br d, J = 12.7 Hz, 1H), 2.07 (br s, 2H), 2.88–3.42 (br m, 6H),

The N-tboc protected compound was obtained by using the gen-

4.34 (br d, J = 12.9 Hz, 2H), 6.46 (s, 2.0H), 7.25 (d, J = 15.3 Hz, 1H),

7.24–7.28 (m, 2H), 7.41 (d, J = 15.5 Hz, 1H), 7.77 (dd, J = 8.2, 5.8 Hz,

eral procedure E with 2-naphthylacetic acid (186 mg, 1 mmol) for

2 h. A mixture of CH Cl and MeOH (40:1) was used for the chro-

1

3

1

2

2H). C NMR (100 MHz, DMSO-d

= 21.6 Hz), 120.0 (d, JC,F = 2.1 Hz), 130.0 (d, JC,F = 8.3 Hz), 132.0 (d,

C,F = 3.1 Hz), 135.1 (br d, JC,F = 1.9 Hz), 139.0, 162.7 (d, JC,F = 247.1),

6

) d 26.6, 28.4, 46.7, 115.7 (d, JC,F

matographic puriﬁcation. After removal of the solvents a white so-

lid (366 mg, 93%) was obtained. The N-tboc protection group of this

solid (309 mg, 0.78 mmol) was cleaved using the general proce-

dure F for 2 h and a white solid 38 (228 mg, 99%) was obtained

after extraction. This solid 38 (228 mg, 0.78 mmol) was transferred

to its fumaric acid salt 38F by using the general procedure I with

fumaric acid (90 mg, 0.78 mmol). Compound 38F (122 mg, 32%)

J

+

167.5, 167.9. ESI-MS: positive mode m/z = 275.1 ([M+H] ). HRMS

(EI) calcd for C16 O 275.1554, found 275.1547. Purity

(>99.9%). IR (cm ) 2952, 2851, 2717, 2640, 1732, 1652, 1620,

H19FN

2

ꢀ1

⁄

1558, 1507, 1316, 1217, 972, 826, 787, 645. Anal. (C16

H

19FN

2

O 1.5-

4 4 4

C H O

) C, H, N.

was obtained as a white solid in 30% yield over three steps; mp

1

81–185 °C (dec). H NMR (400 MHz, DMSO-d

6

) d 1.71 (br d,

4.49. (E)-1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

J = 11.8 Hz, 1H), 1.79 (br d, J = 12.3 Hz, 1H), 2.10 (br s, 1H), 2.13

(pyridin-3-yl)prop-2-en-1-one fumaric acid salt (41F)

(

br s, 1H), 2.88 (br d, J = 11.9 Hz, 1H), 3.04–3.34 (br m, 5H), 3.83

br d, J = 14.2 Hz, 1H), 3.95 (br d, J = 14.5 Hz, 1H), 4.06 (br d,

The N-tboc protected compound was obtained by using the gen-

eral procedure E with trans-3-(pyridine-3-yl)acrylic acid (149 mg,

J = 10.9 Hz, 1H), 4.25 (br d, J = 12.2 Hz, 1H), 6.48 (s, 1.36H), 7.29

d, J = 7.8 Hz, 1H), 7.42 (m, 2H), 7.61 (s, 1H), 7.72-7.86 (m, 3H).

(

1 mmol) for 12 h. A mixture of CH

for the chromatographic puriﬁcation. An additional HPLC puriﬁca-

tion (RP18 silica gel, MeOH-H O gradient) was necessary. After re-

2 2

Cl and MeOH (20:1) was used

1

3

6

C NMR (100 MHz, DMSO-d ) d 25.4, 25.7, 28.1, 40.6, 45.9, 46.7,

4

1

6.8, 49.0, 125.4, 125.9, 127.33, 127.34, 127.4, 127.5, 128.3,

2

31.7, 133.0, 133.6, 135.1, 167.9, 171.6. ESI-MS: positive mode

moval of the solvents a white solid (238 mg, 67%) was obtained.

The N-tboc protection group of this solid (160 mg, 0.45 mmol)

was cleaved using the general procedure F for 4 h and a clear oil

41 (110 mg, 95%) was obtained after extraction. This oil 41

+

m/z = 295.4 ([M+H] ). HRMS (EI) calcd for C19

found 295.1808. Purity (>98%). IR (cm ) 2952, 2852, 1656, 1402,

1

H

22

N

2

O 295.1805,

ꢀ1

⁄ ⁄

22 2 4 4 4 2

218, 1104, 980, 796. Anal. (C19H N O 0.8C H O 1.0H O) C, H, N.

(

92 mg, 0.36 mmol) was transferred to its fumaric acid salt 41F

4

.47. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-(pyridine-

-yl)propanone fumaric acid salt (39F)

by using the general procedure I with fumaric acid (41 mg,

0.36 mmol). Compound 41F (115 mg, 86%) was obtained as a white

1

solid in 55% yield over three steps; mp 82–85 °C (dec). H NMR

The N-tboc protected compound was obtained by using the gen-

2

(400 MHz, D O) d 2.03 (br m, 2H), 2.39 (br s, 2H), 3.23 (br d,

eral procedure E with 3-(pyridine-3-yl)propionic acid (151 mg,

mmol) for 12 h. A mixture of CH Cl and MeOH (20:1) was used

J = 13.5 Hz, 1H), 3.37 (br t, J = 12.1 Hz, 2H), 3.46–3.62 (br m, 3H),

4.35 (br d, J = 13.4 Hz, 1H), 4.49 (br d, J = 14.0 Hz, 1H), 6.58 (s,

1.96H), 7.37 (d, J = 15.7 Hz, 1H), 7.59 (d, J = 15.9 Hz, 1H), 7.83 (dd,

J = 8.1, 5.5 Hz, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.65 (d, J = 5.3 Hz, 1H),

1

2

for the chromatographic puriﬁcation. After removal of the solvents

a white solid (232 mg, 64%) was obtained. The N-tboc protection

group of this solid (190 mg, 0.53 mmol) was cleaved using the gen-

eral procedure F for 2 h and a clear oil 39 (120 mg, 88%) was ob-

tained after extraction. This oil 39 (120 mg, 0.46 mmol) was

transferred to its fumaric acid salt 39F by using the general proce-

dure I with fumaric acid (54 mg, 0.46 mmol). Compound 39F

1

3

2

8.86 (s, 1H). C NMR (100 MHz, D O) d 26.0, 26.3, 28.0, 47.2,

48.0, 48.3, 50.2, 123.4, 126.7, 133.8, 135.7, 137.9, 141.0, 144.9,

+

145.7, 170.5, 173.5. ESI-MS: positive mode m/z = 258.3 ([M+H] ).

HRMS (EI) calcd for C15

H

19

N

3

O 258.1601, found 258.1597. Purity

ꢀ1

(>99%). IR (cm ) 2858, 1699, 1651, 1574, 1418, 1222, 1107, 971,

⁄ ⁄

(

127 mg, 65%) was obtained as a white solid in 37% yield over three

545. Anal. (C15H N O 0.4C H O 7.0H O) C, H, N.

19 3 4 4 4 2

1

steps; mp 149-155 °C (dec). H NMR (400 MHz, D

J = 13.6 Hz, 1H), 1.99 (br d, J = 13.6 Hz, 1H), 2.31 (br s, 2H), 2.86-

.08 (br m, 3H), 3.15 (q, J = 7.0 Hz, 2H), 3.39-3.54 (br m, 3H), 4.06

br d, J = 13.0 Hz, 1H), 4.34 (br d, J = 13.8 Hz, 1H), 6.62 (s, 2.78H),

.98 (dd, J = 7.7, 6.2 Hz, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.63 (d,

2

O) d 1.92 (br d,

4.50. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-2-

phenylprop-2-yn-1-one fumaric acid salt (42F)

3

(

7

The N-tboc protected compound was obtained by using the gen-

eral procedure E with phenylpropiolic acid (146 mg, 1 mmol) for

13

J = 5.6 Hz, 1H), 8.70 (s, 1H). C NMR (100 MHz, D

2

O) d 25.8, 26.1,

7

326

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

1

2 h. A mixture of CH

2

Cl

2

and MeOH (40:1) was used for the chro-

1H), 3.29–3.41 (br m, 2H), 3.45 (br d, J = 13.0 Hz, 1H), 3.52–3.59

(br m, 2H), 3.81 (s, 3H), 4.37 (br d, J = 14.1 Hz, 1H), 4.55 (br d,

J = 13.5 Hz, 1H), 6.63 (s, 1.60H), 7.10 (dd, J = 8.3, 2.5 Hz, 1H), 7.15

(br s, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H). ¹³C NMR

matographic puriﬁcation. After removal of the solvents a white so-

lid (303 mg, 86%) was obtained. The N-tboc protection group of this

solid (250 mg, 0.71 mmol) was cleaved using the general proce-

dure G with anhydrous ZnBr

2

(318 mg, 1.41 mmol) for 48 h and

2

(100 MHz, D O) d 25.6, 26.1, 28.1, 46.5, 47.7, 48.1, 51.5, 56.1, 80.7,

an off-white solid 42 (148 mg, 82%) was obtained after extraction.

This solid 42 (148 mg, 0.58 mmol) was transferred to its fumaric

acid salt 42F by using the general procedure I with fumaric acid

94.2, 118.0, 118.1, 120.9, 126.2, 130.8, 135.3, 157.9, 159.4, 172.1.

+

ESI-MS: positive mode m/z = 285.4 ([M+H] ). HRMS (EI) calcd for

ꢀ1

C H

17 20

N

2

O

2

285.1598, found 285.1605. Purity (>99.5%). IR (cm

)

(

67 mg, 0.58 mmol). Compound 42F (110 mg, 53%) was obtained

2935, 2863, 2207, 1718, 1703, 1611, 1417, 1231, 1106, 989, 682.

⁄ ⁄

20 2 2 4 4 4 2

Anal. (C17H N O 0.84C H O 1.4H O) C, H, N.

as a white solid in 37% yield over three steps; mp 151–154 °C

(

1

3

1

dec). H NMR (400 MHz, DMSO-d

6

) d 1.78 (br d, J = 13.0 Hz, 1H),

.87 (br d, J = 12.7 Hz, 1H), 2.07 (br s, 2H), 2.96-3.14 (br m, 4H),

.24 (br d, J = 12.8 Hz, 1H), 3.46 (br d, J = 13.0 Hz, 1H), 4.26 (br d,

4.53. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(4-

methoxyphenyl)prop-2-yn-1-one fumaric acid salt (45F)

J = 13.5 Hz, 1H), 4.37 (br d, J = 12.0 Hz, 1H), 6.48 (s, 1.80H), 7.44–

7

2

1

.55 (m, 3H), 7.60-7.65 (m, 2H). ¹³C NMR (100 MHz, DMSO-d

5.5, 26.0, 28.6, 45.6, 47.3, 47.4, 50.3, 82.5, 89.4, 120.0, 128.9,

6

) d

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 3-(4-methoxyphenyl)propiolic acid (176 mg,

1 mmol) for 12 h. A mixture of CH Cl and MeOH (40:1) was used

2 2

for the chromatographic puriﬁcation. After removal of the solvents

a clear oil (377 mg, 98%) was obtained. The N-tboc protection group

of this oil (320 mg, 0.83 mmol) was cleaved using the general proce-

dure F for 4 h and a white solid 45 (236 mg, 99%) was obtained after

extraction. This solid 45 (236 mg, 0.83 mmol) was transferred to its

fumaric acid salt 45F by using the general procedure I with fumaric

acid (96 mg, 0.83 mmol). Compound 45F (272 mg, 83%) was ob-

30.4, 132.2, 135.0, 154.3, 167.7. ESI-MS: positive mode m/

+

z = 255.3 ([M+H] ). HRMS (EI) calcd for C16

H

18

N

2

O 255.1492, found

ꢀ1

2

1

55.1507. Purity (>99.5%). IR (cm ) 3536, 3390, 2218, 1658, 1607,

425, 980. Anal. (C16

⁄ ⁄

18 2 4 4 4 2

H N O 1.0C H O 3.0H O) C, H, N.

4

.51. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(2-

methoxyphenyl)prop-2-yn-1-one fumaric acid salt (43F)

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 3-(2-methoxyphenyl)propiolic acid (176 mg,

tained as a white solid in 81% yield over three steps; mp 169–

1

174 °C (dec). H NMR (400 MHz, DMSO-d

6

) d 1.77 (br d, J = 12.5 Hz,

1

mmol) for 12 h. A mixture of CH

2

Cl

2

and MeOH (40:1) was used

1H), 1.86 (br d, J = 12.8 Hz, 1H), 2.07 (br s, 2H), 2.98 (br dd, J = 13.7,

2.8 Hz, 1H), 3.01–3.12 (br m, 3H), 3.23 (br d, J = 12.8 Hz, 1H), 3.41–

3.48 (br m, 1H), 3.81 (s, 3H), 4.25 (br d, J = 13.6 Hz, 1H), 4.37 (br d,

J = 13.0 Hz, 1H), 6.47 (s, 1.92H), 7.02 (d, J = 8.9 Hz, 2H), 7.57 (d,

for the chromatographic puriﬁcation. After removal of the solvents

a white solid (370 mg, 96%) was obtained. The N-tboc protection

group of this solid (370 mg, 0.96 mmol) was cleaved using the gen-

eral procedure F for 4 h and a white solid 43 (260 mg, 95%) was ob-

tained after extraction. This solid 43 (260 mg, 0.91 mmol) was

transferred to its fumaric acid salt 43F by using the general proce-

dure I with fumaric acid (106 mg, 0.91 mmol). Compound 43F

1

3

6

J = 8.8 Hz, 2H). C NMR (100 MHz, DMSO-d ) d 25.5, 25.9, 28.5,

45.6, 47.1, 47.3, 50.3, 55.4, 81.7, 90.1, 111.7, 114.6, 134.1, 135.0,

+

154.6, 160.8, 167.7. ESI-MS: positive mode m/z = 285.3 ([M+H] ).

HRMS (EI) calcd for C17

H

20

N

2

O

2

285.1598, found 285.1594. Purity

ꢀ1

(

284 mg, 78%) was obtained as a white solid in 71% yield over three

(>99%). IR (cm ) 2868, 2198, 1717, 1600, 1511, 1254, 1172. Anal.

1

⁄

4

steps; mp 155–159 °C (dec). H NMR (400 MHz, DMSO-d

.90 (br m, 2H), 2.20 (br s, 2H), 2.96-3.04 (br m, 1H), 3.07–3.23 (br

m, 3H), 3.28 (br d, J = 13.2 Hz, 1H), 3.43 (br d, J = 13.0 Hz, 1H), 3.78

6

) d 1.77–

(C17H N O 0.95C H O 1.6H O) C, H, N.

20 2 2 4 4 2

1

4.54. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(3,4-

(

1

2

1

s, 3H), 4.21 (br d, J = 13.8 Hz, 1H), 4.41 (br d, J = 13.3 Hz, 1H), 6.46

s, 2.00H), 6.97 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 7.45 (m,

dimethoxyphenyl)prop-2-yn-1-one fumaric acid salt (46F)

H), 7.50 (dd, J = 7.6, 1.5 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 3-(3,4-dimethoxyphenyl)propiolic acid

(206 mg, 1 mmol) for 12 h. A mixture of CH Cl and MeOH (40:1)

2 2

was used for the chromatographic puriﬁcation. After removal of

the solvents a white solid (299 mg, 72%) was obtained. The N-tboc

protection group of this solid (260 mg, 0.63 mmol) was cleaved

using the general procedure F for 4 h and a white solid 46 (192 mg,

6

) d

5.8, 26.0, 28.2, 46.4, 47.4, 47.5, 51.1, 56.8, 86.7, 89.1, 109.3,

12.5, 121.9, 133.7, 134.9, 136.0, 156.7, 161.8, 169.7. ESI-MS: posi-

+

tive mode m/z = 285.3 ([M+H] ). HRMS (EI) calcd for C17

2

1

O

H

20

N

2

O

2

ꢀ

1

85.1598, found 285.1603. Purity (>99.5%). IR (cm ) 2939, 2200,

712, 1609, 1421, 1254, 968, 762, 728. Anal. (C17

⁄

H

20

N

2

O

2

1.0C

4

H

4-

⁄

4

1.6H

2

O) C, H, N.

9

7%) was obtained after extraction. This solid 46 (192 mg,

4

.52. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(3-

0.61 mmol) was transferred to its fumaric acid salt 46F by using

the general procedure I with fumaric acid (71 mg, 0.61 mmol). Com-

pound 46F (158 mg, 60%) was obtained as a white solid in 42% yield

methoxyphenyl)prop-2-yn-1-one fumaric acid salt (44F)

1

The N-tboc protected compound was obtained by using the gen-

over three steps; mp 152–153 °C (dec). H NMR (400 MHz, DMSO-

eral procedure E with 3-(3-methoxyphenyl)propiolic acid (176 mg,

6

d ) d 1.78 (br d, J = 12.5 Hz, 1H), 1.87 (br d, J = 12.9 Hz, 1H), 2.08

1

mmol) for 12 h. A mixture of CH

2

Cl

2

and MeOH (40:1) was used

(br s, 2H), 2.98 (br dd, J = 13.7, 3.1 Hz, 1H), 3.01–3.15 (br m, 3H),

3.24 (br d, J = 12.4 Hz, 1H), 3.44 (br dd, J = 12.9 Hz, 2.1 Hz, 1H),

3.79 (s, 3H), 3.80 (s, 3H), 4.25 (br d, J = 13.4 Hz, 1H), 4.37 (br d,

J = 12.9 Hz, 1H), 6.46 (s, 2.11H), 7.02 (d, J = 8.4 Hz, 1H), 7.14 (d,

for the chromatographic puriﬁcation. After removal of the solvents

a clear oil (349 mg, 91%) was obtained. The N-tboc protection group

of this oil (310 mg, 0.81 mmol) was cleaved using the general proce-

dure F for 4 h and a white solid 44 (228 mg, 99%) was obtained after

extraction. This solid 44 (228 mg, 0.80 mmol) was transferred to its

fumaric acid salt 44F by using the general procedure G with fumaric

acid (93 mg, 0.80 mmol). Compound 44F (202 mg, 67%) was ob-

1

3

J = 1.9 Hz, 1H), 7.22 (dd, J = 8.3, 1.9 Hz, 1H). C NMR (100 MHz,

DMSO-d ) d 25.5, 25.9, 28.5, 45.6, 47.0, 47.2, 50.3, 55.6, 55.7, 81.4,

6

90.4, 111.6, 111.9, 114.9, 126.2, 135.0, 148.6, 150.9, 154.6, 167.8.

+

ESI-MS: positive mode m/z = 315.4 ([M+H] ). HRMS (EI) calcd for

ꢀ

1

tained as a white solid in 60% yield over three steps; mp 123–

C

18

H

22

N

2

O

3

315.1703, found 315.1702. Purity (>99%). IR (cm

)

1

⁄

1

26 °C (dec). H NMR (400 MHz, D

2

O) d 1.97 (br d, J = 13.5 Hz, 1H),

3081, 2202, 1695, 1603, 1514, 1252, 1107. Anal. (C18

H

22

2

N O

3

1.5C4-

⁄

2

.04 (br d, J = 13.3 Hz, 1H), 2.36 (br s, 2H), 3.16 (br d, J = 14.0 Hz,

4

O

4

0.5H

2

O) C, H, N.

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7327

4

.55. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(3-chloro-

-methoxyphenyl)prop-2-yn-1-one fumaric acid salt (47F)

transferred to its fumaric acid salt 49F by using the general proce-

dure I with fumaric acid (90 mg, 0.77 mmol). Compound 49F

(

199 mg, 68%) was obtained as a white solid in 60% yield over three

1

The N-tboc protected compound was obtained by using the gen-

2 6

steps; mp 154–158 °C (dec). H NMR (400 MHz, D O + DMSO-d ) d

eral procedure E with 3-(3-chloro-4-methoxyphenyl)propiolic acid

211 mg, 1 mmol) for 12 h. A mixture of CH Cl and MeOH (40:1)

was used for the chromatographic puriﬁcation. After removal of

the solvents an off-white solid (412 mg, 98%) was obtained. The

N-tboc protection group of this solid (360 mg, 0.86 mmol) was

cleaved using the general procedure F for 4 h and an off-white solid

1.84 (br m, 2H), 2.20 (br s, 2H), 3.03 (br d, J = 13.9 Hz, 1H), 3.09-

3.21 (br m, 2H), 3.25 (br d, J = 13.1 Hz, 1H), 3.36 (br d, J = 14.0 Hz,

1H), 3.45 (br d, J = 13.2 Hz, 1H), 4.21 (br d, J = 13.9 Hz, 1H), 4.38 (br

d, J = 13.4 Hz, 1H), 6.47 (s, 1.80H), 7.14–7.25 (m, 1H), 7.25-7.41 (m,

(

2

1

3

2 6

3H). C NMR (100 MHz, D O + DMSO-d ) d 26.2, 26.7, 28.8, 47.2,

48.3, 48.6, 52.1, 82.6, 92.9 (d, JC,F = 3.4 Hz), 119.8 (d, JC,F = 20.8 Hz),

120.5 (d, JC,F = 23.6 Hz), 122.5 (d, JC,F = 9.4 Hz), 130.3 (d, JC,F = 2.7 Hz),

132.4 (d, JC,F = 8.7 Hz), 136.4, 158.0, 163.4 (d, JC,F = 246.0 Hz), 172.0.

4

7 (270 mg, 99%) was obtained after extraction. This solid 47

270 mg, 0.85 mmol) was transferred to its fumaric acid salt 47F

by using the general procedure I with fumaric acid (98 mg,

.85 mmol). Compound 47F (270 mg, 74%) was obtained as an

off-white solid in 72% yield over three steps; mp 169–174 °C

(

+

ESI-MS: positive mode m/z = 273.3 ([M+H] ). HRMS (EI) calcd for

ꢀ1

0

C

16

17

H N

2

O 273.1398, found 273.1401. Purity (>98%). IR (cm

)

3523, 3082, 2867, 2213, 1704, 1610, 1421, 1229, 969, 788. Anal.

1

⁄

4

(

dec). H NMR (400 MHz, DMSO-d

6

) d 1.76–1.89 (br m, 2H), 2.19

17 2 4 4 2

(C16H N O 0.9C H O 1.9H O) C, H, N.

br s, 2H), 3.00 (br d, J = 13.4 Hz, 1H), 3.06–3.17 (br m, 2H), 3.21

br d, J = 13.4 Hz, 1H), 3.33 (br d, J = 13.2 Hz, 1H), 3.43 (br d,

4.58. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

(benzo[d][1,3]dioxol-5-yl)prop-2-yn-1-one fumaric acid salt

(50F)

J = 13.1 Hz, 1H), 3.82 (s, 3H), 4.20 (br d, J = 13.4 Hz, 1H), 4.34 (br

d, J = 13.3 Hz, 1H), 6.46 (s, 1.96H), 7.11 (d, J = 8.8 Hz, 1H), 7.54

1

3

(

5

1

dd, J = 8.6, 1.9 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H).

100 MHz, DMSO-d ) d 25.6, 26.3, 28.5, 46.8, 47.8, 48.1, 51.6,

7.3, 82.4, 92.3, 113.5, 114.3, 122.8, 134.7, 134.9, 136.3, 157.7,

C NMR

6

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 3-(benzo[d][1,3]dioxol-5-yl)propiolic acid

(190 mg, 1 mmol) for 12 h. A mixture of CH Cl and MeOH (40:1)

2 2

+

57.7, 170.9. ESI-MS: positive mode m/z = 319.3 ([M+H] ). HRMS

19ClN 319.1208, found 319.1212. Purity

>99.5%). IR (cm ) 3088, 2205, 1720, 1609, 1426, 1296, 1255,

(

EI) calcd for C17

H

2

O

2

was used for the chromatographic puriﬁcation. After removal of

the solvents a yellow oil (347 mg, 87%) was obtained. The N-tboc

protection group of this oil (290 mg, 0.73 mmol) was cleaved using

the general procedure F for 4 h and an off-white solid 50 (214 mg,

99%) was obtained after extraction. This solid 50 (214 mg,

0.72 mmol) was transferred to its fumaric acid salt 50F by using

the general procedure I with fumaric acid (83 mg, 0.72 mmol).

Compound 50F (254 mg, 77%) was obtained as an off-white solid

ꢀ

1

(

9

⁄ ⁄

2 2 4 4 4 2

H19ClN O 0.8C H O 2.0H O) C, H, N.

69. Anal. (C17

4

.56. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(4-

methylphenyl)prop-2-yn-1-one fumaric acid salt (48F)

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 3-(4-methylphenyl)propiolic acid (160 mg,

1

in 66% yield over three steps; mp 182–186 °C (dec). H NMR

1

mmol) for 12 h. A mixture of CH

2

Cl

2

and MeOH (40:1) was used

6

(400 MHz, DMSO-d ) d 1.77 (br d, J = 13.0 Hz, 1H), 1.88 (br d,

for the chromatographic puriﬁcation. After removal of the solvents

a white solid (350 mg, 95%) was obtained. The N-tboc protection

group of this solid (305 mg, 0.83 mmol) was cleaved using the gen-

eral procedure F for 4 h and a white solid 48 (217 mg, 98%) was ob-

tained after extraction. This solid 48 (217 mg, 0.81 mmol) was

transferred to its fumaric acid salt 48F by using the general proce-

dure I with fumaric acid (94 mg, 0.81 mmol). Compound 48F

J = 13.1 Hz, 1H), 2.10 (br s, 2H), 2.98 (br dd, J = 13.7, 2.8 Hz, 1H),

3.04–3.16 (br m, 3H), 3.27 (br d, J = 12.8 Hz, 1H), 3.43 (br d,

J = 13.0 Hz, 1H), 4.24 (br d, J = 13.4 Hz, 1H), 4.36 (br d, J = 13.0 Hz,

1H), 6.11 (s, 2H), 6.51 (s, 2.80H), 7.00 (d, J = 7.8 Hz, 1H), 7.18 (dd,

J = 9.7, 1.6 Hz, 1H), 7.19 (s, 1H). C NMR (100 MHz, DMSO-d ) d

6

25.2, 25.6, 28.1, 45.5, 46.6, 46.8, 50.2, 81.2, 89.9, 101.9, 109.0,

1

3

111.7, 112.9, 127.9, 134.8, 147.5, 149.3, 154.7, 167.3. ESI-MS: posi-

+

(

244 mg, 78%) was obtained as a white solid in 75% yield over three

tive mode m/z = 299.3 ([M+H] ). HRMS (EI) calcd for C17

H

18

N

2

O

3

1

ꢀ1

steps; mp 202–207 °C (dec). H NMR (400 MHz, DMSO-d

6

) d 1.77

299.1390, found 299.1393. Purity (>99%). IR (cm ) 3495, 3382,

(

2

3

br d, J = 12.7 Hz, 1H), 1.87 (br d, J = 12.7 Hz, 1H), 2.07 (br s, 2H),

.35 (s, 3H), 2.98 (br dd, J = 13.6 Hz, 1H), 3.01-3.13 (br m, 3H),

.24 (br d, J = 12.8 Hz, 1H), 3.45 (br dd, J = 13.1, 1.9 Hz, 1H), 4.25

18 2 3

2196, 1646, 1602, 1425, 1251, 1235, 1038, 977. Anal. (C17H N O -

⁄

4 4 4 2

1.2C H O 2.5H O) C, H, N.

(

7

(

5

br d, J = 13.6 Hz, 1H), 4.36 (br d, J = 12.9 Hz, 1H), 6.47 (s, 2.00H),

4.59. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-

(naphthalene-1-yl)prop-2-yn-1-one fumaric acid salt (51F)

1

3

.28 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H).

) d 21.2, 25.5, 25.9, 28.6, 45.6, 47.0, 47.2,

0.3, 82.2, 89.8, 116.9, 129.6, 132.2, 135.0, 140.5, 154.5, 167.8.

C NMR

100 MHz, DMSO-d

6

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 3-(naphthalene-1-yl)propiolic acid (196 mg,

1 mmol) for 12 h. A mixture of CH Cl and MeOH (40:1) was used

2 2

+

ESI-MS: positive mode m/z = 269.4 ([M+H] ). HRMS (EI) calcd for

C

ꢀ1

17

H

20

N

2

O 269.1648, found 269.1650. Purity (>99.5%). IR (cm

)

3

H

408, 2963, 2867, 2202, 1720, 1605, 1431, 1270, 977. Anal. (C17-

for the chromatographic puriﬁcation. After removal of the solvents

a clear oil (108 mg, 27%) was obtained. The N-tboc protection

group of this oil (108 mg, 0.27 mmol) was cleaved using the gen-

eral procedure F for 4 h and a white solid 51 (74 mg, 91%) was ob-

tained after extraction. This solid 51 (74 mg, 0.24 mmol) was

transferred to its fumaric acid salt 51F by using the general proce-

dure I with fumaric acid (28 mg, 0.24 mmol). Compound 51F

⁄ ⁄

20 2 4 4 4 2

N O 1.0C H O 1.7H O) C, H, N.

4

.57. 1-((1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl)-3-(3-

ﬂuorophenyl)prop-2-yn-1-one fumaric acid salt (49F)

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 3-(3-ﬂuorophenyl)propiolic acid (164 mg,

(60 mg, 58%) was obtained as a white solid in 14% yield over three

1

mmol) for 12 h. A mixture of CH

2

Cl

2

and MeOH (40:1) was used

steps; mp 171–173 °C (dec). H NMR (400 MHz, DMSO-d

6

) d 1.81

for the chromatographic puriﬁcation. After removal of the solvents

a white solid (327 mg, 88%) was obtained. The N-tboc protection

group of this solid (290 mg, 0.78 mmol) was cleaved using the gen-

eral procedure F for 4 h and a white solid 49 (210 mg, 99%) was ob-

tained after extraction. This solid 49 (210 mg, 0.77 mmol) was

(br d, J = 12.5 Hz, 1H), 1.89 (br d, J = 12.7 Hz, 1H), 2.11 (br s, 1H),

2.14 (br s, 1H), 3.02–3.18 (br m, 4H), 3.28 (br d, J = 12.8 Hz, 1H),

3.58 (br d, J = 12.7 Hz, 1H), 4.32 (br d, J = 13.5 Hz, 1H), 4.48 (br d,

J = 12.6 Hz, 1H), 6.48 (s, 2.10H), 7.59 (t, J = 7.7 Hz, 1H), 7.65 (t,

J = 7.5 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 8.05

7

328

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

(

d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H). ¹³C

NMR (100 MHz, DMSO-d ) d 25.5, 25.9, 28.5, 45.7, 47.0, 47.1, 50.5,

7.4, 87.5, 117.4, 125.1, 125.6, 127.1, 127.9, 128.8, 130.8, 132.1,

32.6, 132.8, 135.1, 154.5, 167.9. ESI-MS: positive mode m/

for the chromatographic puriﬁcation. After removal of the solvents

a white solid (366 mg, 92%) was obtained. The N-tboc protection

group of this solid (317 mg, 0.80 mmol) was cleaved using the gen-

eral procedure F for 2 h and a white solid 54 (209 mg, 88%) was ob-

tained after extraction. This solid 54 (209 mg, 0.71 mmol) was

transferred to its fumaric acid salt 54F by using the general proce-

dure I with fumaric acid (82 mg, 0.71 mmol). Compound 54F

6

8

1

+

z = 305.4 ([M+H] ). HRMS (EI) calcd for C20

3

1

H

20

N

2

O 305.1648, found

ꢀ1

05.1644. Purity (>99%). IR (cm ) 3498, 2840, 2199, 1704, 1635,

⁄

214, 970, 768, 644. Anal. (C20

20 2 4 4 4 2

H N O 0.75C H O 1.6H O) C, H, N.

(

149 mg, 36%) was obtained as a white solid in 29% yield over three

1

4

.60. (1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl(4-(pyridin-3-

2

steps; mp 178–181 °C (dec). H NMR (400 MHz, D O) d 2.01 (br m,

yl)phenyl)methanone fumaric acid salt (52F)

2H), 2.25 (br s, 1H), 2.45 (br s, 1H), 3.34–3.64 (br m, 6H), 3.87 (br d,

J = 12.8 Hz, 1H), 4.54 (br d, J = 13.8 Hz, 1H), 6.52 (s, 2.0H), 7.61 (s,

1H), 7.72 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.90 (s, 1H),

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 4-(3-pyridyl)benzoic acid (199 mg, 1 mmol)

1

3

2

9.09 (s, 1H). C NMR (100 MHz, D O) d 25.8, 26.2, 27.9, 47.2,

for 12 h. A mixture of CH

matographic puriﬁcation. After removal of the solvents a white solid

403 mg, 99%) was obtained. The N-tboc protection group of this so-

lid (380 mg, 0.93 mmol) was cleaved using the general procedure F

for 2 h and a white solid 52 (257 mg, 90%) was obtained after extrac-

tion. This solid 52 (257 mg, 0.84 mmol) was transferred to its fuma-

ric acid salt 52F by using the general procedure I with fumaric acid

2

Cl

2

and MeOH (20:1) was used for the chro-

47.4, 48.4, 52.5, 121.6, 122.6, 123.3, 129.5, 135.0, 135.9, 136.4,

137.1, 174.2, 174.5. ESI-MS: positive mode m/z = 297.4 ([M+H] ).

+

(

HRMS (EI) calcd for C17

(>99%). IR (cm ) 3104, 2910, 2699, 1704, 1635, 1523, 1257, 969,

20 4 4 4 4 2

851, 636. Anal. (C17H N O 0.9C H O 1.0H O) C, H, N.

H

20

N

4

O 297.1710, found 297.1700. Purity

ꢀ

1

⁄ ⁄

4.63. (1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl(2-(pyridine-4-

(

97 mg, 0.84 mmol). Compound 52F (202 mg, 56%) was obtained

yl)thiazol-4-yl)methanone fumaric acid salt (55F)

as a white solid in 50% yield over three steps; mp 149–151 °C

1

(

2

dec). H NMR (400 MHz, D

.45 (br s, 1H), 3.33–3.42 (br m, 3H), 3.46–3.58 (br m, 3H), 3.91 (br

d, J = 12.3 Hz, 1H), 4.55 (br d, J = 12.8 Hz, 1H), 6.56 (s, 2.1H), 7.65

2

O) d 2.02 (br m, 2H), 2.24 (br s, 1H),

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 2-(4-pyridyl)thiazole-4-carboxylic acid

(206 mg, 1 mmol) for 12 h. A mixture of CH Cl and MeOH (20:1)

2 2

(

1

d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.98 (dd, J = 8.1, 5.6 Hz,

was used for the chromatographic puriﬁcation. After removal of

the solvents a yellow oil (401 mg, 97%) was obtained. The N-tboc

protection group of this oil (401 mg, 0.97 mmol) was cleaved using

the general procedure F for 2 h and a yellow oil 55 (252 mg, 83%)

was obtained after extraction. This oil 55 (252 mg, 0.80 mmol)

was transferred to its fumaric acid salt 55F by using the general

procedure I with fumaric acid (93 mg, 0.80 mmol). Compound

1

3

H), 8.65 (d, J = 8.2 Hz, 1H), 8.72 (d, J = 5.3 Hz, 1H), 9.00 (s, 1H).

O) d 25.8, 26.2, 28.0, 47.2, 47.4, 48.4, 52.5,

27.3, 128.3, 128.6, 135.7, 136.1, 137.2, 138.9, 142.4, 142.7, 143.0,

C

NMR (100 MHz, D

2

1

(

+

73.6, 175.0. ESI-MS: positive mode m/z = 308.4 ([M+H] ). HRMS

O 308.1757, found 308.1743. Purity (>99%).

IR (cm ) 2855, 2579, 1718, 1604, 1435, 1261, 1099, 970, 633. Anal.

21 3

EI) calcd for C19H N

ꢀ1

⁄

(

C

19

H

21

N

3

O 1.0C

4 4

H O

4

2

1.5H O) C, H, N.

55F (119 mg, 35%) was obtained as an off-white solid in 28% yield

1

over three steps; mp 124–128 °C (dec). H NMR (400 MHz, D

2

O) d

4

.61. (1R,5S)-3,7-Diazabicyclo[3.3.1]nonan-3-yl(4-(pyridin-4-

2.06 (br m, 2H), 2.27 (br s, 1H), 2.45 (br s, 1H), 3.34–3.72 (br m,

6H), 4.33 (br s, 1H), 4.51 (br s, 1H), 6.60 (s, 1.58H), 8.19 (d,

J = 5.6 Hz, 2H), 8.31 (s, 1H), 8.78 (d, J = 5.2 Hz, 2H). ¹³C NMR

yl)phenyl)methanone fumaric acid salt (53F)

The N-tboc protected compound was obtained by using the gen-

2

(100 MHz, D O) d 26.3, 28.6, 47.8, 47.9, 48.0, 52.0, 122.9, 128.9,

eral procedure E with 4-(4-pyridyl)benzoic acid (199 mg, 1 mmol)

135.5, 144.3, 147.1, 150.8, 164.8, 167.9, 173.1. ESI-MS: positive

+

for 12 h. A mixture of CH

2

Cl

2

and MeOH (20:1) was used for the

18 4

mode m/z = 315.4 ([M+H] ). HRMS (EI) calcd for C16H N OS

ꢀ1

chromatographic puriﬁcation. After removal of the solvents a

white solid (246 mg, 60%) was obtained. The N-tboc protection

group of this solid (180 mg, 0.44 mmol) was cleaved using the gen-

eral procedure F for 4 h and a white solid 53 (132 mg, 97%) was ob-

tained after extraction. This solid 53 (132 mg, 0.43 mmol) was

transferred to its fumaric acid salt 53F by using the general proce-

dure I with fumaric acid (50 mg, 0.43 mmol). Compound 53F

315.1274, found 315.1261. Purity (>99.5%). IR (cm ) 3354, 3201,

2860, 2600, 1704, 1630, 1458, 1406, 1247, 1015, 972, 641. Anal.

⁄

(C16H N OS 1.0C H O 1.0H O) C, H, N.

18 4 4 4 4 2

4.64. Calculation of physicochemical properties

The physicochemical properties have been calculated using

ACD/ADME Suite 5.0 and ACD/PhysChem (ACD/Labs).

(

120 mg, 58%) was obtained as a white solid in 34% yield over three

1

steps; mp 175-180 °C (dec). H NMR (400 MHz, D

2

O) d 2.02 (br m,

2

H), 2.25 (br s, 1H), 2.46 (br s, 1H), 3.34-3.60 (br m, 6H), 3.89 (br d,

Acknowledgments

J = 13.2 Hz, 1H), 4.56 (br d, J = 14.0 Hz, 1H), 6.58 (s, 3.00H), 7.70 (d,

J = 8.4 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 8.32 (d, J = 6.7 Hz, 2H), 8.81

The authors thank Tim Deinet, Julia Thomas, Florian Schorr,

Franziska Krumbiegel, and Alia Abdelraman for their technical

assistance. The authors gratefully thank Dr. Jörg Hockemeyer for

providing the propioloic acid derivatives. We thank Dr. Marina R.

Picciotto for many helpful discussions. This work was ﬁnancially

supported by the German Research Council (DFG; GRK 677) (CE,

DG) and the National Institutes of Health P20RR016467 (C.E., I.T.,

D.G.). C.S. and R.L.P. were supported by the James and Esther King

Biomedical Research Grant 1KG12 (CS, RLP). Elemental analyses for

some compounds were conducted by the UH Hilo Analytical Labo-

ratory for this project supported in part by the National Science

Foundation award number EPS-0903833. Any opinions, ﬁndings,

and conclusions or recommendations expressed in this material

are those of the author(s) and do not necessarily reﬂect the views

of the National Science Foundation.

1

3

(

d, J = 6.8 Hz, 2H). C NMR (100 MHz, D

2

O) d 25.8, 26.2, 28.0, 47.1,

4

1

7.7, 48.4, 52.5, 125.3, 128.6, 129.1, 135.5, 137.1, 138.0, 142.4,

+

57.2, 173.0, 174.7. ESI-MS: positive mode m/z = 308.4 ([M+H] ).

O 308.1757, found 308.1749. Purity

>99.5%). IR (cm ) 2906, 2694, 2601, 1698, 1639, 1255, 1171,

21 3

HRMS (EI) calcd for C19H N

(

9

ꢀ1

⁄

69, 834, 636. Anal. (C19

H N O 1.4C H O 0.75H O) C, H, N.

21 3 4 4 4 2

4

.62. (4-(1H-Imidazol-1-yl)phenyl)((1R,5S)-3,7-

diazabicyclo[3.3.1]nonan-3-yl)methanone fumaric acid salt

54F)

(

The N-tboc protected compound was obtained by using the gen-

eral procedure E with 4-(1H-imidazol-1-yl)benzoic acid (188 mg,

mmol) for 12 h. A mixture of CH Cl and MeOH (20:1) was used

1

2

C. Eibl et al. / Bioorg. Med. Chem. 21 (2013) 7309–7329

7329

1

2. Akireddy, S. R.; Bhatti, B. S.; Breining, S. R.; Hammond, P. S.; Heemstra, R. J.;

Mazurov, A.; Melvin, M. S.; Miao, L.; Murthy, V. S.; Strachan, J.-P.; Xiao, Y.-D.

WO2009111550, 2009; PCT Int. Appl. 2009.

Supplementary data

Supplementary data associated with this article can be found, in

the online version, at http://dx.doi.org/10.1016/j.bmc.2013.09.060 .

13. Eibl, C. Ph.D. Thesis, University of Bonn, Germany, July 2009.

14. Gündisch, D.; Eibl, C. Biochem. Pharmacol. 2009 , 78 , 905 .

15. Tomassoli, I.; Eibl, C.; Wulf, M.; Papke, R. L.; Picciotto, M. R.; Gündisch, D.

Biochem. Pharmacol. 2011 , 82 , 1023.

References and notes

1

6. Munoz, L. Ph.D. Thesis, University of Bonn, Germany, November 2005.

7. Picciotto, M.; Gündisch, D.; Munoz, L.; Andrä, M; Mineur, Y. WO 2007100430,

2007; PCT Int. Appl. 2007 .

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Article Doi

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs

DOI: 10.1016/j.bmc.2013.09.060

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