Design, synthesis and activity of novel derivatives of Oxybutynin and Tolterodine

Article abstract of DOI:10.1016/j.bmcl.2005.02.036

Novel derivatives of Tolterodine (1) and Oxybutynin (2) have been designed using conformationally restricted azabicyclics as replacement for open-chain amines. The synthesis and structure-activity relationships are presented.

Full text of DOI:10.1016/j.bmcl.2005.02.036

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2093–2096
Design, synthesis and activity of novel derivatives of
Oxybutynin and TolterodineI
Kirandeep Kaur,a,* Shelly Aeron,a Miriyala Bruhaspathy,a Shankar J. Shetty,a
Suman Gupta,b Laxminarayan H. Hegde,b Arun D. V. Silamkoti,a Anita Mehta,a
Anita Chugh,b Jang B. Gupta,b P. K. S. Sarmaa and Naresh Kumara,*
aRanbaxy Research Laboratories, New Drug Discovery Research, Department of Medicinal Chemistry,
Gurgaon 122 001, Haryana, India
bRanbaxy Research Laboratories, New Drug Discovery Research, Department of Pharmacology, Gurgaon 122 001, Haryana, India
Received 7 January 2005; revised 11 February 2005; accepted 12 February 2005
Available online 19 March 2005
Abstract—Novel derivatives of Tolterodine (1) and Oxybutynin (2) have been designed using conformationally restricted azabicyc-
lics as replacement for open-chain amines. The synthesis and structure–activity relationships are presented.
Ó 2005 Elsevier Ltd. All rights reserved.
Overactive bladder is one of the most common causes of
bladder control problems. It arises from the uncon-
trolled spontaneous activity of the detrusor muscle dur-
ing bladder filling leading to the symptoms of urinary
urgency and increased frequency of micturition with or
without incontinence. A range of therapeutic options
are available but pharmacotherapy with antimuscarinic
drugs remain the mainstay of treatment for the symp-
toms of overactive bladder. Muscarinic receptors are
widely distributed throughout the body and five distinct
subtypes are known to exist (M1–M5). The human uri-
nary bladder smooth muscle contains a mixed popula-
tion of M2- and M3- muscarinic receptor subtypes.
Although the M2- receptors are the predominant choli-
noreceptors present in the bladder, the smaller popula-
tion of M3- receptors appears to be the most
functionally important because they mediate direct con-
traction of the detrusor muscle.1 However, since musca-
rinic receptors are widely distributed throughout the
body, an antimuscarinic action in organs other than
the urinary bladder leads to dose-limiting adverse side
effects including dry mouth, constipation, blurred vi-
sion, headache, somnolence and tachycardia.
The lack of selectivity of Tolterodine (1) and Oxybuty-
nin (2) may be the result of the interaction of different
conformations1 of the ligands with different receptor
subtypes, and so subtype selective ligands, which recog-
nize the different localizations and functions of receptor
subtypes may provide the possibility of developing more
ideal drugs. Herein we describe our work on the conform-
ational restriction of the amine part of antimuscarinic
drugs like 1 and 2.
OH
N
H3C
OH
O
N
O
2
1
The conformational restriction of acyclic amines may be
achieved by use of cyclic systems. We chose to use bicy-
clic amines such as 3-azabicyclo[3.1.0]hexane, which
were, prior to this disclosure, unknown in the musca-
rinic field. The replacement of the diisopropyl and
diethyl groups of Tolterodine and Oxybutynin, respec-
tively, with such bicyclic amines allowed us to confirm
the beneficial effects of conformational restrictions.
Keywords: Selective muscarinic antagonists; Azabicyclohexane; Oxy-
butynin; Tolterodine.
q Presented at 227th ACS meeting, Anaheim.
*
The bicyclic amines (3a–c) were prepared following
reported procedures2 with modifications wherever
Corresponding authors. Tel.: +91 124 519 4920; fax: +91 124 234
3545 (N.K.); e-mail: n.kumar@ranbaxy.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.036

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K. Kaur et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2093–2096
O
R2
R2
HO
R1
OH
NaH, Toluene
15% aq NaOH, 5h
R1
R2
EtO
R1
OEt
OEt
OEt
+
Cl
O
O
O
O
O
R1 = H, CH3
R2 = H,CH3
SOCl2, 1h, reflux
R2
R1
R2
R1
Benzyl amine, heat
R1
LAH
reflux, 5h
(i)H2, Pd\C
(ii) HCl
R2
R2
R1
O
N
H
N
. HCl
O
N
O
O
O
Ph
Ph
3a: R1 = R2 = H
3b: R1 = Me, R2 = H
3c: R1 = R2 = Me
Scheme 1. Synthesis of 3-azabicyclo[3.1.0]hexane derivatives (3a–c).
necessary. Details are shown in Scheme 1. The introduc-
tion of a methyl group at the C-20 position of azabicy-
clo[3.1.0]hexane was achieved by treating 3-benzyl-3-
azabicyclo[3.1.0]hexane-2,4-dione with methyllithium
followed by LAH reduction and debenzylation to give
3d, (Scheme 2).
synthesized by the reaction of 3-azabicyclo[3.1.0]hexane
with 1-chloro-4-hydroxy-2-butyne5 whilst the amine 9
was obtained by alkylation of 3-azabicyclo[3.1.0]hexane
with the phthalimido derivative 86 followed by hydrazi-
nolysis (Scheme 4).
Compound 6a, with a free phenolic group, displayed
high affinity and had twofold selectivity for the M3
receptor over the M2 receptor, see Table 1. Compounds
5c and 5d confirmed the need for a free phenolic group.
Compound 6d was separable7 at C-20 to give 6d0
(3RS,20R*) and 6d00(3RS,20S*). Compound(s) 6d0
showed the Ki value of 79 nM for M3 receptors, while
6d00 showed about three times better activity, that is,
25 nM. As it mimics one of the isopropyl group of Tol-
terodine at nitrogen, further improvement may be possi-
ble by second stereospecific substitution of methyl at
The racemic tosylate (4) was prepared by the known
procedure.3 The synthesis of Tolterodine analogues
was achieved by N-alkylation of amine 3(a–d) with tos-
ylate 4 to give the propylamines 5(a–d), which upon de-
benzylation under hydrogenation conditions, gave
compounds 6(a–d) (Scheme 3).
The syntheses of Oxybutynin analogues involved the
condensation of a-hydroxy acid derivatives4 with the
corresponding alcohol 7 or amine 9. The alcohol 7 was
H
H
H
H
H
H
H
H
MeLi, THF
H2, Pd/C
OH
Me
LAH, THF
N
Me
O
N
N
H
3d
Me
O
N
O
Ph
Ph
Ph
Scheme 2. Synthesis of 2-methyl-3-azabicyclo[3.1.0]hexane (3d).
R1
OBn
OBn
N
H3C
R2
OTs
R1
R2
H3C
R3
K2CO3, KI
5(a-d)
N
R3
.HCl
+
H
3(a-d)
CH3CN-DMF
Pd/C, H2
R1
4
3a: R1=R2=R3=H
OH
3b: R1=Me, R2=R3=H
6'
4'
3c: R1=R2=Me, R3=H
3d : R1=R2=H, R3=Me
3
N
H3C
2'
1
R2
R3
6(a-d)
Scheme 3. Synthesis of Tolterodine analogues.

K. Kaur et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2093–2096
2095
OH
Cl
Et3N, CHCl3
N
N
NH
+
.HCl
7
OH
3a
Cl
NH2
O
Et N, CHCl
(i)
3
3
NH
N
+
.HCl
NH2NH2
(ii)
9
3a
8
O
N
X
R
EDC.HCl, NMM
OH
OH
O
Y
N
OH
+
HOBT, DMF
R
Cy
Cy
O
7, X = OH
9, X = NH2
10(a-g), Y = O
11(a-d), Y = NH
R = H,4-OMe, 4-F
Cy = see Table-2
Scheme 4. Synthesis of Oxybutynin analogues.
Table 1. Activities for Tolterodine analogues
Table 2. Activities for Oxybutynin analogues
R1
N
OR4
OH
Y
N
H3C
R2
R
R3
Cy
O
10,Y = O
5, R4 = Bn
6, R4 = H
11,Y = NH
Compounds
R
Cy
n
M3
M2
Compounds
R1
H
R2
H
R3
n
M3
M2
Ki (nM)8 Ki (nM)8
Ki (nM)8 Ki (nM)8
10a
10b
10c
10d
10e
10f
H
Cyclopentyl
Cyclohexyl
Phenyl
1
1
3
3
3
1
1
1
1
1
1
3
37
35
65
72
5a
5c
H
1
1
1
2
1
1
1
1
>1000
>10,000
>1000
50
>10,000
>10,000
>10,000
105
H
CH3 CH3
H
H
14
39
31
40
5d
6a
6b
6c0
6d
6d00
H
H
H
H
CH3
H
4-F
H
4-Fluorophenyl
Cyclopentyl
Cyclopentyl
H
CH3
6
22
H
118
221
H
102
964
330
2605
291
366
224
1926
425
3582
639
736
CH3 CH3
H
>1000
79
25
>1000
34
42
10g
11a
11b
11c
11d
4-OCH3 Cyclopentyl
H
H
H
H
CH3
CH3
H
Cyclopentyl
Cyclohexyl
Phenyl
H
Tolterodine (1) NA NA NA 10 7.07
6.91
H
4-F
4-Fluorophenyl
NA
Oxybutynin (2) NA
0.95
6.97
C-40. This may result in an understanding of specific
conformation of N,N-diisopropyl groups required in
the receptor cavity for the activity.
Acknowledgements
In the Oxybutynin series, the esters 10(a–g) were more
potent than the corresponding amides 11(a–d), see Table
2. Effect of substitution on the phenyl rings was checked
with compounds 10d and 10g. The R and S isomers of
10a were synthesized and the R isomer (10e)9 found to
be more potent than the S isomer (10f). Compound
10e displayed a selectivity of 3.67-fold for M3 over the
M2 receptor.
Authors would like to thank Dr. Ian Cliff, Dr. Venkata
P. Palle and Dr. DharamVir for their valuable support,
suggestions and discussions.
References and notes
1. Hirose, H.; Aoki, I.; Kimura, T.; Fujikawa, T.; Numaz-
awa, T.; Sasaki, K.; Nishikibe, M.; Noguchi, K. Eur. J.
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Nilvebrant, L. EP 0,325,571, 1991.
In summary, this work reveals the hidden potentials in
new framework design. The bicyclic amine used has
shown its capability to replace acyclic amines in Toltero-
dine (1) and Oxybutynin (2) without affecting core SAR.
Newly emerged compounds like 10e have shown poten-
tial as bladder selective (2.6-fold of 2) ligands.10,11
4. For example: (a) Shacklett, C. D.; Smith, H. A. J. Am.
Chem. Soc. 1953, 77, 2654; (b) Grover, P. T.; Bhongle, N.

2096
K. Kaur et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2093–2096
N.; Wald, S. A.; Senanayake, C. H. J. Org. Chem. 2000,
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3643.
7. The absolute stereochemistry was not established at C-20.
8. The affinity of test compounds for the M2 and M3
muscarinic receptor subtypes was determined by [3H]-N-
methyl scopolamine binding studies using rat heart and
submandibular gland, respectively, as previously described
with minor modifications. For further details see Moriya,
H.; Takagi, Y.; Nakanishi, T.; Hayashi, M.; Tani, T.;
Hirotsu, I. Life Sci. 1999, 64, 2351; and Cheng, Y.;
Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 309.
9. Procedure for synthesis of 10e: To a solution of R(ꢀ)-2-
hydroxy-2-cyclopentyl-2-phenyl acetic acid4b (1.13 mmol)
and alcohol 710 (1.13 mmol) in DMF (8 mL) at 0 °C, 1-
hydroxy benzotriazole (1.13 mmol) was added followed by
N-methyl morpholine (2.27 mmol). The reaction mixture
was stirred for 30 min and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide–HCl (1.13 mmol) was added. The reac-
tion mixture was stirred at same temperature for 1 h and
then at rt for 15 h. After aqueous workup, organic layer
was evaporated to give residue, which was purified by
column chromatography (ethyl acetate/hexane : 20/80) to
1
give pure 10e (0.11 g). HNMR (CDCl3, 300 MHz): 0.45
(m, 1H), 0.8 (m, 1H), 1.33–1.68 (m, 11H), 2.90–2.98 (m,
4H), 3.51 (s, 2H), 3.63 (s, 1H), 4.7–4.85 (dd, J = 15.3 Hz,
2H), 7.26–7.67 (m, 5H).
10. Mehta, A.; Silamkoti, A.V.; Kaur, K.; Gupta, J. B. WO
014853, 2004.
11. Mehta, A.; Silamkoti, A. V.; Bruhaspathy, M.; Gupta, J.
B. WO 014363, 2004.