Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PREPARATION OF BENZO-FUSED HETEROARYL
DERIVATIVES
FIELD OF THE INVENTION
The present invention is directed to processes for the preparation of
benzo-fused heteroaryl derivatives, useful for the treatment of epilepsy and
related disorders. The present invention is further directed to processes for
the
preparation of intermediates in the synthesis of the benzo-fused heteroaryl
derivatives.
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
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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
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.
(harrisonsonline.com,
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
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process suitable for the preparation of large scale material and / or for
commercial preparation of the compounds of formula (I).
SUMMARY OF THE INVENTION
The present invention is directed to a process for the preparation of
compounds of formula (I)
R4 O
H2 1 II R
C-N-S-N
`-' II \2
0 R (I)
wherein
- is selected from the group consisting of
(R5)c
O
5
(R )b I (R )b \ \
IicIIJ3
O and
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;
R4 is selected from the group consisting of hydrogen and lower alkyl;
R1 and R2 are each independently selected from the group consisting of
hydrogen and lower alkyl;
or pharmaceutically acceptable salts thereof; comprising
OOAP
cCH
lip A
g
(X) O (XI) O
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protecting a compound of formula (X) wherein is selected
(R5)c
(R5)b C,( (R5)b
~f' a
from the group consisting of ands
to yield the corresponding compound of formula (XI), wherein Pg' is an alcohol
protecting group;
01" Pgi
A ao
O
(XI) IO (X11) ~O
reacting the compound of formula (XI) with an oxidizing agent; in an
organic solvent; to yield the corresponding compound of formula (XII);
ao INI Pgi O11% Pg1
O OH
(X11) \O (X111)
reacting the compound of formula (XI I) with an organic or inorganic
base; in an organic solvent, in a mixture of organic solvents or in a mixture
of
one or more organic solvents and water; to yield the corresponding compound
of formula (XIII);
ao ~ Pgi O". P40- A g
OH O
(XIII) (XIV) 0
reacting the compound of formula (XIII) with a source of epoxy-
methylene; in the presence of an inorganic base; at a temperature greater than
about room temperature; in an organic solvent; to yield the corresponding
compound of formula (XIV);
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aA01-1 OH
Pg
0. A
0 11~1 0--~ * \ 7
(XIV) 0 (XV) 0
de-protecting the compound of formula (XIV); to yield the corresponding
compound of formula (XV);
aOH aOr OH
0--" * O
(XV) 0 (V)
reacting the compound of formula (XV) with an organic or inorganic
base; in a organic solvent; to yield the corresponding compound of formula
(V);
O 0_C-N-S-N
II R2
0 (V) (I) 0
reacting the compound of formula (V); to yield the corresponding
compound of formula (I).
The present invention is further directed to a process for the preparation
of a compound of formula (V)
aor OH
O
(V)
wherein
(R5)b
` is selected from the group consisting of
(R5)c
OP,
(R5)b
and
5
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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;
comprising
OH OAP
A A g
(X) IO (XI) O
protecting a compound of formula (X); to yield the corresponding
compound of formula (XI), wherein Pg' is an alcohol protecting group;
01" Pgi
A ao
O
(XI) IO (X11) `~Z-O
reacting the compound of formula (XI) with an oxidizing agent; in an
organic solvent; to yield the corresponding compound of formula (XI I);
ao INI Pg1 O11% Pgi
O OH
(X11) \O (X111)
reacting the compound of formula (XI I) with an organic or inorganic
base; in an organic solvent, in a mixture of organic solvents or in a mixture
of
one or more organic solvents and water; to yield the corresponding compound
of formula (XIII);
ao "I Pgi OAP
q g
OH O
(XI II) (XIV) 0
reacting the compound of formula (XIII) with a source of epoxy-
methylene; in the presence of an inorganic base; at a temperature greater than
about room temperature; in an organic solvent; to yield the corresponding
compound of formula (XIV);
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aA01-1 OH
Pg
0. A
O~j 0~7
(XIV) 0 (XV) 0
de-protecting the compound of formula (XIV); to yield the corresponding
compound of formula (XV);
aOH aOr OH
0--"~
O
(XV) 0 (V)
reacting the compound of formula (XV) with an organic or inorganic
base; in a organic solvent; to yield the corresponding compound of formula
(V).
In an embodiment, the present invention is directed to a process for the
preparation of a compound of formula (I-S)
0
0 S.11NH2
00*111 N / \
\
Cl O (I-S)
or a pharmaceutically acceptable salt thereof (wherein the compound of
formula (I-S) is also known as N-[[(2S)-6-chloro-2,3-dihydro-1,4-benzodioxin-2-
yl]methyl]-sulfamide); comprising
OH P
1 1 g
CI CI
(X-S) 0 (XI-S) O
protecting a compound of formula (X-S); to yield the corresponding
compound of formula (XI-S), wherein Pg' is an alcohol protecting group;
1~1 pgi \ 0-'Pgi
I I
CI I CI ~ O
(XI-S) 0 (XII-S)
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reacting the compound of formula (XI-S) with an oxidizing agent; in an
organic solvent; to yield the corresponding compound of formula (X11-S);
\ O~"pg1 0
~Pg1 10 CI O
(X1 1-S) CI OH
\O (X111-S)
reacting the compound of formula (X11-S) with an organic or inorganic
base; in an organic solvent, in a mixture of organic solvents or in a mixture
of
one or more organic solvents and water; to yield the corresponding compound
of formula (X111-S);
\ ((pg1 ON. (*(pg1
Cl / (R)
O
OH Cl
(X111-S) (XIV-S) 0
reacting the compound of formula (X111-S) with a source of (R)-epoxy-
methylene; in the presence of an inorganic base; at a temperature greater than
about room temperature; in an organic solvent; to yield the corresponding
compound of formula (XIV-S);
((Opg1 OH
(R) (R)
Cl 0O' Cl O'"
(XIV-S) 0 (XV-S) ,,O//
de-protecting the compound of formula (XIV-S); to yield the
corresponding compound of formula (XV-S);
OH O
(S) OH I'o'oo'oo'oI!%%%%"'%;~
(R)
Cl 0 j7 Cl O
(XV-S) ,0 (V-S)
reacting the compound of formula (XV-S) with an organic or inorganic
base; in a organic solvent; to yield the corresponding compound of formula (V-
S);
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0
\ 0 OH O S
Cl O
(S)
I \ ~s) H %O
CI ~ O
(V-S) (I-S)
reacting the compound of formula (V-S); to yield the corresponding
compound of formula (I-S).
In another embodiment, the present invention is directed to a process for
the preparation of a compound of formula (V-S)
\ O
Cl O (s) OH (V-S)
also known as (6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-(S)-methanol;
comprising
OH
I P g
CI CI
(X-S) O (XI-S) O
protecting a compound of formula (X-S); to yield the corresponding
compound of formula (XI-S), wherein Pg' is an alcohol protecting group;
"I Pg OAPgi
I I
CI I CI \ ~ O
(XI-S) O (XII-S) l
~O
reacting the compound of formula (XI-S) with an oxidizing agent; in an
organic solvent; to yield the corresponding compound of formula (XII-S);
\ O~"Pgi O10 CI O
(XII-S) CI OH
(XI I I-S)
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reacting the compound of formula (X11-S) with an organic or inorganic
base; in an organic solvent, in a mixture of organic solvents or in a mixture
of
one or more organic solvents and water; to yield the corresponding compound
of formula (X111-S);
\ ((pg1 ((pg1
Cl OH Cl O
(X111-S) (XIV-S) 0
reacting the compound of formula (X111-S) with a source of (R)-epoxy-
methylene; in the presence of an inorganic base; at a temperature greater than
about room temperature; in an organic solvent; to yield the corresponding
compound of formula (XIV-S);
O~ Pg OH
(R) (R)
Cl O Cl
O-~
(XIV-S) 0 (XV-S) ,,O//
de-protecting the compound of formula (XIV-S); to yield the
corresponding compound of formula (XV-S);
~ OH O
(S) OH
/ (R)te I /
CI O~ 7 Cl O
(XV-S) 0 (V-S)
reacting the compound of formula (XV-S) with an organic or inorganic
base; in a organic solvent; to yield the corresponding compound of formula (V-
S).
The present invention is further directed to a process for the preparation
of a compound of formula (1)
R4 O 1
H2 1 II R
C-N-S-N
II \ 2
O R (1)
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wherein
is selected from the group consisting of
(R5)c
O O
31 4 ,
(R )b I (R )b \ \
O and O
b is an integer from 0 to 4; and wherein c is an integer from 0 to 2;
5 each R5 is independently selected from the group consisting of halogen,
lower alkyl and nitro;
R4 is selected from the group consisting of hydrogen and lower alkyl;
R1 and R2 are each independently selected from the group consisting of
hydrogen and lower alkyl;
or pharmaceutically acceptable salts thereof; comprising
Q Q
q A
OH O " \7
(XVI) (XVII) 0
cc
reacting a compound of formula (XVI) wherein is selected
(R5)c
(R5)b / Izr
(R5)b
from the group consisting of ands
and wherein Q is selected from the group consisting of -C(O)-(C1_4alkyl); with
a
source of epoxy-methylene; in the presence of an inorganic base; at a
temperature greater than about room temperature; in an organic solvent; to
yield the corresponding compound of formula (XVII);
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Q o Q
A A
(XVII) 0 (XVIII) 0
reacting the compound of formula (XVII) with an oxidizing agent; in an
organic solvent; to yield the corresponding compound of formula (XVIII);
011. Q cm OH
O O (V)
(XVIII) 0
reacting the compound of formula (XVIII) with an organic or inorganic
base; in a organic solvent; to yield the corresponding compound of formula
(V);
O R 0 R 1
OH (:j:~_H2 1 II p` C-N-S-N
11 R2
0 (V) O
(I)
reacting the compound of formula (V); to yield the corresponding
compound of formula (I).
The present invention is further directed to a process for the preparation
of a compound of formula (V)
ao:r OH
O
(V)
wherein
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(R5)b
is selected from the group consisting of
(R5)c
(R5)b
and
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;
comprising
CQ Q
q A
OH O/
(XVI) (XVII) 0
reacting a compound of formula (XVI) wherein Q is selected from the
group consisting of -C(O)-(C1_4alkyl); with a source of epoxy-methylene; in
the
presence of an inorganic base; at a temperature greater than about room
temperature; in an organic solvent; to yield the corresponding compound of
formula (XVII);
Q o Q
A A
(XVII) 0 (XVIII) 0
reacting the compound of formula (XVII) with an oxidizing agent; in an
organic solvent; to yield the corresponding compound of formula (XVIII);
011.1 Q aor OH
O-" ' O (V)
(XVIII) 0
reacting the compound of formula (XVIII) with an organic or inorganic
base; in a organic solvent; to yield the corresponding compound of formula
(V).
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In an embodiment, the present invention is directed to processes for the
preparation of a compound of formula (I-S)
0
O % "NH2
I \ N / \O
CI O H (I-S)
or a pharmaceutically acceptable salt thereof (wherein the compound of
formula (I-S) is also known as N-[[(2S)-6-chloro-2,3-dihydro-1,4-benzodioxin-2-
yl]methyl]-sulfamide); comprising
\ Q \ Q
Cl I OH Cl ,00
O~
(XVI-S) (XVII-S) 0
reacting a compound of formula (XVI-S) wherein Q is selected from the
group consisting of -C(O)-(C1_4alkyl); with a source of (R)-epoxy-methylene;
in
the presence of an inorganic base; at a temperature greater than about room
temperature; in an organic solvent; to yield the corresponding compound of
formula (XVII-S);
\ Q \ O~
Q
CI / O ( CI O (R)
(XVII-S) O
(XVIII-S) O
reacting the compound of formula (XVII-S) with an oxidizing agent; in an
organic solvent; to yield the corresponding compound of formula (XVIII-S);
O O
I\ Q I\ (S, OH
CI O 11"~ CI O
(XVIII-S) 0 (V-S)
reacting the compound of formula (XVIII-S) with an organic or inorganic
base; in a organic solvent; to yield the corresponding compound of formula (V-
S);
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O O O "INH2
(S) OH
ON. I N H O
CI / /
O (V-S) CI O (I-S)
reacting the compound of formula (V-S); to yield the corresponding
compound of formula (I-S).
In another embodiment, the present invention is directed to processes
for the preparation of the compound of formula (V-S)
\ O
Cl / O (S) OH (V-S)
also known as (6-chloro-2,3-dihydro-benzo[1, 4]dioxin-2-yl)-(S)-methanol;
comprising
\ Q \ Q
O(R)
Cl OH Cl
(XVI-S) (XVII-S) 0
reacting a compound of formula (XVI-S) wherein Q is selected from the
group consisting of -C(O)-(C1_4alkyl); with a source of (R)-epoxy-methylene;
in
the presence of an inorganic base; at a temperature greater than about room
temperature; in an organic solvent; to yield the corresponding compound of
formula (XVII-S);
\ Q \
Q
CI / O ( CI / O (R)
(XVII-S) O
(XVIII-S) O
reacting the compound of formula (XVII-S) with an oxidizing agent; in an
organic solvent; to yield the corresponding compound of formula (XVIII-S);
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ON, O
Q I~ ~S, OH
CI O' ,, CI O
(XVIII-S) 0 (V-S)
reacting the compound of formula (XVIII-S) with an organic or inorganic
base; in a organic solvent; to yield the corresponding compound of formula (V-
S).
The present invention is further directed to crystalline forms of the
compound of formula (I-S)
0
O S.11NH2
00*111 I \ N / \
Cl O (I-S).
In an embodiment, the present invention is directed to crystalline form (I-
SA), as hereinafter defined. In another embodiment, the present invention is
directed to crystalline form (I-SB), as hereinafter defined.
The present invention is further directed to a product prepared according
to any of the processes described herein.
Illustrative of the invention is a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and any of the crystalline forms as
described herein or a product prepared according to any of the processes
described herein. An illustration of the invention is a pharmaceutical
composition made by mixing any of the crystalline forms as described herein or
a product prepared according to any of the processes described herein and a
pharmaceutically acceptable carrier. Illustrating the invention is a process
for
making a pharmaceutical composition comprising mixing any of the crystalline
forms as described herein or a product prepared according to any of the
processes 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
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effective amount of any of the compounds or pharmaceutical compositions
described above.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates representative XRD Spectra for representative
samples of Crystalline Form (I-SA) (labeled b and c) and Crystalline form (I-
SB)
(labeled a).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of
compound of formula (I)
R4 O
H2 1 II R
C-N-S-N
`-' II \ 2
O R (1)
~ R ~
wherein R1, R2, R4 and \ 9 are as herein defined. The compounds
of the present invention are useful in the treatment of epilepsy and related
disorders.
The present invention is further directed to processes for the preparation
of compounds of formula (V), which can be represented herein by either of the
following formulas
O
* OH G-C-OH H2 (V) or '4
The compounds of formula (V) are useful as intermediates in the
synthesis of the compounds of formula (I).
In an embodiment, the present invention is directed to processes for the
preparation of the compound of formula (I-S)
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0
% "NH2
O S
\ N / \
Cl O (I-S)
or pharmaceutically acceptable salts thereof. In another embodiment,
the present invention is directed to processes for the preparation of the
compound of formula (V-S)
O
(S)r OH
In embodiment, the present invention is directed to processes for the
synthesis of compounds of formula (I-A)
0
O \\ NH2
N/%
(R5)b / H
O r 0 (I-A)
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, R5 is 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 R2 is selected from the group consisting of hydrogen and methyl. In
yet another embodiment of the present invention R1 and R2 are each hydrogen
or R1 and R2 are each methyl.
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 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
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.
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In an embodiment of the present invention R5 is selected from the group
consisting of 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, - is a ring structure
(R3)b
selected from the group consisting of ao:
0 and
(R3 )c
(R3)b
0 . In another embodiment of the present
invention, - is selected from the group consisting of
(R3)b
O
In an embodiment of the present invention, - is a ring structure
selected from the group consisting of 2-(6-chloro-2,3-dihydro-
benzo[1,4]dioxinyl), 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)
and
2-(2,3-dihydro-naphtho[2,3-b][1,4]dioxinyl). 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-
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).
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In an embodiment of the present invention, - is selected from the
group consisting of 2-(2,3-dihydro-benzo[1,4]dioxinyl),-2-(6-chloro-2,3-
dihydro-
benzo[1,4]dioxinyl), 2-(6-fluoro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(5-fluoro-
2,3-
dihydro-benzo[1,4]dioxinyl), 2-(7-chloro-2,3-dihydro-benzo[1,4]dioxinyl), 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-2,3-dihydro-
benzo[1,4]dioxinyl),
2-(8-chloro-2,3-dihydro-benzo[1,4]dioxinyl) and 2-(2,3-dihydro-naphtho[2,3-
b][1,4]dioxinyl).
In another embodiment of the present invention, - is selected
from the group consisting 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, 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%, more preferably greater than about 98%, most preferably greater
than about 99%.
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Representative compounds of the present invention, are as listed in
Tables 1 and 2, below. In Tables 1 and 2 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 0 R
(CH2)a N-S-N
11 \R2
ID No. Stereo (CH2)a NR4 R1 R2
2-(2,3-dihydro-
1 benzo[1,4]dioxinyl) CH2 NH H H
2-(2,3-dihydro-
4 benzo[1,4]dioxinyl) S CH2 NH H H
2-(2,3-dihydro-
5 benzo[1,4]dioxinyl) R CH2 NH H H
2-(2,3-dihydro-
6 benzo[1,4]dioxinyl) CH2 NH methyl methyl
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- (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
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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-
20 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
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
Additional embodiments of the present invention, include those wherein
the substituents selected for one or more of the variables defined herein
(e.g.
R1, R2, R4, b and R5, etc.) are independently selected to be any individual
substituent or any subset of substituents selected from the complete list as
defined herein.
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.
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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, 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.
Abbreviations used in the specification, particularly the Schemes and
Examples, are as follows:
DCE = Dichloroethane
DCM = Dichloromethane
DIPEA or DIEA = Diisopropylethylamine
DMF = N,N-Dimethylformamide
DMSO = Dimethylsulfoxide
EtOH = Ethanol
m-CPBA = 3-Chloroperoxybenzoic acid
MeOH = Methanol
MOM = Methoxymethyl
MTBE = Methyl-t-butyl ether
NMP = N-methyl-2-pyrrolidinone
NMR = Nuclear Magnetic Resonance
Pd/C = Palladium on Carbon Catalyst
SEM = 2-(Trim ethylsilyl)ethoxymethyl
TEA = Triethylamine
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THE = Tetrahydrofuran
THP = Tetrahydropyranyl
TMS = Trimethylsilyl
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
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
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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/tyre/ (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.
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
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wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, 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-pentamethylchroman-6-yl-, 2,3,6-trim ethyl-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.
As used herein, unless otherwise noted, the term "alcohol protecting
group" shall mean a group which may be attached to the oxygen of a hydroxy
group (OH)) to protect said hydroxy group from participating in a reaction,
and
which may be readily removed following the reaction. Suitable alcohol
protecting groups include, but are not limited to, t-butyl-dimethylsilyl,
trimethylsilyl (TMS), MOM, ethoxyethyl, THP, SEM, benzyl, 4-nitrobenzyl, 4-
methoxybenzyl, allyl, and the like. Other suitable alcohol 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, which is herein incorporated
by reference in its entirety.
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 75%, more
preferably, the enantiomer is present at an enantiomeric excess of greater
than
or equal to about 85%, 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 75%, more preferably,
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the diastereomer is present at an diastereomeric excess of greater than or
equal to about 85%, more preferably, at an diastereomeric 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
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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
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 (V) as described in more detail in Scheme 1 below.
OH ON, P9i ON
A A P~ ' ` A Pg
O OH
(X) (XI) (X11) (XIII)
GCOl OH aOr Pg OH
O~ O~ O
(XIV) 0 (XV) \\O// (V)
Scheme 1
Accordingly, a suitably substituted compound of formula (X), wherein
op, Ilzr
a`s ` (R5)b
is selected from the group consisting of " and
(R5)c
(R5)b
a known compound or compound prepared by
known methods is protected, by reacting with a suitable protecting agent (i.e.
a
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protecting agent stable under subsequent reaction condition, e.g. hydrolysis,
oxidation) such as benzyl bromide, allyl bromide, 2-
(trimethylsilyl)ethoxymethyl
chloride (SEM-CI), t-butyl-diphenylsilyl chloride, methoxy or nitro-
substituted
benzyl bromides (for example, 4-nitro-benzyl bromide, 4-methoxybenzyl
bromide, and the like), 1-(C1_4alkoxy)methyl halide or 1-(C1_4alkoxy)ethyl
halide,
wherein the halide is Cl, Br or I (for example, MOM-CI, ethoxyethylchloride,
and
the like), and the like; in the presence of an organic or inorganic base such
as
K2CO3, Na2CO3, Cs2CO3, tetramethylguanidine, TEA, and the like; preferably
K2CO3; wherein the base is preferably present in an amount greater than or
equal to about 1 molar equivalent, more preferably an excess amount; at a
temperature greater than about room temperature, preferably at a temperature
in the range of form about 40 C to about 100 C, more preferably, at a
temperature in the range of from about 60 C to about 80 C, most preferably, at
a temperature of about 60 C; in an organic solvent such as DMF, THF, N-
methylpyrrolidinone, and the like; to yield the corresponding compound of
formula (XI), wherein Pg' is the corresponding alcohol protecting group. For
example, wherein the protecting agent is benzyl bromide, Pg' is benzyl;
wherein the protecting agent is allyl bromide, Pg' is allyl; wherein the
protecting
agent is MOM-CI, Pg' is methoxy methyl ether (MOM). One skilled in the art
will recognize that additional protecting groups and methods for incorporating
said protecting groups are known in the art, as for example, described in T.W.
Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley &
Sons, 1991, which is herein incorporated by reference in its entirety.
The compound of formula (XI) is reacted with a suitably selected
oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid,
monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein
the oxidizing agent is present in an amount of at least about 1 molar
equivalent,
preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE,
DCM, chloroform, acetonitrile, NMP, and the like, preferably DCM; preferably,
at about room temperature; to yield the corresponding compound of formula
(XI I).
The compound of formula (XI I) is reacted with an organic or inorganic
base such as NaOCH3, K-t-butoxide, sodium carbonate, potassium
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bicarbonate, and the like, preferably NaOCH3; wherein the base is preferably
present in an amount in the range of from about 1 to about 5 molar
equivalents,
more preferably in an amount in the range of from about 2 to about 3 molar
equivalents; in an organic solvent or mixture thereof such as methanol,
ethanol,
propanol, a mixture of THE and an alcohol, and the like, or in a mixture of
one
or more organic solvents and water; preferably in an alcohol, more preferably
in
methanol; preferably at a temperature in the range of from about room
temperature to about reflux temperature, more preferably at about room
temperature; to yield the corresponding compound of formula (XIII).
The compound of formula (XIII) is reacted with is reacted with a source
O~
of epoxy-methylene (i.e. ) such as glycidyl-m-nosylate, glycidyl-
tosylate, epichlorohydrin, epibromohydrin, and the like, preferably glycidyl-m-
nosylate or glycidyl-tosylate, preferably enantiomerically enriched source of
epoxy-methylene, more preferably (R)-glycidyl-m-nosylate or (R)-glycidyl-
tosylate; wherein the source of epoxy-methylene is preferably present in an
amount in an amount in the range of from about 1 to about 5 molar equivalents,
more preferably present in an amount in an amount in the range of from about
1 to about 2 molar equivalents, more preferably in an amount in the range of
from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic
base such as K2CO3, Na2CO3, Cs2CO3, NaH, KH, and the like, preferably
K2CO3; wherein the inorganic base is preferably present in an amount greater
than or equal to about 1 molar equivalent, more preferably, an excess amount;
at a temperature greater than about room temperature, preferably at a
temperature in the range of form about room temperature to about 100 C, more
preferably, at a temperature in the range of from about 40 C to about 60 C,
most preferably, at a temperature of about 40 C; in an organic solvent such as
DMF, THF, N-methylpyrrolidinone, and the like, preferably DMF; to yield the
corresponding compound of formula (XIV).
The compound of formula (XIV) is de-protected according to known
methods, to yield the corresponding compound of formula (XV). For example,
wherein the compound of formula (XIV) Pg' is benzyl, allyl, and the like, the
compound of formula (XIV) may be de-protected by reacting with hydrogen or a
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source of hydrogen, preferably with hydrogen gas in the presence of a catalyst
such as Pd/C, Pt, Pd(sulfide)/C, and the like; wherein the hydrogen gas is
introduced at a pressure in the range of from about 10 psi to about 15 psi; in
an
organic solvent such as ethyl acetate, THF, isopropyl acetate, 2-methyl-THF,
methyl-t-butyl ether, ethanol, and the like. Wherein Pg' is SEM or a silyl
protecting group, the compound of formula (XIV) may be de-protected by
reacting with a source of fluoride such as tetrabutylammonium fluoride, and
the
like, in an organic solvent such as THF, and the like. One skilled in the art
will
recognize that additional methods for removing protecting groups are known in
the art, as for example, described in T.W. Greene & P.G.M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991.
One skilled in the art will recognize that the reagent(s) selected for the
de-protection of the compound of formula (XIV) are selected to be
substantially
un-reactive to the epoxy group on the compound of formula (XIV).
The compound of formula (XV) is reacted with an organic or inorganic
base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably
NaOCH3; wherein the base is preferably present in an amount greater than or
equal to about 1 molar equivalent, more preferably an excess amount; in a
organic solvent such as methanol, ethanol, THF, acetonitrile, and the like,
preferably methanol; preferably at about room temperature; to yield the
corresponding compound of formula (V).
One skilled in the art will recognize that when the source of epoxy-
methylene is enatiomerically enriched with one of the enantiomers, then on
opening the epoxide, the compound of formula (V) is prepared as the
corresponding enantiomerically enriched compound. For example, wherein
enantiomerically enriched (R)-glycicyl-m-nosylate or (R)-glycidyl tosylate is
reacted with the compound of formula (XIII), then the process as described in
Scheme 1 above yield the corresponding compound of formula (V)
ao:r OH
O (V)
as the enantiomericaly enriched (S) enantiomer at the starred
position.
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Preferably, the process as described in Scheme 1 above is applied to
the preparation of compounds of formula (V) wherein each R5 is other than
nitro. One skilled in the art will recognize that wherein one or more of the
R5
groups are nitro, the compound of formula (V) may be prepared from the
corresponding compound of formula (V) wherein the substituent group at the
position at which one or more nitro groups is desired, is hydrogen, by
converting said hydrogen(s) to the corresponding nitro group(s) according to
known methods, for example by reacting with a mixture of nitric acid and
sulfuric acid, a mixture of nitric acid and acetic acid or by reacting with
potassium nitrate and sulfuric acid.
The present invention is further directed to a process for the preparation
of compounds of formula (V), as described in more detail in Scheme 2, below.
aqQ Q O
A (Al
OH O-
(XVI) (XVII) 0
(XVIII) ^^ 0
aor
OH
O (V)
Scheme 2
Accordingly, a suitably substituted compound of formula (XVI) wherein Q
is selected from the group consisting of -C(O)-(C1_4alkyl), wherein the C1_4
alkyl
is preferably a primary C1_4alkyl, more preferably -C(O)-CH3, and the like, a
known compound or compound prepared by known methods is reacted with a
source of epoxy-methylene (i.e. ) such as glycidyl-m-nosylate,
glycidyl-tosylate, epichlorohydrin, epibromohydrin, and the like, preferably
glycidyl-m-nosylate or glycidyl-tosylate, preferably enantiomerically enriched
source of epoxy-methylene, more preferably (R)-glycidyl-m-nosylate or (R)-
glycidyl-tosylate; wherein the source of epoxy-methylene is preferably present
in an amount in an amount in the range of from about 1 to about 5 molar
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equivalents, more preferably present in an amount in an amount in the range of
from about 1 to about 2 molar equivalents, more preferably in an amount in the
range of from about 1.1 to about 1.5 molar equivalent; in the presence of an
inorganic base such as K2CO3, Na2CO3, Cs2CO3, NaH, KH, and the like,
preferably K2CO3; wherein the inorganic base is preferably present in an
amount greater than or equal to about 1 molar equivalent, more preferably, an
excess amount; at a temperature greater than about room temperature,
preferably at a temperature in the range of form about room temperature to
about 100 C, more preferably, at a temperature in the range of from about
40 C to about 60 C, most preferably, at a temperature of about 40 C; in an
organic solvent such as DMF, THF, N-methylpyrroIidinone, and the like,
preferably DMF; to yield the corresponding compound of formula (XVII).
The compound of formula (XVII) is reacted with a suitably selected
oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid,
monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein
the oxidizing agent is present in an amount of at least about 1 molar
equivalent,
preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE,
DCM, chloroform, acetonitrile, NMP, and the like, preferably DCM; preferably,
at about room temperature; to yield the corresponding compound of formula
(XVIII). Wherein Q is -C(O)-(CH3) the compound of formula (XVII) is reacted
under conditions other than with monomagnesium peroxyphthalate in DMF.
The compound of formula (XVIII) is reacted with an organic or inorganic
base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably
NaOCH3; wherein the base is preferably present in an amount greater than or
equal to about 1 molar equivalent, more preferably an excess amount; in a
organic solvent such as methanol, ethanol, THF, acetonitrile, and the like,
preferably methanol; preferably at about room temperature; to yield the
corresponding compound of formula (V).
One skilled in the art will recognize that when the source of epoxy-
methylene is enatiomerically enriched with one of the enantiomers, then on
opening the epoxide, the compound of formula (V) is prepared as the
corresponding enantiomerically enriched compound. For example, wherein
enantiomerically enriched (R)-glycicyl-m-nosylate or (R)-glycidyl-tosylate is
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reacted with the compound of formula (XIII), then the process as described in
Scheme 2 above yield the corresponding compound of formula (Va)
aor OH
O (V)
as the enantiomericaly enriched (S) enantiomer at the starred ("*")
position.
The compound of formula (V) may be further reacted according to
known methods (for example, as disclosed in McComsey, D., et al. in US
Patent Publication US 2006/0041008 Al, published February 23, 2006;
McComsey, D., et al. in US Patent Publication US 2005/0282887 Al, published
December 22, 2005) to yield the corresponding compound of formula (1).
For example, compounds of formula (1) wherein R4 is hydrogen may be
prepared according to the process outlined in Scheme 3.
O N RO
O O O
rOH
ar IN
0 O O
(V) (XIX) (XX)
O H2 0
11
II 0 C-NH- i -NH2
H2N-S-NH2
A * O
0 0 (la)
H2
O C-NH2
1
* H O R
(XXI) 2 II
0 0 O *C N-S-N
II R H 0 \R2
CI- i-N 2 (I b)
0 R O
(XXII)
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Scheme 3
Accordingly, a suitably substituted compound of formula (V), prepared
as for example outlined in Scheme 1 or 2 above, is activated, according to
known method, to yield the corresponding compound of formula (XIX), wherein
J is a suitable leaving group, such tosylate, Cl, Br, I, mesylate, triflate,
and the
like.
The compound of formula (XIX) is reacted with a phthalimide salt such
as potassium phthlimide, sodium phthalimide, and the like, in an organic
solvent such as DMF, DMSO, acetonitrile, and the like, preferably, at an
elevated temperature in the range of from 50 C to about 200 C, more
preferably, wherein the organic solvent is DMF, DMSO and the like, at
temperature in the range of from about 50 C to about 150 C and wherein the
organic solvent is acetonitrile, and the like, at about reflux temperature, to
yield
the corresponding compound of formula (XX).
The compound of formula (XX) is reacted with N2H4, a known
compound, in an organic solvent such as ethanol, methanol, and the like,
preferably, at an elevated temperature in the range of from about 50 C to
about
100 C, more preferably, at about reflux temperature, and the like, to yield
the
corresponding compound of formula (XXI).
The compound of formula (XXI) is reacted with sulfamide (NH2-SO2-
NH2), a known compound, preferably wherein the sulfamide is present in an
amount in the range of about 2 to about 5 equivalents, in an organic solvent
such as THF, dioxane, and the like, preferably at an elevated temperature in
the range of about 50 C to about 100 C, more preferably at about reflux
temperature, to yield the corresponding compound of formula (la), a compound
of formula (I) wherein R1 and R2 are each hydrogen.
Alternatively, the compound of formula (XXI), is reacted with a suitably
substituted compound of formula (XXII), a known compound or compound
prepared by known methods, in the presence of a base such as TEA, DIPEA,
pyridine, and the like, in an organic solvent such as DMF, DMSO, and the like,
to yield the corresponding compound of formula (lb).
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In an embodiment, the present invention is directed to a process for the
preparation of the compound of formula (V-S), as outlined in Scheme 4 below.
OH ON. pgi \ O~Pgi
CI CI CI O
(X-S) 0 (XI-S) IO (XII-S)
0
\ pg )aoPgCI OH CI
(X111-S) (XIV-S) 0
\
\ OH I OH
Cl O (R) Cl O
(XV-S) 0 (V-S)
Scheme 4
Accordingly, a suitably substituted compound of formula (X-S), a known
compound or compound prepared by known methods is protected by reacting
with a suitable protecting agent (i.e. a protecting agent stable under
subsequent reaction condition, e.g. hydrolysis, oxidation) such as benzyl
bromide, ally) bromide, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-CI), t-
butyl-
diphenylsilyl chloride, methoxy or nitro-substituted benzyl bromides (for
example, 4-nitro-benzyl bromide, 4-methoxybenzyl bromide, and the like), 1-
(Ci_4alkoxy)methyl halide or 1-(CI_4alkoxy)ethyl halide, wherein the halide is
Cl,
Br or I (for example, MOM-CI, ethoxyethylchloride, and the like), and the
like; in
the presence of an organic or inorganic base such as K2CO3, Na2CO3, Cs2CO3,
tetramethylguanidine, TEA, and the like; preferably K2CO3; wherein the base is
preferably present in an amount greater than or equal to about 1 molar
equivalent, more preferably an excess amount; at a temperature greater than
about room temperature, preferably at a temperature in the range of form about
40 C to about 100 C, more preferably, at a temperature in the range of from
about 60 C to about 80 C, most preferably, at a temperature of about 60 C; in
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an organic solvent such as DMF, THF, N-methylpyrrolidinone, and the like; to
yield the corresponding compound of formula (XI-S), wherein Pg' is the
corresponding alcohol protecting group. For example, wherein the protecting
agent is benzyl bromide, Pg' is benzyl; wherein the protecting agent is ally)
bromide, Pg' is allyl; wherein the protecting agent is MOM-CI, Pg' is methoxy
methyl ether. One skilled in the art will recognize that additional protecting
groups and methods for incorporating said protecting groups are known in the
art, as for example, described in T.W. Greene & P.G.M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991, which is herein
incorporated by reference in its entirety.
The compound of formula (XI-S) is reacted with a suitably selected
oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid,
monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein
the oxidizing agent is present in an amount of at least about 1 molar
equivalent,
preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE,
DCM, chloroform, acetonitrile, NMP, and the like, preferably DCM; preferably,
at about room temperature; to yield the corresponding compound of formula
(X11-S).
The compound of formula (X11-S) is reacted with an organic or inorganic
base such as NaOCH3, K-t-butoxide, sodium carbonate, potassium
bicarbonate, and the like, preferably NaOCH3; wherein the base is preferably
present in an amount in the range of from about 1 to about 5 molar
equivalents,
more preferably in an amount in the range of from about 2 to about 3 molar
equivalents; in an organic solvent or mixture thereof such as methanol,
ethanol,
propanol, a mixture of THE and an alcohol, and the like, or in a mixture of
one
or more organic solvents and water; preferably in an alcohol, more preferably
in
methanol; preferably at a temperature in the range of from about room
temperature to about reflux temperature, more preferably at about room
temperature; to yield the corresponding compound of formula (X111-S).
The compound of formula (XIII) is reacted with is reacted with a source
O~
of (R)-epoxy-methylene (i.e. ) such as (R)-glyci dyl-m-nosylate, (R)-
glycidyl-tosylate, (R)-epichlorohydrin, (R)-epibromohydrin, and the like,
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preferably (R)-glycidyl-m-nosylate or (R)-glycidyl-tosylate,; wherein the
source
of epoxy-methylene is preferably present in an amount in an amount in the
range of from about 1 to about 5 molar equivalents, more preferably present in
an amount in an amount in the range of from about 1 to about 2 molar
equivalents, more preferably in an amount in the range of from about 1.1 to
about 1.5 molar equivalent; in the presence of an inorganic base such as
K2CO3, Na2CO3, Cs2CO3, NaH, KH, and the like, preferably K2CO3; wherein the
inorganic base is preferably present in an amount greater than or equal to
about 1 molar equivalent, more preferably, an excess amount; at a temperature
greater than about room temperature, preferably at a temperature in the range
of form about room temperature to about 100 C, more preferably, at a
temperature in the range of from about 40 C to about 60 C, most preferably, at
a temperature of about 40 C; in an organic solvent such as DMF, THF, N-
methylpyrrolidinone, and the like, preferably DMF; to yield the corresponding
compound of formula (XIV-S).
The compound of formula (XIV-S) is de-protected according to known
methods, to yield the corresponding compound of formula (XV-S). For
example, wherein the compound of formula (XIV-S) Pg' is benzyl, allyl, and the
like, the compound of formula (XIV-S) may be de-protected by reacting with
hydrogen or a source of hydrogen, preferably with hydrogen gas in the
presence of a catalyst such as Pd/C, Pt, Pd(sulfide)/C, and the like; wherein
the
hydrogen gas is introduced at a pressure in the range of from about 10 psi to
about 15 psi; in an organic solvent such as ethyl acetate, THF, isopropyl
acetate, 2-methyl-THF, methyl-t-butyl ether, ethanol, and the like. Wherein
Pg'
is SEM or a silyl protecting group, the compound of formula (XIV-S) may be de-
protected by reacting with a source of fluoride such as tetrabutylammonium
fluoride, and the like, in an organic solvent such as THF, and the like. One
skilled in the art will recognize that additional methods for removing
protecting
groups are known in the art, as for example, described in T.W. Greene &
P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,
1991.
One skilled in the art will recognize that the reagent(s) selected for the
de-protection of the compound of formula (XIV-S) are selected to be
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substantially un-reactive to the epoxy group on the compound of formula (XIV-
S).
The compound of formula (XV-S) is reacted with an organic or inorganic
base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably
NaOCH3; wherein the base is preferably present in an amount greater than or
equal to about 1 molar equivalent, more preferably an excess amount; in a
organic solvent such as methanol, ethanol, THF, acetonitrile, and the like,
preferably methanol; preferably at about room temperature; to yield the
corresponding compound of formula (V-S).
In another embodiment, the present invention is directed to a process for
the preparation of the compound of formula (V-S), as outlined in Scheme 5
below.
\ Q \ Q
/ (R)
/0~
Cl OH Cl
(XVI-S) (XVII-S) 0
ON, OH
\ Q (S)
CI O' CI O
(XVIII-S) ,,0 (V-S)
Scheme 5
Accordingly, a suitably substituted compound of formula (XVI-S) wherein
Q is selected from the group consisting of -C(O)-(C1_4alkyl), wherein the C1_4
alkyl is preferably a primary C1_4alkyl, more preferably -C(O)-CH3, and the
like,
a known compound or compound prepared by known methods is reacted with a
O,
source of (R)-epoxy-methylene (i.e. ) such as (R)-glycidyl-m-
nosylate, (R)-glycidyl-tosylate, (R)-epichlorohydrin, (R)-epibromohydrin, and
the
like, preferably (R)-glycidyl-m-nosylate or (R)-glycidyl-tosylate; wherein the
source of epoxy-methylene is preferably present in an amount in an amount in
the range of from about 1 to about 5 molar equivalents, more preferably
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present in an amount in an amount in the range of from about 1 to about 2
molar equivalents, more preferably in an amount in the range of from about 1.1
to about 1.5 molar equivalent; in the presence of an inorganic base such as
K2CO3, Na2CO3, Cs2CO3, NaH, KH, and the like, preferably K2CO3; wherein the
inorganic base is preferably present in an amount greater than or equal to
about 1 molar equivalent, more preferably, an excess amount; at a temperature
greater than about room temperature, preferably at a temperature in the range
of form about room temperature to about 100 C, more preferably, at a
temperature in the range of from about 40 C to about 60 C, most preferably, at
a temperature of about 40 C; in an organic solvent such as DMF, THF, N-
methylpyrrolidinone, and the like, preferably DMF; to yield the corresponding
compound of formula (XVII-S).
The compound of formula (XVIII-S) is reacted with a suitably selected
oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid,
monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein
the oxidizing agent is present in an amount of at least about 1 molar
equivalent,
preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE,
DCM, chloroform, acetonitrile, NMP, and the like, preferably DCM; preferably,
at about room temperature; to yield the corresponding compound of formula
(XVIII-S). Wherein Q is -C(O)-(CH3) the compound of formula (XVII-S) is
reacted under conditions other than with monomagnesium peroxyphthalate in
DMF.
The compound of formula (XVIII-S) is reacted with an organic or
inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like,
preferably NaOCH3; wherein the base is preferably present in an amount
greater than or equal to about 1 molar equivalent, more preferably an excess
amount; in a organic solvent such as methanol, ethanol, THF, acetonitrile, and
the like, preferably methanol; preferably at about room temperature; to yield
the
corresponding compound of formula (V-S).
The compound of formula (V-S) may be further reacted to yield the
corresponding compound of formula (I-S) according to known methods (for
example, as disclosed in McComsey, D., et al. in US Patent Publication US
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2006/0041008 Al, published February 23, 2006; McComsey, D., et al. in US
Patent Publication US 2005/0282887 Al, published December 22, 2005).
For example, the compound of formula (I-S) may be prepared according
to the process outlined in Scheme 6, below.
RO
O
r2H O
IS)
c5 (V-S) (XIX-S) (XX-S)
0
\\ iNH2
11 N
H2N-S-NH2 I H O
O CI O
O IS
/ I (S) NH2 (- )
CI O 0 O NH2
(XXI-S) CI-S-NH2 (S1 N \O
I I I H
(XXII-S) CI O (I-S)
Scheme 6
Accordingly, a suitably substituted compound of formula (V-S), prepared
as for example outlined in Scheme 1, 2, 4 or 5 above, is activated, according
to
known method, to yield the corresponding compound of formula (XIX-S),
wherein J is a suitable leaving group, such as tosylate, Cl, Br, I, mesylate,
triflate, and the like.
The compound of formula (XIX-S) is reacted with a phthalimide salt such
as potassium phthlimide, sodium phthalimide, and the like, in an organic
solvent such as DMF, DMSO, acetonitrile, and the like, preferably, at an
elevated temperature in the range of from 50 C to about 200 C, more
preferably, wherein the organic solvent is DMF, DMSO and the like, at
temperature in the range of from about 50 C to about 150 C and wherein the
organic solvent is acetonitrile, and the like, at about reflux temperature, to
yield
the corresponding compound of formula (XX-S).
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The compound of formula (XX-S) is reacted with N2H4, a known
compound, in an organic solvent such as ethanol, methanol, and the like,
preferably, at an elevated temperature in the range of from about 50 C to
about
100 C, more preferably, at about reflux temperature, and the like, to yield
the
corresponding compound of formula (XXI-S).
The compound of formula (XXI-S) is reacted with sulfamide (NH2-SO2-
NH2), a known compound, preferably wherein the sulfamide is present in an
amount in the range of about 2 to about 5 equivalents, in an organic solvent
such as THF, dioxane, and the like, preferably at an elevated temperature in
the range of about 50 C to about 100 C, more preferably at about reflux
temperature, to yield the corresponding compound of formula (I-S).
Alternatively, the compound of formula (XXI-S), is reacted with
compound of formula (XXII-S), a known compound, also known as sulfamoyl
chloride, in the presence of a base such as TEA, DIPEA, pyridine, and the
like,
in an organic solvent such as DMF, DMSO, and the like, to yield the
corresponding compound of formula (I-S).
The present invention is further directed to crystalline forms of the
compound of formula (I-S), hereinafter referred to as crystalline form (I-SA)
and
(I-SB). The crystalline forms of the compound of formula (I-S) may be
characterized by their corresponding Powder X-ray Diffraction (PXRD) spectra.
In an embodiment, the crystalline forms of the compound of formula (I-S)
may be characterized by their 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 (I-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 (I-S) may be characterized by its corresponding PXRD
peaks, wherein the peaks are defined by their position ( 20) and d-spacing
(A).
Powder XRD spectra were measured for representative samples of the
crystalline forms of the compound of formula (I-S) with peaks as listed in
Tables
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2 and 3 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.
Crystalline form (I-SA) may be prepared for example, as described in
Example 13 below. The melting point of crystalline form (I-SA) was measured
for a representative sample and showed a melting point onset of 98.6 C and a
100.8 C. Crystalline form (I-SA) may be characterized by its powder XRD
peaks, as listed in Table XRD-1 below.
Table 2: Form (II-SA)
Position [ 20] d-spacing [A] Relative Intensity
4.50 19.62 42
15.57 5.69 13
17.38 5.10 45
18.63 4.76 100
19.97 4.45 14
20.96 4.24 22
21.62 4.11 20
22.01 4.04 11
23.97 3.71 13
25.08 3.55 21
26.91 3.31 13
28.35 3.15 12
30.76 2.91 12
Crystalline form (I-SB) may be prepared by re-crystallizing the
compound of formula (I-S) from water, according to known methods, for
example as described in Example 14 below. The melting point of crystalline
form (I-SA) was measured for a representative sample and showed a melting
point onset of 100.7 C and a 102.8 C. Crystalline form (I-SB) may be
characterized by its powder XRD peaks, as listed in Table 3 below.
Table 3: Form (I-SB)
Position [ 20] d-spacing [A] Relative Intensity
4.48 19.74 100
8.91 9.92 19
13.36 6.62 7
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17.84 4.97 6
18.61 4.77 4
22.33 3.98 5
26.86 3.32 28
Figure 1 illustrates representative powder X-ray diffraction patterns
corresponding to the following samples: (a) the topmost scan corresponds to a
representative sample of crystalline form (I-SB); (b) the middle and bottom
scans correspond to two separately prepared samples of crystalline form (I-
SA).
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
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
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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
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
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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
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
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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.
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,
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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.
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 10,000 mg per adult human per day, or any range therein. 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, 500 and 1000 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the patient to be treated. An effective amount of
the
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drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to
about
500.0 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 50.0 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
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.
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Example 1
2-Benzyloxy-5-ch loro-be nzaldehyde
O
Cl A 2 L three-necked flask (equipped with mechanical stirrer, nitrogen
inlet, and a thermocouple) was charged with 5-chlorosalicylaldehyde (7, 23 g,
0.147 mol), benzyl bromide (25.1 g, 0.147 mol), potassium carbonate (20.3 g,
0.147 mol), and N,N-dimethylformamide (650 mL). The reaction mixture was
heated to 60 C for 18 h (overnight). The reaction mixture was poured into
water (700 mL) and then extracted with ethyl ether (3 x 300 mL). The
combined organics were washed with brine (2 x 200 mL), dried (MgSO4), and
concentrated to yield a crude product. The crude product was dissolved in 1:1
heptane-dichloromethane and loaded onto a Biotage 75S (200 g silica gel) and
eluted with heptane (1 L), then 1:9 (3L), and 3:7 (2 L) ethyl acetate-heptane
to
yield the title compound as a solid
1 H NMR (CDC13) 6 ppm: 10.48 (s, 1 H), 7.81 (d, J= 3.1 Hz, 1 H), 7.42 (m,
6H), 7.01 (d, J = 8.9 Hz, 1 H), 5.19 (s, 2H).
Example 2
Formic acid, 2-benzyloxy-5-chloro-phenyl ester
,00
a
~ O
I/
CI O
\O
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In a 1 L one-neck flask (equipped with magnetic stirrer, and nitrogen
inlet, was charged 2-benzyloxy-5-chloro-benzaldehyde (8, 28.1 g, 0.114 mol)
and dichloromethane (360 mL). To this solution was added m-CPBA (-75%,
31.4 g, 0.137 mol). The reaction mixture was stirred at room temperature for
17 h (overnight) to yield a white slurry. The white solid was removed by
filtration, then the filtrate was washed with 10% (w/w) sodium bisufite (200
mL)
and each phase was tested by starch iodide paper to see if any oxidant
remained. This test was negative and the organic phase was washed with
saturated sodium bicarbonate (2 x 150 mL), dried (MgSO4), and concentrated
to yield crude product, as a solid. The crude product was used in subsequent
steps without further purification.
1 H NMR (CDC13) 6 ppm: 8.25 (s, 1 H), 7.37 (m, 5H), 7.15 (m, 2H), 6.95
(d, J = 8.7 Hz, 1 H), 5.09 (s, 2H).
Example 3
2-Benzyloxy-5-ch loro-phenol
O
Cl OH
A one-neck flask (equipped with magnetic stirring, and a nitrogen inlet),
was charged with crude formic acid, 2-benzyloxy-5-chloro-phenyl ester (9, 28
g,
0.107 mol), sodium methoxide (25% (w/w) in methanol, 26.5 mL, 0.123 mol),
and methanol (175 mL). The reaction mixture was stirred for 18 h (overnight).
The reaction mixture was concentrated to a red oil that was partitioned
between
saturated ammonium chloride (200 mL) and ethyl ether (200 mL). The
aqueous was extracted with ethyl ether (100 mL) and the combined organics
were washed with brine (100 mL), dried (MgSO4), and concentrated to yield the
title compound as a oil. The product was used in subsequent steps without
further purification.
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1H NMR (CDC13) 6 ppm: 7.41 (m, 5H), 6.95 (d, J = 1.8Hz, 1 H), 6.82 (m,
2H), 5.71 (s, 1 H), 5.09 (s, 2H).
Example 4
(R)-2-(2-Benzyloxy-5-chloro-phenoxymethyl)-oxirane
~
(R)
CI /0~
O
In a 500 mL, three-necked flask (equipped with a magnetic stir bar,
thermocouple, and a nitrogen inlet) was charged 2-benzyloxy-5-chloro-phenol
(10, 11.3 g, 48.2 mmol), (R)-glycidyl m-nitrophenylsulfonate (11.3 g, 43.8
mmol), and N,N-dimethylformamide (200 mL). The reaction mixture was
heated to 40 C for 12hrs, then cooled to room temperature and poured into
water (300 mL). The aqueous phase was extracted with ethyl ether (3 x 200
mL). The combined organic phases were washed with 1 M sodium hydroxide
(aq), brine (3 x 100 mL), dried (MgSO4), and concentrated in vacuo to yield
crude product as an oil. The oil was dissolved in 1:1 heptane-dichloromethane
and loaded onto an Isco cartridge (120 g silica gel) and eluted to yield the
title
compound as an oil.
1H NMR (CDC13) 6 ppm: 7.38 (m, 5H), 6.94 (d, J = 2.5Hz, 1 H), 6.85 (m,
2H), 5.11 (s, 2H), 4.28 (dd, J = 11.4, 3.3 Hz, 1 H), 4.01 (dd, J = 11.3, 5.5
Hz,
1 H), 3.38 (m, 1 H), 2.89 (dd, J = 5.1, 4.9 Hz, 1 H), 2.77 (dd, J = 5.0, 2.6
Hz, 1 H).
Example 5
(R)-4-Ch loro-2-oxiranylmethoxy-phenol
OH
Nlzzz~ (R)
Cl /O'7
O
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A Parr reaction bottle was charged with 5% palladium on carbon (dry,
1.0 g), (R)-2-(2-benzyloxy-5-chloro-phenoxymethyl)-oxirane (11, 11.7 g, 40.2
mmol), and ethyl acetate (250 mL). The reaction mixture was agitated on a
Parr shaker at room temperature under 5-7 psi of hydrogen gas for 2.5 h. The
catalyst was removed by filtration and the ethyl acetate removed in vacuo to
yield the title compound as an oil that solidified upon standing. The product
was used in subsequent steps without further purification.
1 H NMR (CDC13) 6 ppm: 6.87 (m, 3H), 6.09 (bs, 1 H), 4.25 (dd, J = 11.4,
2.6 Hz, 1 H), 3.98 (dd, J = 11.3, 5.7 Hz, 1 H), 3.39 (m, 1 H), 2.96 (t, J =
4.6 Hz,
1 H), 2.85 (dd, J = 5.2, 2.7 Hz, 1 H).
Example 6
(S)-(6-Chloro-2,3-dihydro-benzof1,41dioxin-2-yl)-methanol
(S)r OH
CI O
A one-neck flask (equipped with magnetic stirring, and a nitrogen inlet),
was charged (R)-4-chloro-2-oxiranylmethoxy-phenol (12, 8.1 g, 40.4 mmol),
sodium methoxide (25% (w/w) in methanol, 10.5 mL, 48.4 mmol), and methanol
(90 mL). The reaction was stirred for 18 h (overnight). The reaction mixture
was concentrated to a red oil that was partitioned between water (250 mL) and
ethyl ether (200 mL). The aqueous layer was extracted with ethyl ether (2 x
100 mL), and the combined organics were washed with 1 M aqueous sodium
hydroxide (150 mL), brine (2 x 100 mL), dried (MgSO4), and concentrated to
yield crude product. The crude product was dissolved in dichloromethane and
loaded onto a Biotage 40M (90 g silica gel) and eluted with dichloromethane
(250 mL) and 1:19 ethyl acetate-dichloromethane (1 L) to yield the title
compound as a white solid (19415-132A).
Melting Point: 73 - 75 C.
Optical rotation: [aID = -58.0 (c 1.99, MeOH, 23 C)
1 H NMR (CDC13) 6 ppm: 6.82 (m, 3H), 4.30 (dd, J = 11. 1, 2.2 Hz, 1H),
4.24 (m, 1 H), 4.10 (dd, J = 11.2, 7.4 Hz, 1 H), 3.87 (m, 2H), 1.95 (t, J =
6.6 Hz,
1 H).
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Example 7
(R)-1-(4-Chloro-2-oxiranvlmethoxy-phenvl)-ethanone
0
A (R)
Cl O `7
0
In a 22 L, four-necked flask (equipped with a mechanical stirrer,
thermocouple, Teflon stopper, and a argon inlet) was charged 4-chloro-2-
hydroxy-acetophenone (13, 687.2 g, 4.03 mol) and N,N-dimethylformamide
(14.0 L). To this solution was added potassium carbonate (613 g, 4.43 mol)
and (R)-glycidyl m-nitrophenylsulfonate (1.045 kg, 4.03 mol). The reaction
mixture was heated to 40 C for 20 h (overnight) then cooled to room
temperature and split into two portions. Each portion was poured into water (9
L) and extracted with methyl tert-butyl ether (3 x 2 L) and ethyl ether (2L).
The
two organic phases were each washed with brine (2 x 4 L), dried (MgSO4), and
concentrated in vacuo to yield crude product, which was used in subsequent
steps without further purification.
1H NMR (CDC13) 6 ppm: 7.71 (d, J = 8.5 Hz, 1 H), 7.02 (dd, J = 8.8, 1.7
Hz, 1 H), 6.95 (d, J = 1.8 Hz, 1 H), 4.39 (dd, J = 11.0, 2.8 Hz, 1 H), 3.98
(dd, J =
10.8, 6.1 Hz, 1 H), 3.41 (m, 1 H), 2.96 (t, J = 4.4 Hz, 1 H), 2.78 (dd, J =
5.1, 2.7
Hz, 1 H), 2.64 (s, 3H).
A small portion of the product prepared as described above was
chromatographed (Isco silica - 40 g) to yield a white powder:
MP: 79-80 C.
Optical Rotation: [aID = -19.4 (c 2.02, MeOH, 23 C).
High-Resolution MS: (as C11H1203C1, M+H) : Calculated: 227.48;
Measured: 227.05
Example 8
(R)-Acetic acid, 4-chloro-2-oxiranylmethoxy-phenyl ester
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O*f
O
(R)
Cl
O~
0
In a 22 L four-necked flask (equipped with mechanical stirrer, two
stoppers, and a condenser with a argon inlet), was charged (R)-1-(4-chloro-2-
oxiranylmethoxy-phenyl)-ethanone (14, 815 g, 3.60 mol) and dichloromethane
(8.8 L). To this solution was added m-CPBA (-75% Lancaster, 993 g, 4.31 mol
oxidant). The reaction mixture was heated at mild reflux for 22 h over 3 days
(heat was only applied with supervision). We then added additional m-CPBA
(100 g, -0.36 mol) and continued reflux for 8 h. The reaction mixture was then
allowed to cool overnight to yield a white slurry upon cooling. The white
solid
was removed by filtration and the filtrate was split into four portions. Each
portion was washed with 10% (w/w) sodium bisufite (1 L) and both phases were
tested by starch iodide paper to see if any oxidant remained. This test was
negative and the aqueous phase was back extracted with dichloromethane (2 x
250 mL) and the combined organic phases (four portions) were washed with
saturated sodium bicarbonate (3 x 500 mL), dried (MgSO4), and concentrated
to yield crude product, which was used in subsequent steps without further
purification.
1 H NMR (CDC13) 6 ppm: 6.96 (m, 3H), 4.25 (dd, J = 10.9, 2.4 Hz, 1H),
3.94 (dd, J = 11.5, 5.6 Hz, 1 H), 3.30 (m, 1 H), 2.88 (t, J = 4.8 Hz, 1 H),
2.71 (dd,
J = 4.8, 2.6 Hz, 1 H), 2.31 (s, 3H).
A small portion of the crude product prepared as described above was
chromatographed (Isco silica - 12 g) to yield a clear oil:
Optical Rotation: [aID = -8.29 (c 2.05, MeOH, 23 C).
High-Resolution MS: (as C11H1103C1, M+): Calculated: 242.03;
Measured: 242.03
Example 9
(S)-(6-Chloro-2,3-dihvdro-benzof1,41dioxin-2-vl)-methanol
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~
Cl ~ O ,s, OH
A four-necked 12 L flask (equipped with mechanical stirring, two
stoppers, and a nitrogen inlet), was charged (R)-acetic acid, 4-chloro-2-
oxiranylmethoxy-phenyl ester (15, 1.019 kg impure, assumed 874 g, 3.60 mol),
sodium methoxide (25% (w/w) in methanol, 972 mL, 4.50 mol), and methanol
(6.0 L). The reaction mixture was stirred for 20 h (overnight) and then
treated
with 3 M aqueous sodium hydroxide (500 mL) and stirred for an additional 6
days. The reaction mixture was concentrated to a red oil that was diluted with
water to a volume of 4.0 L. This material was split into two portions and each
aqueous phase was extracted with methyl tert-butyl ether (2 x 1.0 L) and ethyl
ether (1 L). The organic phases were washed with 10% aqueous sodium
bisulfite (500 mL), saturated sodium bicarbonate (500 mL), brine (2 x 500 mL),
dried (MgSO4), and concentrated to yield crude product. The crude product
was used in subsequent steps without further purification.
1 H NMR (CDC13) 6 ppm: 6.89 (m, 1H), 6.2 (m, 2H), 4.30 (dd, J = 11.3,
2.2 Hz, 1 H), 4.23 (m, 1 H), 4.10 (dd, J = 10.9, 7.6 Hz, 1 H), 3.91 (dd, J =
12.0,
4.2 Hz, 1 H), 3.83 (dd, J = 12.1, 5.4 Hz, 1 H).
A small portion of the crude product prepared as decsribed above was
chromatographed (Isco silica - 12 g) to yield a white solid:
Melting Point: 79-810C.
Optical rotation: [aID = -58.2 (c 2.05, MeOH, 23 C);
Chiral HPLC: Chiralpak AS-H, Hexane/IPA (97:3), Rt = 16.095 min,
>99%ee.
High-Resolution MS: (as C9H903C1, M+): Calculated: 200.02 : Measured:
200.02
Example 10
(R)-Toluene-4-sulfonic acid, 6-chloro-2,3-dihvdro-benzof1,41dioxin-2-vl-
methvl ester
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O
O S
(R) O/ ~O
Cl \ O
To a 12 L, four necked flask (equipped with mechanical stirrer, nitrogen
inlet, and two stoppers) was charged (S)-(6-chloro-2,3-dihydro-
benzo[1,4]dioxin-2-yl)-methanol (2, 300 g, 1.50 mol) and 4.5 L of
tetrahydrofuran/dichloromethane (9:1). This solution was treated with N-
methylmorpholine (362 mL, 3.29 mol), N,N-dimethylaminopyridine (36.4 g,
0.298 mol), and p-toluenesulfonyl chloride (341 g, 1.79 mol). The reaction
mixture was stirred under nitrogen at room temperature for 10 days (reaction
appeared complete after -4 days). The reaction mixture was filtered to remove
amine hydrochloride and split into two portions. Each portion was stirred with
20% aqueous potassium bicarbonate (3 L) for 2.5 h. Each portion was then
extracted with i-propyl acetate (2 x 1.5 L) and the organics were washed with
2
M hydrochloric acid (2 x 1 L), saturated sodium bicarbonate (2 x 1 L), brine
(500 mL), and dried (MgSO4). The resulting mixture was concentrated to yield
crude product. The crude product was dissolved in dichloromethane/heptane
(1:3) and loaded onto a Biotage 150L (5 kg silca gel) and eluted (30 psi) with
heptane (8 L), 1:9 ethyl acetate-heptane (24 L), 15:85 ethyl acetate-heptane
(48 L), and 1:2 ethyl acetate-heptane (18 L) to yield the title compound as an
off-white solid.
'H NMR (DMSO-d6) 6 ppm: 7.79 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.0 Hz,
2H), 6.94 (d, J = 2.5 Hz, 1 H), 6.87 (dd, J = 8.8, 2.5 Hz, 1 H), 6.8 (d, J =
8.8 Hz,
1 H), 4.46 (m, 1 H), 4.35 (dd, J = 11.7, 3.1 Hz, 1 H), 4.29 (dd, J = 11.7, 2.5
Hz,
1 H), 4.20 (dd, J = 11.3, 6.4 Hz, 1 H), 3.99 (dd, J = 11.5, 6.2 Hz, 1 H), 2.42
(s,
1 H).
Optical rotation: [a]p = -34.73 (c 2.02, MeOH, 23 C).
Example 11
(S)-2-(6-Ch loro-2,3-dihvdro-benzof 1,41dioxin-2-vlmethvl)-isoindole-1,3-
dione
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O
O
(S) N
Cl O
A 12-L four necked flask (equipped with mechanical stirrer, air
condenser topped with a nitrogen inlet, and two stoppers) was charged with
(R)-toluene-4-sulfonic acid, 6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl-methyl
ester (3, 443 g, 1.25 mol), potassium phthalimide (301 g, 1.62 mol), and N,N-
dimethylformamide (5 L). The reaction mixture was heated to 100 C for 2 h
then cooled to room temperature over 16 h (overnight). The reaction mixture
was diluted into water (6 L) and stirred for 2.5 h. The resulting white solid
was
collected by vacuum filtration and dried in a vacuum oven at 55 C to yield the
title compound as an off-white solid.
'H NMR (DMSO-d6) 6 ppm: 7.84 (m, 4H), 6.98 (d, J = 2.9 Hz, 1 H), 6.87
(dd, J = 8.4, 2.8 Hz, 1 H), 6.83 (d, J = 8.3 Hz, 1 H), 4.49 (qd, J = 6.1, 2.2,
1 H),
4.36 (dd, J = 11.4, 2.7 Hz, 1 H), 4.13 (dd, J = 11.9, 2.5 Hz, 1 H), 3.88 (m,
2H).
Melting Point: 126-127 C.
Example 12
(S)-(6-Chloro-2,3-dihvdro-benzof 1,41dioxin-2-vl)-methylamine
O
\ (S) N I-12
Cl O
A 12-L four necked flask (equipped with mechanical stirrer, water
condenser topped with a nitrogen inlet, and two stoppers) was charged with
(S)-2-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione
(4,
370 g, 1.12 mol), hydrazine (65.2 mL, 2.08 mol), and ethanol (4 L). The
reaction mixture was heated to reflux for 1.5 h and then cooled to room
temperature. The reaction mixture was acidified with 1 M hydrochloric acid (2
L) and filtered. The filtrate was concentrated to remove ethanol then basified
with 3 M sodium hydroxide (1 L) and extracted with ethyl ether (2 L, then 2 x
1
L). The combined organics were washed with brine (2 x 600 mL), dried
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(MgSO4), and concentrated to yield the title compound as a white solid, which
was used in subsequent steps without further purification.
'H NMR (DMSO-d6) 6 ppm: 6.95 (d, J = 1.9 Hz, 1 H), 6.87 (m, 2H), 4.37
(dd, J = 11.5, 2.6, 1 H), 4.07 (m, 1 H), 3.98 (dd, J = 10.9, 7.7 Hz, 1 H),
2.83 (dd, J
=12.7,5.4,1H),2.77(dd,J=12.7,6.1,1H).
Melting Point: 70-71 C.
Optical rotation: [a]p = -81.0 (c 2.00, MeOH, 23 C).
Example 13
(S)-N-(6-Chloro-2,3-dihydro-benzof1,41dioxin-2-ylmethyl)-sulfamide
0
O \S~NH2
\ (s) H N / ~O
Cl
O
A 12-L four necked flask (equipped with mechanical stirrer, water
condenser topped with a nitrogen inlet, and two stoppers) was charged with
(S)-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine (5, 214 g, 1.07
mol), sulfamide (412 g, 4.29 mol), and iso-propyl acetate (4 L). The reaction
mixture was then heated to reflux for a total of 15 h over 3 days and then
cooled to room temperature. The reaction mixture was chilled in an ice-bath
and the residues were collected by filtration and washed with iso-propyl
acetate. The filtrate was washed with 1 M hydrochloric acid (3 L), dried
(MgSO4), and concentrated to yield crude product. The entire portion of crude
product was dissolved in ethyl acetate and absorbed onto silica gel (600 g)
and
loaded into a Biotage sample induction module, then eluted onto a Biotage
150M (2.5 g silica gel) using heptane (2 L), 1:9 ethyl acetate-heptane (4 L),
3:7
ethyl acetate-heptane (12 L), and 1:1 ethyl acetate-heptane (16 L) to yield
the
product along with mixed fractions. The mixed fractions were re-
chromatographed on a Biotage 75L (800 g silica) using heptane (1 L), 1:9 ethyl
acetate-heptane (2 L), 3:7 ethyl acetate-heptane (6 L), and 1:1 ethyl acetate-
heptane (8 L) to yield additional product. The two lots of product were
combined to yield the title compound as an off-white solid.
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The title compound prepared according to the procedure as described in
this Example yielded form (I-SA).
'H NMR (DMSO-d6) 6 ppm: 6.98 (d, J = 1.9 Hz, 1 H), 6.89 (m, 3H), 6.67
(bs, 2H), 4.36 (dd, J = 11.7, 1.6, 1 H), 4.28 (m, 1 H), 4.00 (dd, J = 11.5,
6.8 Hz,
1 H), 3.19 (m, 1 H), 3.11 (m, 1 H).
Melting Point: 99-100 C.
Optical rotation: [a]p = -57.6 (c 2.14, MeOH, 23 C).
Chiral HPLC: Chiralpak AD-H, Hex(0.1 % TEA)/IPA (80:20), Rt = 11.407
min, >99%ee.
Elemental Analysis for C9H11CIN2O4S:
Calculated: %C 38.78, %H 3.98, %CI 12.72, %N 10.05, %S 11.51.
Measured: %C 38.81, %H 3.74, %CI 12.83, %N 9.93, %S 11.53.
Example 14
Water Recrystallization of (S)-N-(6-Chloro-2,3-dihvdro-benzof1,41dioxin-2-
yimethyl)-sulfamide
Distilled water (5 mL) was added to (S)-N-(6-Chloro-2,3-dihydro-
benzo[1,4]dioxin-2-ylmethyl)-sulfamide (0.050g) in a test tube and the
resulting
mixture was heated. The white solid was observed to dissolve in the water
before the water boiled. As the water cooled, material dropped out as a
suspension and formed white needle-like crystals over two hours. The crystals
were filtered off, rinsed with water, air dried, and collected to yield
crystalline
form (I-SB) as herein defined.
Example 15
(R)-Toluene-4-sulfonic acid, (7-chloro-2,3-dihvdro-benzof1,41dioxin-2-vl)-
methyl ester
0
OAS
O
CI O
R) "[II H
O
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(S)-(7-Chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol {[a]D = -35.6
(c=1.45, EtOH), 7.12 g, 35.4 mmol}, prepared according to the method as
disclosed in A. M. Birch et al. Journal of Medicinal Chemistry 1999, 42, 3342-
3355, was dissolved in pyridine (50 mL) and cooled to 0 C. To the resulting
mixture was added p-toluenesulfonyl chloride (6.68 g, 35.5 mmol) and the
reaction mixture stirred at room temperature for 20h. The reaction mixture was
then cooled in an ice bath and 1 N HCI (750 mL) was added. The reaction
mixture was extracted with diethyl ether (3x, 200 mL). The combined diethyl
ether was washed with 1 N HCI (2x, 250 mL), water, brine (2x) and dried
(MgSO4) and evaporated in vacuo to yield the title compound as a white solid..
'H NMR (CDC13) 6 7.79 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 6.76
(m, 3H), 4.40 (m, 1 H), 4.21 (m, 3H), 4.03 (dd, J = 6.2, 11.6 Hz, 1 H), 2.61
(s,
3H).
Example 16
(S)-2-(7-Chloro-2,3-dihydro-benzof1,41dioxin-2-ylmethyl)-
isoindole-1,3-dione
0
N
Cl ""'a I
O
(R)-Toluene-4-sulfonic acid, (7-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-
methyl ester (10.65 g), prepared as in Example 15 above) was combined with
potassium phthalimide (8.90 g, 48 mmol) in DMF (100 mL) and the resulting
mixture was heated to reflux for 1 h, then cooled to room temperature and
poured into vigorously stirring ice water (750 mL) and stirred 30 min. The
resulting white solid was filtered and washed several times with water, then
dried under vacuum (16h) to yield the title compound as white powdery solid.
'H NMR (CDC13) 6 7.89 (m, 2H), 7.75 (m, 2H), 6.82 (m, 3H), 4.50 (m,
1 H), 4.29 (dd, J = 2.3, 11.6 Hz, 1 H), 4.05 (m, 2H), 3.89 (dd, J = 5.4, 14.2
Hz,
1 H).
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Example 17
(S)-(7-Chloro-2,3-dihvdro-benzof1,41dioxin-2-vl)-methylamine
NH2
CI O
a O !) r-I -
(S)-2-(7-chloro-2,3-Dihydro-benzo[1,4]dioxin-2-yImethyI)-isoindoIe-1,3-
dione (8.1 g, 24.6 mmol; prepared as in Example 16 above) was combined with
hydrazine (1.57 g, 49 mmol) in EtOH (120 mL) and heated at reflux for 2 h,
then cooled to room temperature. To the reaction mixture was then added 1 N
HCI to pH 2.0 and the resulting mixture was stirred for 45 min. The resulting
white solid was filtered and washed several times with fresh EtOH and the
solid
discarded. The filtrate was evaporated in vacuo to yield a solid, which was
partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether
solution was washed once with brine, dried (Na2SO4) and evaporated in vacuo
to yield the title compound as a clear viscous oil.
MS 200 (MH+)
'H NMR (CDC13) 6 6.90 (dd, J = 1.54, 1.1 Hz, 1 H), 6.79 (m, 2H), 4.26
(dd, J = 11.2, 2.2 Hz, 1 H), 4.13 (m, 1 H), 3.98 (dd, J = 11.3, 7.5 Hz, 1 H),
2.98
(m, 2H), 1.25 (bd s, NH2)
Optical Rotation [a]p = -54.2 (c = 1.55, CHC13)
Example 18
(S)-N-(7-Chloro-2,3-dihvdro-benzof1,41dioxin-2-ylmethyl)-sulfamide
(Compound of Formula (I-S))
NHSO2NH2
Cl o
(S) ""'--H
""a
O
(S)-(7-chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine (4.7 g, 23.5
mmol) and sulfamide (4.51 g, 47 mmol) were refluxed in dioxane (125 mL) for 3
h, then cooled to room temperature, filtered and evaporated in vacuo to yield
a
solid. The solid (crude product) was purified by flash column chromatography
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(DCM:MeOH 20:1) to yield a white solid, which was recrystallized from ethyl
acetate/hexane to yield the title compound as a white crystalline solid.
mp 118-119 C
MS 277 (M-1)
Optical Rotation [aID = -40.0 (c = 1.20, MeOH)
'H NMR (DMSOd6) 6 6.97 (d, J = 2.2 Hz, 1 H), 6.90 (m, 3H), 6.67 (s, 2H,
NH2), 4.35 (m, 2H), 4.01 (m, 1 H), 3.15 (m, 2 H)
Chemical Analysis:
Calculated C, 38.78; H, 3.98; N, 10.05; S, 11.51
Measured: C, 38.83; H, 3.88; N, 10.08; S, 11.31
Example 19
Liquid Formulation
The compound of formula (I-S), prepared for example as described
above, was formulated according to known methods into liquid formulations of
mg and 100 mg, respectively, with components as listed in Table 4 below.
Table 4: 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
20 Example 20 - Prophetic Example
As a specific embodiment of an oral composition, 100 mg of the
compound prepared as in Example 18 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.
25 While the foregoing specification teaches the principles of the present
invention, with examples provided for the purpose of illustration, it will be
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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.
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