Note: Descriptions are shown in the official language in which they were submitted.
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
PROCESS FOR THE PREPARATION OF BENZO-FUSED HETEROARYL SULFAMATES AND
CRYSTALLINE FORM OF
N-(((2S)-6-CHLORO-2,3-DIHYDRO-1,4-BENZODIOXIN-2-YL)METHYL-SULFAMTDE
FIELD OF THE INVENTION
The present invention is directed to a process for the preparation of
benzo-fused heteroaryl sulfamates, useful for the treatment of epilepsy and
related disorders.
BACKGROUND OF THE INVENTION
Epilepsy describes a condition in which a person has recurrent seizures
due to a chronic, underlying process. Epilepsy refers to a clinical phenomenon
rather than a single disease entity, since there are many forms and causes of
epilepsy. Using a definition of epilepsy as two or more unprovoked seizures,
the incidence of epilepsy is estimated at approximately 0.3 to 0.5 percent in
different populations throughout the world, with the prevalence of epilepsy
estimated at 5 to 10 people per 1000.
An essential step in the evaluation and management of a patient with a
seizure is to determine the type of seizure that has occurred. The main
characteristic that distinguishes the different categories of seizures is
whether
the seizure activity is partial (synonymous with focal) or generalized.
Partial seizures are those in which the seizure activity is restricted to
discrete areas of the cerebral cortex. If consciousness is fully preserved
during
the seizure, the clinical manifestations are considered relatively simple and
the
seizure is termed a simple-partial seizure. If consciousness is impaired, the
seizure is termed a complex-partial seizure. An important additional subgroup
comprises those seizures that begin as partial seizures and then spread
diffusely throughout the cortex, which are known as partial seizures with
secondary generalization.
Generalized seizures involve diffuse regions of the brain simultaneously
in a bilaterally symmetric fashion. Absence or petit mal seizures are
characterized by sudden, brief lapses of consciousness without loss of
postural
control. Atypical absence seizures typically include a longer duration in the
lapse of consciousness, less abrupt onset and cessation, and more obvious
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
motor signs that may include focal or lateralizing features. Generalized Tonic-
clonic or grand mal seizures, the main type of generalized seizures, are
characterized by abrupt onset, without warning. The initial phase of the
seizure
is usually tonic contraction of muscles, impaired respiration, a marked
enhancement of sympathetic tone leading to increased heart rate, blood
pressure, and pupillary size. After 10-20 s, the tonic phase of the seizure
typically evolves into the clonic phase, produced by the superimposition of
periods of muscle relaxation on the tonic muscle contraction. The periods of
relaxation progressively increase until the end of the ictal phase, which
usually
lasts no more than 1 min. The postictal phase is characterized by
unresponsiveness, muscular flaccidity, and excessive salivation that can cause
stridorous breathing and partial airway obstruction. Atonic seizures are
characterized by sudden loss of postural muscle tone lasting 1-2 s.
Consciousness is briefly impaired, but there is usually no postictal
confusion.
Myoclonic seizures are characterized by a sudden and brief muscle contraction
that may involve one part of the body or the entire body. (Harrison's Online,
March 29, 2001)
McComsey, D., et al. in US Patent Publication US 2006/0041008 Al,
published February 23, 2006 and McComsey, D., et al. in US Patent
Publication US 2005/0282887 Al, published December 22, 2005 disclose
compounds of formula (I) and their use in the treatment of epilepsy and
related
disorders. McComsey, D., et al. in US Patent Publication US 2006/0041008 Al
and McComsey, D., et al. in US Patent Publication US 2005/0282887 Al
further disclose a process for the preparation of the compounds of formula (I)
comprising reacting a suitable substituted amine with sulfamide.
In the process(es) as disclosed in McComsey D., et al. compounds of
formula (I) wherein R1 and R2 are each hydrogen describes the use of
sulfamoyl chloride (CI-SO2-NH2) as a reagent, which reagent is unsuitable for
large scale / commercial preparation. There remains, however, a need for a
process suitable for the preparation of large scale material and / or for
commercial preparation of the compounds of formula (I).
2
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
SUMMARY OF THE INVENTION
The present invention is directed to processes for the preparation of
compounds of formula (I)
R 4 0 R1
~-~
R (CH2)a N- i -NH
O (I)
wherein
R1 is selected from the group consisting of hydrogen and lower alkyl;
R4 is selected from the group consisting of hydrogen and lower alkyl;
a is an integer from 1 to 2;
is selected from the group consisting of
O
(R5)b \ I (R5)b
, O
(R5)c
O /
(R5)b >-~- (R5)
b
O O
(RS)b (R5)b
(R5)c iiiiii:ii-- Ojl~
\ and
(R5)c
\0 O
(RS)b \ \ I
O
wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to
2;
each R5 is independently selected from the group consisting of halogen,
lower alkyl and nitro;
3
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
O
(R5 )b '
\R~ /
provided that when is O or
(R5),
(R5)b
M O ,thenais1;
or a pharmaceutically acceptable salt thereof.
The present invention is directed to a process for the preparation of
compounds of formula (IA)
R4 O R1
II /
(CH2)a N- i-NH
O (IA)
wherein
R1 is hydrogen;
R4 is selected from the group consisting of hydrogen and lower alkyl;
a is an integer from 1 to 2;
is selected from the group consisting of
O O
(RS)b (R5)b /}-
O
(R5)c
O 5
(R5)b >-~- (R )b
O O
4
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
(R5)c O
(RS)b (R5)b
O cco and
(R5),
O
(R5)b
O
wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to
2;
each R5 is independently selected from the group consisting of halogen,
lower alkyl and nitro;
O
= (R5)b
I R I
4-
provided that when is O or
(R5)c
(R5)b \ \ I
O ,then ais1;
or a pharmaceutically acceptable salt thereof;
comprising
0
II
CI-S-NH 4
\-=
R4 p Oj-OR I R I (CH2)a-N
I\ R ~I (CH2)a-NH (XI I) O/S\
/OR
(XI) HN_(
(X) \\
O
reacting a compound of formula (X) with a compound of formula (XI)
wherein -C(O)OR is a nitrogen protecting group; in the presence of an organic
or inorganic base, wherein the organic or inorganic base is not reactive with
the
chloro group on the compound of formula (XI); in an aprotic organic solvent;
to
yield the corresponding compound of formula (XII);
5
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
_ R4 R4 O
I\ R /I (CH2)a N I\ R /I (CH2)a N-S-NH2
iO 0
(XII) O~S\ OR (IA)
HN-<O
de-protecting the compound of formula (XII); to yield the corresponding
compound of formula (IA).
The present invention is further directed to a process for the preparation
of a compound of formula (IB)
1
~-~ R 4 0 R
R I (CH2)a N- i-NH
O (IB)
wherein
R1 is selected from the group consisting of lower alkyl;
R4 is selected from the group consisting of hydrogen and lower alkyl;
a is an integer from 1 to 2;
I R I
is selected from the group consisting of
O O
(R5)b \ I (R5)b I / }
O
(R5)c
O 5
(R5)b >-~- (R )b
O O
6
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
(R5)c O
(RS)b (R5)b
O cco and
(R5),
O
(R5)b
O
wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to
2;
each R5 is independently selected from the group consisting of halogen,
lower alkyl and nitro;
O
= (R5)b
I R I
4-
provided that when is O or
(R5)c
(R5)b \ \ I
O ,then ais1;
or a pharmaceutically acceptable salt thereof;
comprising
0
II
CI-S-NH 4
\-=
R4 p Oj-OR I R I (CH2)a-N
I\ R ~I (CH2)a-NH (XI I) O/S\
/OR
(XI) HN_(
(X) \\
O
reacting a compound of formula (X) with a compound of formula (XI)
wherein -C(O)OR is a nitrogen protecting group; in the presence of an organic
or inorganic base, wherein the organic or inorganic base is not reactive with
the
chloro group on the compound of formula (XI); in an aprotic organic solvent;
to
yield the corresponding compound of formula (XII);
7
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
R4
(CH2)a-N R1-Q (CH2)a-N
O~S\ /OR (XV) OAS OR \ --~
HNC( N
(XII) O (XVI) R1 O
reacting the compound of formula (XII) with a compound of formula (XV),
wherein Q is a leaving group; in an organic solvent; to yield the
corresponding
compound of formula (XVI)
R4 R4
I R I \
(CH2)a-N R I (CH2)a-N /
SAO OR0 \ !~"O
/ i
O/ \N- . (IB) O/ HN-R1
(XVI) R1 O
de-protecting the compound of formula (XVI); to yield the corresponding
compound of formula (IB).
In an embodiment, the present invention is directed to a process for the
preparation of a compound of formula (I-S)
0
O \S~NH2
\ (S) N / %
H
Cl O (I-S)
or a pharmaceutically acceptable salt thereof (also known as N-[[(2S)-6-
chloro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl]-sulfamide) comprising
0
II
CI-S-NH O H o
II Jj-OR ~~ ~N` /OR
O O // O "IS III(
\ (S) N H 2 O \ (S) H \O O
CI O (XI) CI O
(X-S) (XII-S)
reacting a compound of formula (X-S) with a compound of formula (XI),
wherein -C(O)OR is a nitrogen protecting group; in the presence of an organic
or inorganic base, wherein the organic or inorganic base is not reactive with
the
8
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
chloro group on the compound of formula (XI); in an aprotic organic solvent;
to
yield the corresponding compound of formula (XII-S);
H
O SAN OR O SIINH2
(s) N O Y (s) N ~O
/ H o 1 / H
CI O CI O (I-S)
(XII-S)
de-protecting the compound of formula (XII-S); to yield the
corresponding compound of formula (I-S).
The present invention is further directed to a crystalline form of the
compound of formula (I-S).
The present invention is further directed to compounds of formula (XII)
R4
/-\
R I (CH2)a N
\
S OR
I -~
R, 0 (XII)
R I
wherein -C(O)OR is a nitrogen protecting group and wherein
a, R4 and R1 are as herein defined. Preferably, -C(O)OR is a nitrogen
protecting group wherein R is selected from the group consisting of C1_4alkyl
(preferably t-butyl), benzyl, p-methoxybenzyl and 9-fluorenylmethyl. The
compounds of formula (XII) are useful as intermediates in the synthesis of the
compounds of formula (I).
The present invention is further directed to a product prepared according
to the process described herein.
Illustrative of the invention is a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and the product prepared according to the
process described herein. An illustration of the invention is a pharmaceutical
composition made by mixing the product prepared according to the process
9
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
described herein and a pharmaceutically acceptable carrier. Illustrating the
invention is a process for making a pharmaceutical composition comprising
mixing the product prepared according to the process described herein and a
pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating epilepsy or a related
disorder comprising administering to a subject in need thereof, a
therapeutically
effective amount of any of the compounds or pharmaceutical compositions
described above.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates a representative XRD Spectra for Crystalline Form of
the Compound of Formula (I-S)
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of
compound of formula (I)
R4 O R1
II /
R I (CH2)a N- i-NH
O (I)
wherein R1, R4, a and R are as herein defined. The compounds
of formula (I) are useful in the treatment of epilepsy and related disorders.
In an embodiment, the present invention is directed to a process for the
synthesis of compounds of formula (IA)
1
i-~ R 4 0 R
R I (CH2)a N- i-NH
O (IA)
I R I
wherein R1 is hydrogen, and wherein R4, a and 9 are as herein
defined; and pharmaceutically acceptable salts thereof.
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
In another embodiment, the present invention is directed to a process for
the preparation of compounds of formula (IB)
R4 0 R1
` I II /
R (CH2)a N- i-NH
O (IB)
wherein R1 is selected from the group consisting of lower alkyl, and
wherein R4, a and - are as herein defined; and pharmaceutically
acceptable salts thereof.
In another embodiment, the present invention is directed to a process for
the synthesis of compounds of formula (IC)
0
O \ NH2
(S) N / O
(Rs)b H
0 (I-C)
and pharmaceutically acceptable salts thereof, wherein b and R5 are as
herein defined. Preferably, b is an integer from 0 to 2; more preferably, b is
an
integer from 0 to 1. Preferably R5 is halogen, more preferably chloro.
In an embodiment of the present invention R1 is selected from the group
consisting of hydrogen and methyl. In another embodiment of the present
invention, R1 is hydrogen.
In an embodiment of the present invention -(CH2)a is selected from the
group consisting of -CH2- and -CH2-CH2-. In another embodiment of the
present invention -(CI2)a- is -CH2-.
In an embodiment of the present R4 is selected from the group
consisting of hydrogen and methyl, preferably, R4 is hydrogen.
In an embodiment of the present invention a is 1.
In an embodiment of the present invention b is an integer from 0 to 2. In
another embodiment of the present invention c is an integer from 0 to 2. In
another embodiment of the present invention b is an integer from 0 to 1. In
another embodiment of the present invention c is an integer from 0 to 1. In
yet
another embodiment of the present invention the sum of b and c is an integer
11
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
form 0 to 2, preferably an integer from 0 to 1. In yet another embodiment of
the
present invention b is an integer from 0 to 2 and c is 0.
In an embodiment of the present invention, - is a ring structure
(R3)b
selected from the group consisting of
(R)b4 /`- (R3)b
/
O O and
(R3 )c
(R3)b
0 . In another embodiment of the present
invention, - is a ring structure selected from the group consisting of
(R3)c
3 / O O
(R )b (R )b
O and O
In an embodiment of the present invention, - is a ring structure
selected from the group consisting of 2-(chromanyl), 2-(6-chloro-2,3-dihydro-
benzo[1,4]dioxinyl), 2-(benzo[1,3]dioxolyl), 2-(5-chloro-2,3-dihydro-
benzo[1,4]dioxinyl), 2-(7-nitro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(6,7-
dichloro-
2,3-dihydro-benzo[1,4]dioxinyl), 2-(2,3-dihydro-naphtho[2,3-b][1,4]dioxinyl)
and
2-(7-chloro-benzo[1,3]dioxolyl). In another embodiment of the present
invention, - is a ring structure selected from the group consisting of 2-
(5-chloro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(7-nitro-2,3-dihydro-
12
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
benzo[1,4]dioxinyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxinyl) and 2-
(2,3-
dihydro-naphtho[2,3-b][1,4]dioxinyl).
I R
In an embodiment of the present invention, - is selected from the
O O
(RS)b (R5)b I / }
group consisting of O
(R5)c
/ O / 5) O
(R)b- I (R b
5 \ O O and
O
(R5)b
0 )+. In another embodiment of the present invention,
O
R I (R5)b is selected from the group consisting of 0
(R5)c
O
5 O 31~ 5 c-',aO
(R )b I (R )b
O and I R
In an embodiment of the present invention, - is selected from the
group consisting of 2-(2,3-dihydro-benzo[1,4]dioxinyl), 2-
(benzo[1,3]dioxolyl), 2-
(3,4-dihydro-benzo[1,4]dioxepinyl), 2-(6-chloro-2,3-dihydro-
benzo[1,4]dioxinyl),
2-(6-fluoro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(chromanyl), 2-(5-fluoro-2,3-
dihydro-benzo[1,4]dioxinyl), 2-(7-chloro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(6-
chloro-benzo[1,3]dioxolyl), 2-(7-nitro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(7-
methyl-2,3-dihydro-benzo[1,4]dioxinyl), 2-(5-chloro-2,3-dihydro-
benzo[1,4]dioxinyl), 2-(6-bromo-2,3-dihydro-benzo[1,4]dioxinyl), 2-(6,7-
dichloro-
13
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
2,3-dihydro-benzo[1,4]dioxinyl), 2-(8-chloro-2,3-dihydro-benzo[1,4]dioxinyl),
2-
(2,3-dihydro-naphtho[2,3-b][1,4]dioxinyl) and 2-(4-methyl-benzo[1,3]dioxolyl).
In another embodiment of the present invention, - is selected
from the group consisting 2-(benzo[1,3]dioxolyl), 2-(2,3-dihydro-
benzo[1,4]dioxinyl), 2-(6-chloro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(7-chloro-
2,3-
dihydro-benzo[1,4]dioxinyl), 2-(7-methyl-2,3-dihydro-benzo[1,4]dioxinyl), 2-(6-
bromo-2,3-dihydro-benzo[1,4]dioxinyl) and 2-(6,7-dichloro-2,3-dihydro-
~
benzo[1,4]dioxinyl). In another embodiment of the present invention, -
is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4]dioxinyl), 2-
(7-
methyl-2,3-dihydro-benzo[1,4]dioxinyl) and 2-(6-bromo-2,3-dihydro-
benzo[1,4]dioxinyl).
In an embodiment of the present invention R3 is selected from the group
consisting of halogen, lower alkyl, hydroxy substituted lower alkyl, -O-(lower
alkyl), nitro, cyano, amino, lower alkylamino and di(lower alkyl)amino. In
another embodiment of the present invention R3 is selected from the group
consisting of halogen and nitro. In another embodiment of the present
invention R3 is selected from the group consisting of chloro and nitro.
In an embodiment of the present invention R5 is selected from the group
consisting of (II) halogen and lower alkyl. In another embodiment of the
present invention R5 is selected from chloro, fluoro, bromo and methyl.
In an embodiment of the present invention, in the compound of formula
O ,
~~ R ~~ (R3)b
(I), - is other than O wherein b is 1 and R3 is
selected from the group consisting of halogen, nitro, cyano, amino, lower
alkyl,
lower alkoxy and -C(O)O-(lower alkyl). In another embodiment of the present
14
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
invention, in the compound of formula (I), - is other than
O ,
(R3)b
\ O wherein b is 1.
In an embodiment of the present invention, the stereo-center on the
compound of formula (I) is in the S-configuration. In another embodiment of
the present invention, the stereo-center on the compound of formula (I) is in
the
R-configuration.
In an embodiment of the present invention the compound of formula (I)
is present as an enantiomerically enriched mixture, wherein the % enantiomeric
enrichment (%ee) is greater than about 75%, preferably greater than about
85%, more preferably greater than about 90%, more preferably greater than
about 95%, most preferably greater than about 98%.
In another embodiment, the present invention is directed to one or more
of the representative compounds of formula (I) as listed in Table 1, below. In
Table 1 below, the column headed "stereo" defines the stereo-configuration at
the carbon atom of the heterocycle attached at the starred bond. Where no
designation is listed, the compound was prepared as a mixture of stereo-
configurations. Where an "R" or "S" designation is listed, the stereo-
configuration was based on the enantiomerically enriched starting material.
Table 1: Representative Compounds of Formula (I)
R 4 O R
' ~ I II i
(CH2)a N-S-N
IOI \R2
ID No. Stereo (CH2)a NR4 R1 R2
2-(2,3-dihydro-
1 benzo[1,4]dioxinyl) CH2 NH H H
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
2 2-(benzo[1,3]dioxolyl) CH2 NH H H
2-(3,4-dihydro-2H-
3 benzo[1,4]dioxepinyl) CH2 NH H H
2-(2,3-dihydro-
4 benzo[1,4]dioxinyl) S CH2 NH H H
2-(2,3-dihydro-
benzo[1,4]dioxinyl) R CH2 NH H H
2-(2,3-dihydro-
7 benzo[1,4]dioxinyl) CH2 N(CH3) H H
2-(6-chloro-2,3-dihydro-
8 benzo[1,4]dioxinyl) S CH2 NH H H
2- (6-fluoro-2 , 3- d i h yd ro-
9 benzo[1,4]dioxinyl) S CH2 NH H H
2-(chromanyl) CH2 NH H H
2- (5-fluoro-2 , 3- d i h yd ro-
13 benzo[1,4]dioxinyl) S CH2 NH H H
2-(7-chloro-2,3-dihydro-
14 benzo[1,4]dioxinyl) S CH2 NH H H
2-(6-chloro-
benzo[1,3]dioxolyl) CH2 NH H H
2-(2,3-dihydro-
16 benzo[1,4]dioxinyl) CH2CH2 NH H H
2-(7-nitro-2,3-dihydro-
18 benzo[1,4]dioxinyl) S CH2 NH H H
2-(7-methyl-2,3-d ihydro-
19 benzo[1,4]dioxinyl) S CH2 NH H H
2-(5-chloro-2,3-dihydro-
benzo[1,4]dioxinyl) S CH2 NH H H
2-(8-methoxy-2,3-
dihydro-
22 benzo[1,4]dioxinyl) S CH2 NH H H
16
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
2- (6- b ro m o-2 , 3- d i h yd ro-
24 benzo[1,4]dioxinyl) S CH2 NH H H
2-(6,7-dichloro-2,3-
dihydro-
29 benzo[1,4]dioxinyl) S CH2 NH H H
2-(8-chloro-2,3-dihydro-
30 benzo[1,4]dioxinyl) S CH2 NH H H
2-(2,3-dihydro-
naphtho[2,3-
33 b][1,4]dioxinyl) S CH2 NH H H
2-(4-methyl-
35 benzo[1,3]dioxolyl) CH2 NH H H
Additional embodiments of the present invention, include those wherein
the substituents selected for one or more of the variables defined herein
(e.g. a,
~ R ~
R1, R4, R5, = - , etc.) are independently selected to be any individual
substituent or any subset of substituents selected from the complete list as
defined herein.
The present invention is further directed to compounds of formula (XII)
R4
(CH2)a N
= ~ O
~S OR
I -~
R1 0 (XII)
~ R ~
wherein -C(O)OR is a nitrogen protecting group and wherein = - ,
a, R4 and R1 are as herein defined. In an embodiment, the present invention is
directed to a compound of formula (XII-S)
17
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
O H
O 'IN OR
(s) N Y
H O
Cl O (XII-S)
wherein -C(O)OR is a nitrogen protecting group. Preferably, -C(O)OR
is a nitrogen protecting group wherein R is selected from the group
consisting
of alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl. More preferably, R is
selected from the group consisting of C1_4alkyl (preferably t-butyl), benzyl,
p-
methoxybenzyl, phenylethyl, phenyl, naphthyl, cycloalkyl and 9-
fluorenylmethyl.
More preferably, R is selected from the group consisting of C1_4alkyl
(preferably t-butyl), benzyl, p-methoxybenzyl and 9-fluorenylmethyl. More
preferably still, R is selected from the group consisting of t-butyl, benzyl,
p-
methoxybenzyl and 9-fluorenylmethyl.
As used herein, unless otherwise noted, "halogen" shall mean chlorine,
bromine, fluorine and iodine.
As used herein, unless otherwise noted, the term "alkyl" whether used
alone or as part of a substituent group, includes straight and branched
chains.
For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted,
"lower"
when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
As used herein, unless otherwise noted, "alkoxy" shall denote an oxygen
ether radical of the above described straight or branched chain alkyl groups.
For
example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the
like.
As used herein, unless otherwise noted, "aryl" shall refer to unsubstituted
carbocylic aromatic groups such as phenyl, naphthyl, and the like, preferably
phenyl.
As used herein, unless otherwise noted, "aralkyl" shall mean any lower
alkyl group substituted with an aryl group such as phenyl, naphthyl and the
like.
For example, benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and the like,
preferably benzyl.
18
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
As used herein, unless otherwise noted, the term "cycloalkyl" shall
mean any stable monocyclic, bicyclic or polycyclic, saturated ring system,
preferably a monocyclic or bicyclic saturated ring system, more preferably a
monocyclic saturated ring system. Suitable examples include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, adamantyl, and the like.
As used herein, the notation "*" shall denote the presence of a
stereogenic center.
As used herein, unless otherwise noted, the term "enantiomerically
enriched" when used to describe a compound with one stereogenic center,
shall mean that one stereo-configuration of the compound is present in a
greater amount than the opposite stereo-configuration of said compound.
Preferably, when the compound is said to be enantiomerically enriched, the
desired enantiomer of said compound is present in an enantiomeric excess of
at least about 75 percent ee, more preferably at least 85 percent ee, more
preferably at least 90 percent ee, more preferably at least 95 percent ee,
more
preferably at least 98 percent ee, most preferably at least 99 percent ee.
As used herein, unless otherwise noted, the term "nitrogen protecting
group" shall mean any ester group which can act as a protecting group for a
amine, amide, sulfamide or sulfanomide nitrogen. Suitable examples include,
but
are not limited to alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, and
the
like. For example, the nitrogen protecting group may be of the formula -
C(O)OR , wherein R is C1_4alkyl (preferably t-butyl), benzyl, p-
methoxybenzyl,
phenylethyl, phenyl, naphthyl, cycloalkyl, 9-fluorenylmethyl, and the like,
and
wherein any of the R groups may be further substituted.
Abbreviations used in the specification, particularly the Schemes and
Examples, are as follows:
BOC or Boc = t-Butoxycarbonyl (-C(O)O-C(CH3)3)
DIPEA or DIEA = Diisopropylethylamine
DMAP = 4-(N,N-Dimethylamino)pyridine
19
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
DMF = N,N-Dimethylformamide
EtOAc = Ethyl acetate
Fmoc = 9-Fluorenylmethoxycarbonyl
MTBE = Methyl t-butyl ether
Pd/C = Palladium on Carbon Catalyst
RBF = Round bottom flask
RT or rt = Room temperature
TEA = Triethylamine
TFA = Trifluoroacetic Acid
THE = Tetrahydrofuran
XRD = X-ray Diffraction
As used herein, unless otherwise noted, the terms "epilepsy and related
disorders" or "epilepsy or related disorder" shall mean any disorder in which
a
subject (preferably a human adult, child or infant) experiences one or more
seizures and / or tremors. Suitable examples include, but are not limited to,
epilepsy (including, but not limited to, localization-related epilepsies,
generalized
epilepsies, epilepsies with both generalized and local seizures, and the
like),
seizures as a complication of a disease or condition (such as seizures
associated
with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's
progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes,
drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, and the
like),
essential tremor, restless limb syndrome, and the like. Preferably, the
disorder is
selected from epilepsy (regardless of type, underlying cause or origin),
essential
tremor or restless limb syndrome, more preferably, the disorder is epilepsy
(regardless of type, underlying cause or origin) or essential tremor.
The term "subject" as used herein, refers to an animal, preferably a
mammal, most preferably a human, who is or has been the object of treatment,
observation or experiment.
The term "therapeutically effective amount" as used herein, means that
amount of active compound or pharmaceutical agent that elicits the biological
or
medicinal response in a tissue system, animal or human that is being sought by
a
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
researcher, veterinarian, medical doctor or other clinician, which includes
alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well
as any product which results, directly or indirectly, from combinations of the
specified ingredients in the specified amounts.
One skilled in the art will recognize that, where not otherwise specified,
the reaction step(s) in the specification and claims are performed under
suitable conditions (e.g. temperature, pressure, with appropriate solvents
and/or reactants), according to known methods, to provide the desired product.
The term "suitable conditions" shall mean a reaction step is performed under
appropriate conditions (e.g. temperature, pressure, with appropriate solvents
and/or reactants) according to known methods to provide the desired product.
One skilled in the art will also recognize that, in the specification and
claims as presented herein, wherein a reagent or reagent class/type/ (e.g.
base, solvent, etc.) is recited in more than one step of a process, the
individual
reagents are independently selected for each reaction step and may be the
same of different from each other. For example wherein two steps of a process
recite an organic or inorganic base as a reagent, the organic or inorganic
base
selected for the first step may be the same or different than the organic or
inorganic base of the second step.
To provide a more concise description, some of the quantitative
expressions given herein are not qualified with the term "about". It is
understood that whether the term "about" is used explicitly or not, every
quantity given herein is meant to refer to the actual given value, and it is
also
meant to refer to the approximation to such given value that would reasonably
be inferred based on the ordinary skill in the art, including approximations
due
to the experimental and/or measurement conditions for such given value.
As used herein, unless otherwise noted, the term "aprotic solvent" shall
mean any solvent that does not yield a proton. Suitable examples include, but
are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane,
dichloromethane, MTBE, toluene, and the like.
21
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
As used herein, unless otherwise noted, the term "leaving group" shall
mean a charged or uncharged atom or group which departs during a
substitution or displacement reaction. Suitable examples include, but are not
limited to, Br, Cl, I, mesylate, tosylate, and the like.
As used herein, unless otherwise noted, the term "nitrogen protecting
group" shall mean a group which may be attached to a nitrogen atom to
protect said nitrogen atom from participating in a reaction and which may be
readily removed following the reaction. Suitable nitrogen protecting groups
include, but are not limited to carbamates - groups of the formula -C(O)O-R
wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, p-
methoxybenzyl, 9-fluorenylmethyl, and the like, CH2=CH-CH2-, and the like;
amides - groups of the formula -C(O)-R' wherein R' is for example methyl,
phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives - groups of the
formula -S02-R" wherein R" is for example tolyl, phenyl, trifluoromethyl,
2,2,5,7,8-pentamethyl chrom an-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and
the like. Other suitable nitrogen protecting groups may be found in texts such
as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John
Wiley & Sons, 1991.
Where the compounds according to this invention have at least one
chiral center, they may accordingly exist as enantiomers. Where the
compounds possess two or more chiral centers, they may additionally exist as
diastereomers. It is to be understood that all such isomers and mixtures
thereof are encompassed within the scope of the present invention. Preferably,
wherein the compound is present as an enantiomer, the enantiomer is present
at an enantiomeric excess of greater than or equal to about 80%, more
preferably, at an enantiomeric excess of greater than or equal to about 90%,
more preferably still, at an enantiomeric excess of greater than or equal to
about 95%, more preferably still, at an enantiomeric excess of greater than or
equal to about 98%, most preferably, at an enantiomeric excess of greater than
or equal to about 99%. Similarly, wherein the compound is present as a
diastereomer, the diastereomer is present at an diastereomeric excess of
greater than or equal to about 80%, more preferably, at an diastereomeric
22
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
excess of greater than or equal to about 90%, more preferably still, at an
diastereomeric excess of greater than or equal to about 95%, more preferably
still, at an diastereomeric excess of greater than or equal to about 98%, most
preferably, at an diastereomeric excess of greater than or equal to about 99%.
Furthermore, some of the crystalline forms for the compounds of the
present invention may exist as polymorphs and as such are intended to be
included in the present invention. In addition, some of the compounds of the
present invention may form solvates with water (i.e., hydrates) or common
organic solvents, and such solvates are also intended to be encompassed
within the scope of this invention.
One skilled in the art will recognize that wherein a reaction step of the
present invention may be carried out in a variety of solvents or solvent
systems,
said reaction step may also be carried out in a mixture of the suitable
solvents
or solvent systems.
Where the processes for the preparation of the compounds according to
the invention give rise to mixture of stereoisomers, these isomers may be
separated by conventional techniques such as preparative chromatography.
The compounds may be prepared in racemic form, or individual enantiomers
may be prepared either by enantiospecific synthesis or by resolution. The
compounds may, for example, be resolved into their component enantiomers
by standard techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric
acid
and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization
and
regeneration of the free base. The compounds may also be resolved by
formation of diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the compounds
may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect sensitive
or
reactive groups on any of the molecules concerned. This may be achieved by
means of conventional protecting groups, such as those described in Protective
Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and
T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John
23
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
Wiley & Sons, 1991. The protecting groups may be removed at a convenient
subsequent stage using methods known from the art.
For use in medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts." Other salts may, however, be
useful in the preparation of compounds according to this invention or of their
pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts
of the compounds include acid addition salts which may, for example, be
formed by mixing a solution of the compound with a solution of a
pharmaceutically acceptable base (preferably a strong base) such as NaOH,
KOH, NaH, chloline hydroxide, and the like.
The present invention is directed to a process for the preparation of
compounds of formula (I). Compounds of formula (IA) (compounds of formula
(I) wherein R1 is hydrogen) may be prepared as outlined in more detail in
Scheme 1, below.
0
II
CI-S-NH
R4 p -OR
(CH2)a-NH
(XI)
(X)
R4 R4 O
N-S-NH2
(CH2)a N I~ R ~I k'-"121a
O
(XII) OiS\ /OR (IA) O
HNC(
O
Scheme 1
Accordingly, a suitably substituted compound of formula (X), a known
compound or compound prepared by known methods, is reacted with a suitably
substituted compound of formula (XI), wherein -C(O)OR is a suitably selected
nitrogen protecting group, for example, an alkoxycarbonyl, aryloxycarbonyl,
aralkyloxycarbonyl, and the like, for example, wherein R is C1_4alky1
(preferably
t-butyl), benzyl, p-methoxybenzyl, phenylethyl, phenyl, naphthyl, cycloalkyl,
9-
24
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
fluorenylmethyl, and the like, and wherein any of the R groups may be further
substituted, a known compound or compound prepared by known methods;
in the presence of an organic or inorganic base, wherein the organic or
inorganic base is not reactive with the chloro group on the compound of
formula (XI), preferably, an organic base, more preferably a tertiary amine
base such DIPEA, TEA, pyridine, N-methylmorpholine, N-methylpiperidine, and
the like, preferably pyridine; wherein the base is preferably present in an
amount greater than about 1 molar equivalent, more preferably, the base is
present in an amount in the range of from about 1.1 to about 3.0 molar
equivalents; most preferably in an amount of about 2.0 molar equivalents; in
an
aprotic organic solvent such as DMF, THF, acetonitrile, and the like,
preferably
aceonitrile; preferably at a temperature in the range of from about 0 C to
about
50 C; to yield the corresponding compound of formula (XII).
The compound of formula (XII) is de-protected according to known
methods, to yield the corresponding compound of formula (IA). For example,
by reacting the compound of formula (XII) with an acid or reacting the
compound of formula (XII) with hydrogen or a source of hydrogen. Preferably,
wherein the nitrogen protecting group (-C(O)OR ) is BOC, the compound of
formula (XII) is de-protected by reacting with an acid such as TFA, HCI, and
the
like, preferably HCI; in an organic solvent such as THF, ethyl acetate, and
the
like. Alternatively, wherein the nitrogen protecting group (-C(O)OR ) is
benzyl,
the compound of formula (XII) is de-protected by reacting with hydrogen or a
source of hydrogen, such as hydrogen gas, in the present of a catalyst such as
Pd/C, at a pressure in the range of from about 10 psi to about 60 psi, in an
organic solvent such as ethanol, methanol, toluene acetic acid, and the like.
Alternatively, wherein the nitrogen protecting group (-C(O)OR ) is 9-
fluorenylmethyl, the compound of formula (XII) is de-protected by reacting
with
a base such as an amine base such as piperidine, morpholine, and the like, in
an organic solvent DMF, and the like.
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
Compounds of formula (IB) (compounds of formula (I) wherein R1 is
selected from the group consisting of lower alkyl) may be prepared according
to
the process as outlined in Scheme 2, below.
R4
R4
(CH2)a-N R1-Q (CH2)a-N
\ OR (XV) OAS OR
N
HN -~
(XII) (XVI)
O 11 O
R
R4
R (CH2)a N
Sp
(IB) O HN-R1
Scheme 2
Accordingly, a suitably substituted compound of formula (XII), prepared
as in Scheme 1 above, is reacting with a suitably selected compound of
formula (XV), an alkyl halide or alkyl sulfonate, wherein Q is a suitable
leaving
group such as Cl, Br, I, -O-SO2-CH3 (mesylate) -O-SO2-CF3 (triflate)-O-SO2-
tolyl (tosylate), and the like; in the presence of an organic or inorganic
base
such as K2CO3, Na2CO3, NaOH, KOH, pyridine, DIPEA, TEA, and the like,
preferably a tertiary amine base, more preferably pyridine; in an organic
solvent
such as THF, acetonitrile, DMF, and the like; preferably at a temperature in
the
range of from about 0 C to about 50 C; to yield the corresponding compound of
formula (XVI).
The compound of formula (XVI) is de-protected according to known
methods, to yield the corresponding compound of formula (IB). For example,
by reacting the compound of formula (XVI) with an acid or reacting the
compound of formula (XVI) with hydrogen or a source of hydrogen. Preferably,
wherein the nitrogen protecting group (-C(O)OR ) is BOC, the compound of
formula (XVI) is de-protected by reacting with an acid such as TFA, HCI, and
the like, preferably HCI; in an organic solvent such as THF, ethyl acetate,
and
the like. Alternatively, wherein the nitrogen protecting group (-C(O)OR ) is
benzyl, the compound of formula (XVI) is de-protected by reacting with
hydrogen or a source of hydrogen, such as hydrogen gas, in the present of a
catalyst such as Pd/C, at a pressure in the range of from about 10 psi to
about
26
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
60 psi, in an organic solvent such as ethanol, methanol, toluene acetic acid,
and the like. Alternatively, wherein the nitrogen protecting group (-C(O)OR )
is
9-fluorenylmethyl, the compound of formula (XVI) is de-protected by reacting
with a base such as an amine base such as piperidine, morpholine, and the
like, in an organic solvent DMF, and the like.
The compound of formula (I) is isolated according to known methods, for
example by filtration, solvent evaporation, and the like. Preferably, the
compound of formula (I) is further purified according to known methods, for
example by recrystallization from a suitable solvent such as water, toluene,
and
the like, preferably toluene.
In an embodiment, the present invention is directed to a process for the
preparation of the compound of formula (I-S), as outlined in Scheme 3, below.
0
II
CI-S-NH
II -OR
O
(S) NI-12 O
CI O (XI)
(X-S)
O H
OR 0
'IN Y
O ,S \\ iNH2
Is
O
\ (S) H O O \ 0o(
CI ~ O CI ~
-S)
(XII-S)
Scheme 3
Accordingly, a suitably substituted compound of formula (X-S), also
known as C-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine, a known
compound, wherein -C(O)OR is a suitably selected nitrogen protecting group,
for example, an alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, and the
like, for example, wherein R is C1_4alkyl (preferably t-butyl), benzyl, p-
methoxybenzyl, phenylethyl, phenyl, naphthyl, cycloalkyl, 9-fluorenylmethyl,
27
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
and the like, and wherein any of the R groups may be further substituted, a
known compound or compound prepared by known methods;
in the presence of an organic or inorganic base, wherein the organic or
inorganic base is not reactive with the chloro group on the compound of
formula (XI), preferably, an organic base, more preferably a tertiary amine
base such DIPEA, TEA, pyridine, N-methylmorpholine, N-methylpiperidine, and
the like, preferably pyridine; wherein the base is preferably present in an
amount greater than about 1 molar equivalent, more preferably, the base is
present in an amount in the range of from about 1.1 to about 3.0 molar
equivalents; most preferably in an amount of about 2.0 molar equivalents; in
an
aprotic organic solvent such as DMF, THF, acetonitrile, and the like,
preferably
aceonitrile; preferably at a temperature in the range of from about 0 C to
about
50 C; to yield the corresponding compound of formula (XII-S).
The compound of formula (XII-S) is de-protected according to known
methods, to yield the corresponding compound of formula (I-S). For example,
by reacting the compound of formula (XII-S) with an acid or reacting the
compound of formula (XII-S) with hydrogen or a source of hydrogen.
Preferably, wherein the nitrogen protecting group (-C(O)OR ) is BOC, the
compound of formula (XII-S) is de-protected by reacting with an acid such as
TFA, HCI, and the like, preferably HCI; in an organic solvent such as THF,
ethyl
acetate, and the like. Alternatively, wherein the nitrogen protecting group (-
C(O)OR ) is benzyl, the compound of formula (XII-S) is de-protected by
reacting with hydrogen or a source of hydrogen, such as hydrogen gas, in the
present of a catalyst such as Pd/C, at a pressure in the range of from about
10
psi to about 60 psi, in an organic solvent such as ethanol, methanol, toluene
acetic acid, and the like. Alternatively, wherein the nitrogen protecting
group (-
C(O)OR ) is 9-fluorenylmethyl, the compound of formula (XII-S) is de-protected
by reacting with a base such as an amine base such as piperidine, morpholine,
and the like, in an organic solvent DMF, and the like.
The compound of formula (I-S) is isolated according to known methods,
for example by filtration. Preferably, the compound of formula (I-S) is
further
28
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
purified according to known methods, for example by recrystallization from a
suitable solvent such as water, toluene, and the like, preferably toluene.
Compounds of formula (XI) are known compounds or compounds which
may be prepared according to known methods. For example, the compounds
of formula (XI) may be prepared according to the process as outlined in
Scheme 4, below.
O R -OH O
CI-S-N=C=O CI-S-NH
0 (XIV) 0 OR
(X111)
O (XI)
Scheme 4
Accordingly, a suitably substituted compound of formula (XIII), a known
compound or compound prepared by known methods, is reacted with a suitably
selected alcohol, a compound of formula (XIV); wherein the compound of
formula (XIV) is preferably present in about 1 molar equivalent; neat or in an
aprotic organic solvent such as acetonitrile, ethyl acetate, toluene, and the
like,
provided that the compound of formula (XIII) and the compound of formula
(XIV) are at least partially soluble in the solvent and unreactive to the
solvent;
preferably, at a temperature in the range of from about 0 to about room
temperature; to yield the corresponding compound of formula (XI).
Compounds of formula (XI-S) wherein R is t-butyl may be prepared
according to the process outlined in Scheme 5.
O OH O
11 11
CI-S-N=C=O CI-S-NH
0 (XIV-S) 0 ~O
(X111)
O (XI-S)
Scheme 5
Accordingly, isocyanatidosulfuryl chloride, a known compound, is
reacted t-butanol, a known compound, wherein the t-butanol is preferably
present in about 1 molar equivalent; neat or in an aprotic organic solvent
such
29
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
as, aceotnitrile, ethyl acetate, toluene, and the like, provided that the
compound
of formula (XIII) and the compound of formula (XIV) are at least partially
soluble
in the solvent and unreactive to the solvent, preferably neat or in
acetonitrile;
preferably, at a temperature in the range of from about 0 to about room
temperature, morepreferably, at a temperature of about 0 C; to yield the
corresponding compound of formula (XI-S), also known as [(1,1-
dimethylethoxy)carbonyl]-sulfamoyl chloride.
The present invention is further directed to a crystalline form of the
compound of formula (1-S). The crystalline form of the compound of formula (I-
S) may be characterized by their corresponding Powder X-ray Diffraction
(PXRD) spectra.
In an embodiment, the crystalline form of the compound of formula (1-S)
may be characterized by its corresponding PXRD peaks, wherein the peaks
have a relative intensity of greater than or equal to about 10% relative
intensity;
preferably, wherein the peaks have a relative intensity of greater than or
equal
to about 25% relative intensity.
In an embodiment, the crystalline form of the compound of formula (1-S)
may be characterized by its corresponding PXRD peaks, wherein the peaks are
defined by their position ( 20), d-spacing (A) and relative intensity (%). In
another embodiment, the crystalline form of the compound of formula (1-S) may
be characterized by its corresponding PXRD peaks, wherein the peaks are
defined by their position ( 20) and d-spacing (A).
A powder XRD spectra was measured for a representative sample of the
crystalline form (1-SA) of the compound of formula (1-S), as shown in Figure
1,
with characteristic peaks as listed in Table 2 below. The PXRD spectra were
measured using an X-Celerator detector, scanning form 3 to 35 20, at a step
size of 0.0165 20, a time per step of 10.16 sec, an effective scan speed of
0.2067 /sec, instrument voltage of 45 kV and a current setting of 40 mA.
Table 2: Form (I-S)
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
Position 20d-s acin (A) Relative Intensity
4.44 19.92 33
15.50 5.72 14
17.32 5.12 48
18.57 4.78 100
19.39 4.58 10
19.86 4.47 30
20.03 4.43 20
20.88 4.26 51
21.57 4.12 23
21.93 4.05 24
22.71 3.92 13
23.19 3.84 14
23.90 3.72 29
24.53 3.63 16
25.02 3.56 25
26.04 3.42 19
26.71 3.34 16
26.84 3.32 13
28.28 3.16 26
29.96 2.98 12
30.70 2.91 21
The present invention further comprises pharmaceutical compositions
containing one or more of the compounds prepared according to any of the
processes described herein with a pharmaceutically acceptable carrier.
Pharmaceutical compositions containing one or more of the compounds of the
invention described herein as the active ingredient can be prepared by
intimately mixing the compound or compounds with a pharmaceutical carrier
according to conventional pharmaceutical compounding techniques. The
carrier may take a wide variety of forms depending upon the desired route of
administration (e.g., oral, parenteral). Thus for liquid oral preparations
such as
suspensions, elixirs and solutions, suitable carriers and additives include
water,
glycols, oils, alcohols, flavoring agents, preservatives, stabilizers,
coloring
agents and the like; for solid oral preparations, such as powders, capsules
and
tablets, suitable carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and the like.
Solid
oral preparations may also be coated with substances such as sugars or be
enteric-coated so as to modulate major site of absorption. For parenteral
administration, the carrier will usually consist of sterile water and other
31
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
ingredients may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous carriers along
with appropriate additives.
To prepare the pharmaceutical compositions of this invention, one or
more compounds of the present invention as the active ingredient is intimately
admixed with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques, which carrier may take a wide
variety of forms depending of the form of preparation desired for
administration,
e.g., oral or parenteral such as intramuscular. In preparing the compositions
in
oral dosage form, any of the usual pharmaceutical media may be employed.
Thus, for liquid oral preparations, such as for example, suspensions, elixirs
and
solutions, suitable carriers and additives include water, glycols, oils,
alcohols,
flavoring agents, preservatives, coloring agents and the like; for solid oral
preparations such as, for example, powders, capsules, caplets, gelcaps and
tablets, suitable carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and the like.
Because of their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are obviously employed. If desired, tablets may be sugar coated or
enteric coated by standard techniques. For parenterals, the carrier will
usually
comprise sterile water, through other ingredients, for example, for purposes
such as aiding solubility or for preservation, may be included. Injectable
suspensions may also be prepared, in which case appropriate liquid carriers,
suspending agents and the like may be employed. The pharmaceutical
compositions herein will contain, per dosage unit, e.g., tablet, capsule,
powder,
injection, teaspoonful and the like, an amount of the active ingredient
necessary to deliver an effective dose as described above. The
pharmaceutical compositions herein will contain, per unit dosage unit, e.g.,
tablet, capsule, powder, injection, suppository, teaspoonful and the like, of
from
about 1-1000 mg and may be given at a dosage of from about 0.01-300
mg/kg/day, or any range therein, preferably from about 0.5-100 mg/kg/day, or
any range therein, more preferably from about 1.0-25.0 mg/kg/day, or any
range therein. The dosages, however, may be varied depending upon the
32
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
requirement of the patients, the severity of the condition being treated and
the
compound being employed. The use of either daily administration or post-
periodic dosing may be employed.
Preferably these compositions are in unit dosage forms from such as
tablets, pills, capsules, powders, granules, sterile parenteral solutions or
suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector
devices or suppositories; for oral parenteral, intranasal, sublingual or
rectal
administration, or for administration by inhalation or insufflation.
Alternatively,
the composition may be presented in a form suitable for once-weekly or once-
monthly administration; for example, an insoluble salt of the active compound,
such as the decanoate salt, may be adapted to provide a depot preparation for
intramuscular injection. For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose, sucrose,
sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums,
and other pharmaceutical diluents, e.g. water, to form a solid preformulation
composition containing a homogeneous mixture of a compound of the present
invention, or a pharmaceutically acceptable salt thereof. When referring to
these preformulation compositions as homogeneous, it is meant that the active
ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective dosage forms
such as tablets, pills and capsules. This solid preformulation composition is
then subdivided into unit dosage forms of the type described above containing
from 0.1 to about 500 mg of the active ingredient of the present invention.
The
tablets or pills of the novel composition can be coated or otherwise
compounded to provide a dosage form affording the advantage of prolonged
action. For example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope over the
former. The two components can be separated by an enteric layer which
serves to resist disintegration in the stomach and permits the inner component
to pass intact into the duodenum or to be delayed in release. A variety of
material can be used for such enteric layers or coatings, such materials
33
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
including a number of polymeric acids with such materials as shellac, cetyl
alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention
may be incorporated for administration orally or by injection include, aqueous
solutions, suitably flavoured syrups, aqueous or oil suspensions, and
flavoured
emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or
peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include synthetic
and natural gums such as tragacanth, acacia, alginate, dextran, sodium
carboxymethylcelIulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The method of treating epilepsy or a related disorder described in the
present invention may also be carried out using a pharmaceutical composition
comprising any of the compounds as defined herein and a pharmaceutically
acceptable carrier. The pharmaceutical composition may contain between about
0.1 mg and 1000 mg, preferably about 50 to 500 mg, of the compound, or any
range therein, and may be constituted into any form suitable for the mode of
administration selected. Carriers include necessary and inert pharmaceutical
excipients, including, but not limited to, binders, suspending agents,
lubricants,
flavorants, sweeteners, preservatives, dyes, and coatings. Compositions
suitable
for oral administration include solid forms, such as pills, tablets, caplets,
capsules
(each including immediate release, timed release and sustained release
formulations), granules, and powders, and liquid forms, such as solutions,
syrups,
elixers, emulsions, and suspensions. Forms useful for parenteral
administration
include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered
in a single daily dose, or the total daily dosage may be administered in
divided
doses of two, three or four times daily. Furthermore, compounds for the
present
invention can be administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to those of
ordinary skill in that art. To be administered in the form of a transdermal
delivery
system, the dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
34
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
For instance, for oral administration in the form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic pharmaceutically
acceptable inert carrier such as ethanol, glycerol, water and the like.
Moreover,
when desired or necessary, suitable binders; lubricants, disintegrating agents
and
coloring agents can also be incorporated into the mixture. Suitable binders
include, without limitation, starch, gelatin, natural sugars such as glucose
or beta-
lactose, corn sweeteners, natural and synthetic gums such as acacia,
tragacanth
or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,
sodium acetate, sodium chloride and the like. Disintegrators include, without
limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the
like.
The liquid forms in suitably flavored suspending or dispersing agents such
as the synthetic and natural gums, for example, tragacanth, acacia, methyl-
cellulose and the like. For parenteral administration, sterile suspensions and
solutions are desired. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is desired.
To prepare a pharmaceutical composition of the present invention, a
compound of formula (I) as the active ingredient is intimately admixed with a
pharmaceutical carrier according to conventional pharmaceutical compounding
techniques, which carrier may take a wide variety of forms depending of the
form of preparation desired for administration (e.g. oral or parenteral).
Suitable
pharmaceutically acceptable carriers are well known in the art. Descriptions
of
some of these pharmaceutically acceptable carriers may be found in The
Handbook of Pharmaceutical Excipients, published by the American
Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
Methods of formulating pharmaceutical compositions have been
described in numerous publications such as Pharmaceutical Dosage Forms:
Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by
Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications,
Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms:
Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by
Marcel Dekker, Inc.
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
Compounds of this invention may be administered in any of the foregoing
compositions and according to dosage regimens established in the art whenever
treatment of epilepsy or related disorders is required.
The daily dosage of the products may be varied over a wide range from
0.01 to 1,000 mg per adult human per day. For oral administration, the
compositions are preferably provided in the form of tablets containing, 0.01,
0.05,
0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500
milligrams of the active ingredient for the symptomatic adjustment of the
dosage
to the patient to be treated. An effective amount of the drug is ordinarily
supplied
at a dosage level of from about 0.01 mg/kg to about 300.0 mg/kg of body weight
per day, or any range therein. Preferably, the range is from about 0.5 to
about
100.0 mg/kg of body weight per day, or any range therein, more preferably,
from
about 1.0 to about 25.0 mg/kg of body weight per day, or any range therein.
The
compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those
skilled in the art, and will vary with the particular compound used, the mode
of
administration, the strength of the preparation, the mode of administration,
and
the advancement of the disease condition. In addition, factors associated with
the
particular patient being treated, including patient age, weight, diet and time
of
administration, will result in the need to adjust dosages.
One skilled in the art will recognize that, both in vivo and in vitro trials
using suitable, known and generally accepted cell and / or animal models are
predictive of the ability of a test compound to treat or prevent a given
disorder.
One skilled in the art will further recognize that human clinical trails
including first-in-human, dose ranging and efficacy trials, in healthy
patients
and / or those suffering from a given disorder, may be completed according to
methods well known in the clinical and medical arts.
The following Examples are set forth to aid in the understanding of the
invention, and are not intended and should not be construed to limit in any
way
the invention set forth in the claims which follow thereafter.
In the Examples which follow, some synthesis products are listed as
having been isolated as a residue. It will be understood by one of ordinary
skill
36
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
in the art that the term "residue" does not limit the physical state in which
the
product was isolated and may include, for example, a solid, an oil, a foam, a
gum, a syrup, and the like.
Example 1
Toluene-4-sulfonic acid 6-chloro-2,3-dihydro-benzof1,41dioxin-2-ylmethyl
ester
OS
O
(R) O/
Cl
O
A 5L three-neck-round bottom flask equipped with a reflux condenser,
nitrogen outlet, overhead stirrer, heating mantle and temperature control unit
was charged with 6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol (176 g
877.28 mmoles), tetrahydrofuran (2 L), 4-pyridinamine, DMAP (25 g; 204.63
mmoles) and p-toluenesulfonyl chloride (1.05 moles; 200.70 g;). The reaction
mixture was then warmed to 40 C. An additional portion of DMAP (5g) and p-
toluenesulfonyl chloride (10 g; 52.45 mmoles) were added and the reaction was
continued overnight. Upon consumption of starting material the reaction was
quenched with water (500mL) and the resulting mixture extract with MTBE
(1.2L), washed with water (300mL, 200mL), then with 1 N HCI wash (400mL,
100mL), and an additional water wash (100mL), followed by a bicarbonate
wash (100mL). The organic layer was dried over Na2SO4, (50g) and silica
(60g). The resulting solution was filtered and concentrated to the title
compound as a thick oil.
Example 2
2-(6-Chloro-2,3-dihydro-benzoFl,41dioxin-2-ylmethyl)-isoindole-1,3-dione
O
O
\ (S) N
/ O
Cl
OOOI
37
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
A three-necked-round bottom flask equipped with a nitrogen outlet,
magnetic stir bar, heating mantle and temperature control unit was charged
with toluene-4-sulfonic acid 6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl
ester (300 g; 845.52 mmoles), dimethylformamide (330.00 mL) and potassium
phthalimide (1.10 moles; 203.59 g). The resulting slurry was warmed to 100 C
and allowed to heat for 2h. The reaction mixture was then cooled to room
temperature in an ice bath and quenched into a stirred ice / water mixture (1
L).
A white solid developed upon stirring. After 2h at room temperature, the solid
was filtered and air dried to yield the title compound as an off-white solid.
Example 3
C-(6-Chloro-2,3-dihvdro-benzof1,41dioxin-2-vl)-methylamine
(s) N I-12
a O
Cl O
A 5L four-neck round bottom flask equipped with a nitrogen outlet, reflux
condenser, overhead stirrer, heating mantle and temperature control unit was
charged with (S)-2-((6-chloro-2,3-dihydrobenzo[b][1,4]dioxin-2-
yl)methyl)isoindoline-1,3-dione (242 g; 733.91 mmoles), ethanol (2.6 L) and
hydrazine (48 g; 1.50 moles). The resulting mixture was heated to reflux.
After
7h the reaction mixture was cooled to room temperature and treated with HCI
(2N) until acidic; and the resulting solids were filtered off. The filtrate
was
concentrated, then treated with MTBE (1 L) and sodium hydroxide (3N, 200mL).
The organic layer was separated and washed with water (200mL), followed by
a brine (200mL) wash. The organic layer was dried (Na2SO4), filtered and
concentrated to yield the title compound.
Example 4
N-FF(2S)-6-chloro-2,3-dihvdro-1,4-benzodioxin-2-vllmethvll-M-F(11-
dimethvlethoxv)carbonvll-sulfamide
38
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
O H
O %S'INY011~
1-11
H O O
CI aO
A 5L three-necked-RBF equipped with a nitrogen outlet, magnetic stir
bar, addition funnel, internal thermometer and cooling bath was treated with C-
(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine (135 g; 676.23
mmoles), acetonitrile (1000 mL), 4-pyridinamine, DMAP (16.91 mmoles; 2.07 g)
and pyridine (82.02 mL; 80.24 g). Upon cooling the reaction mixture to 0 C an
acetonitrile solution (50mL) of CI-SO2-NH-Boc (168 g; 779.01 mmoles) was
added via addition funnel. The resulting mixture was then allowed to warm to
room temperature with subsequent heating to 45 C (5h). The reaction was
then quenched by addition of 1 N HCI until acidic. The product was extracted
with ethyl acetate (500mL). After phase separation, the organic layer was
treated with 3N NaOH (300mL), the basic aqueous layer was then cooled in an
ice bath and treated with water (20mL) and 2N HCI. The product was extracted
with ethyl acetate (500 mL), dried (Na2SO4), filtered and concentrated to
yield
the title compound as a light yellow solid.
Example 5
N-ff(2S)-6-chloro-2,3-dihydro-1,4-benzodioxin-2-yllmethyll-sulfamide
O
\
O 'INH2
\ (S) H N / ~O
Cl
O
A 2L three-necked round bottom flask equipped with and 250mL addition
funnel, nitrogen outlet, overhead stirrer, heating mantle and temperature
control
unit was charged with (S)-tert-butyl N-((6-chloro-2,3-
dihydrobenzo[b][1,4]dioxin-
2-yl)methyl)sulfamoylcarbamate (256 g; 540.61 mmoles), ethyl Acetate (409.60
mL) followed by addition of hydrogen chloride (2.16 moles; 177.54 mL). The
resulting mixture was warmed to 50 C for 1 h, then cooled to room temperature
then neutralized by addition of NaOH (2N, 220mL) and the product extracted
using ethyl acetate (2 x 200mL), the organic layer was washed with brine
39
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
(100mL), phase separated and dried with Na2SO4 (20g), filtered and
concentrated to yield a thick oil (100 g crude).
The oil was taken up in hot water (750mL + 200mL) hot filtered to
remove insoluble oil and other impurities. The resulting mixture was cooled to
25 C and the resulting solids were filtered and dried to yield the title
compound
as a white solid.
Example 6
f(1,1-dimethylethoxy)carbonyll- sulfamoyl chloride
O H
\S11 N YO
CIS \\
O O
A 100mL three-necked-RBF equipped with a nitrogen outlet, addition
funnel, temperature sensor and ice bath was treated with chlorosulfonyl
Isocyanate (811.47 mmoles; 70.76 mL) and acetonitrile (50mL). Upon cooling
to 0 C t-butyl alcohol (811.47 mmoles; 77.08 mL; 60.15 g) was added as a
solution in acetonitile (50mL) via addition funnel, while the internal
temperature
of the reaction mixture was maintained at less than 10 C. After addition the
reaction was determined to be complete. The reaction mixture was
concentrated to a white foam (1 68g), which was washed with heptane on the
filter pad to yield the title compound.
Example 7
Toluene Recrystallization of N-FF(2S)-6-chloro-2,3-dihydro-1,4-
benzodioxin-2-yllmethyll-sulfamide
0
O \ .INH2
\ (S) H N / %O
Cl
O
N-[[(2S)-6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl]-sulfamide
(0.5g) was dissolved in hot toluene (5mL), hot-filtered to remove insoluble
material and then allowed to slowly cool to room temperature. The resulting
CA 02719624 2010-09-24
WO 2009/120191 PCT/US2008/058233
solid was collected by filtration, washed with heptane and air dried to yield
the
title compound as a crystalline, white solid.
M.P. 98 C.
Example 8
Liquid Formulation
The compound of formula (I-S), prepared for example, as in Example 7
above, was formulated according to known methods into liquid formulations of
25mg and 100 mg, respectively, with components as listed in Table 3 below.
Table 3: Liquid Formulations
25 mg/mL 100 mg/mL
Component Role Suspension Suspension
Compound of formula (I-S) Active 25 mg 100 mg
Hypromellose
(also known as HPMC or Suspending
hydroxypropylmethylcelIulose) agent 5 mg 5 mg
Purified water Solvent q.s. ad. 1 mL q.s. ad. 1 mL
Example 9 - Prophetic Example
As a specific embodiment of an oral composition, 100 mg of the
compound of formula (I-S), prepared as in Example 7 is formulated with
sufficient finely divided lactose to provide a total amount of 580 to 590 mg
to fill
a size 0 hard gel capsule.
While the foregoing specification teaches the principles of the present
invention, with examples provided for the purpose of illustration, it will be
understood that the practice of the invention encompasses all of the usual
variations, adaptations and/or modifications as come within the scope of the
following claims and their equivalents.
41
