Indian Patents
Title of Invention

NOVEL SUBSTITUTED SULFAMATE ANTICONVULSANT DERIVATIVES
Abstract The present invention is directed to novel compounds of the formula (I) wherein X, R1, R2, R3, R4, R5 and R6 are as described in the specification, processes for the preparation of and pharmaceutical compositions comprising said derivatives The compounds of the present invention are useful for the treatment of epilepsy. The invention is further directed to a process for the preparation of compounds of formula (XX), wherein X, R3, R4, R5 and R6 are as described in the specification.
Full Text NOVEL SUBSTITUTED SULFAMATE ANTICONVOULSANT DERIVATIVES
Cross Reference to Related Application
This application claims the benefit of U.S.
Provisional Application 60/378,017, filed on May 13,
2002, which is incorporated by reference herein in its
entirety.
Field of the Invention
The present invention relates to novel
anticonvulsant derivatives of the general formula (I):

wherein R1, R2, R3, R4, R5, R6 and X are as herein
defined, and pharmaceutical compositions containing said
derivatives. The compounds of formula (I) are useful in
the treatment of epilepsy.
The present invention is further directed to a
process for the preparation of compounds of formula (XX)

wherein X, R3, R4, R5 and R6 are as herein defined.
The present invention is further compounds prepared according to any of the processing
described herein.
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 in
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 petitamal seizures are characterized by
sudden, brief lapses of consciousness without loss of
postural control. Atypical absence seizures typically
include a longer duration in the lapse of consciousness,
less abrupt onset and cessation, and more obvious 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 superitnposition 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.
(www.harrisonsonline.com, March 29, 2001)
U. S. Patent No. 4,513,006 discloses a class of
novel anti-epileptic compounds',. One of. these compounds

2,3:4,5- bis-O- (1- methyletbylidene) ß-D-fructopyranose
sulfate. known as topiramate, has been demonstrated in
clinical trials of human epilepsy to be. effective; as
adjunctive therapy or as monotherapy in treating simple
and complex partial seizure and secondarily generalized
seizures (E. Faught, B.J. Wilder, R.E. Ramsey, R.A.
Reife, L.D. Kramer, G. . Pledger, R.M. Karint, et al.,
Epilepsia, 36 (S4) 33, (1995); S.K. Sachdeo, R.C.
Sachdeo, R.A. Reife, P. Lim and C5. Pledger, Epilepsia, 36
(S4) 33, (1995)).
Brief Summary of the Invention
The present invention relates to novel compounds of
the formula (I)

wherein
X is selected from CH?, or O;
R1 is selected from the group consisting of hydrogen,
alkyl, cilkenyl, alkynyl, cycloalkyl, cycloalkyl - alky 1,
cycloalkenyl, aryl, aralky], heteroaryl, heteroaryl-
alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,
alkoxycarbonylalkyl, - (C-2-8alkyl) -O-C(O) - (alkyl) , -C(O) -R9,
-C(O) - (alkyl) -O- (alkyl) , alkoxycarbonyl, aryloxycarbonyl.,
aralkyloxycarbonyl, -Si (R10) (O0-1R11)2, -SC)2R12 and SEM;
wherein the alkyl, cycloalkyl, aryl, heteroaryl or
heterocycloalkyl group, whether alone or so part of the Rl
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
4
hydroxy, carboxy, alkyl, alkoxy, aryl , aralkyl, amino,
alky] amino, dialkylamino, nitro or cyano;
R2 is selected from the group consisting of hydroxy,
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyl-
alkyl, cycloalkenyl, aryl, aryloxy, aralkyl, aralkyloxy,
heteroaryl, heteroaryl-alkyl, heterocycloalkyl,
heterocycloalkylalkyl, alkoxycarbonylalkyl, - (C2-8alkyl)-
O-C(O)-(alkyl) , -C(O)-R9, -C(O)-(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, aralkyloxy carbonyl,
C(O)0-Si(R17)3, -Si(R10) (O0-1R11)2, -SO2R12, -P(=O) (R13)2 and
SEN;
wherein the alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl or heterocycloalkyl group, whether alone or as
part of the R2 substituent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro or
cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part, of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone, or as part of an R10 substited.
group, is optionally substituted with one or more
substituents independently selected from halogen,

hydroxy, carboxy, alkyl, alkoxy, aryl, arolky] , amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, ary], aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R12 is independently selected from
amino, alkylamino, dialkylamino, alky], aryl, aralkyl or
heteroaryl; wherein the alkyl, aryl or heteroaryl groups,
whether alone or as part of an R12 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, trifluoromethyl,
trifluoromechoxy, alkyl, alkoxy, nitro, amino,
alkylamino, dialkylamino, alkylcarbonylamino,
arylcarbonylamino, aralkylcarbonylatr.ino, aryl,
heteroaryl, benzenesulfonyl or phenoxy; wherein the
phenoxy group is optionally substituted with one or more
substituents independently selected from halogen, alkyl ,
alkoxy or nitro;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;

wherein each R17 is independently selected from
alky], aryl or aralkyl; wherein the alky] or aryl group,
whether alone or as part of an R17 subfitituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively, R1 and R2 are taken together with the
N atom to which they are bound to form a heteroaryi or
heterocycloalkyl group; wherein the heteroaryi or
heterocycloalkyl group is optiona3.1y substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, oxo, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro, cyano, -C(=NH}-
amino, -C(=NH)alkylamino or --C{=NH)-dialkylamino; wherein
the aryl substiutent is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro, cyano, -C(=NH)-amino, -
C(=NH)-alkylamino or -C(-NH)-dialkylamino; wherein the -
C(=NH)-amino, -C (=-NH)-alkylamino or -C (=NH) -dialkylamino
group is bound to a nitrogen or carbon atom on the aryl,
heteroaryi or heterocycloalkyl; and wherein no more than
one -C(=NH)-amino, -C(=NH)-alkylamino or -C(=NH)-
dialkylamino group is bound to the aryl, heteroaryi or
heterocycloalkyl;
alternatively R1 and R2 are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected front
hydrogen, cycloalky] , alkyl, dialkyl amino, aryl or
aralkyl; wherein the alkyl, cyslalkyl or aryl group,

whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently Delected from halogen, hydroxy, carboxy,
alkyl, alkcxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl ;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is O, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are the same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopontyl or cyclohexyl ring;
provided that when R1 is alkyl, R2 is other that
alkyl;

provided further that when R1 La hydrogen, R2 is
other than alkyl, methylcarbonyl, phenyl , benzyl or
carboxyalkyl;
provided further that R1 and R2 when taken together
with the nitrogen atom to which they are bound is other
than imidazolyl;
provided further that when X is 0, R2 and R3 are
taken together to form a methylenedioxy group of the
formula:
R4 and R5 are taken together to form a methylenedioxy
group of the formula:

wherein R7 and R8 in each instance are each methyl,
and R1 is hydrogen then R2 is other than
isopropylsulfonyl, 4- (N-benzyl) -pipcridinyl or 4-pyridyl ;
or a pharmaceutically acceptable salt thereof.
Illustrative of the invention is a pharmaceutical
composition comprising any of the compounds described
herein and a pharmaceutically acceptable carrier.
Exemplifying the invention is a pharmaceutical
composition made by combining any of the compounds
described herein and a pharmaceutically acceptable
carrier.

An example of: the invent ion is a process for making
a pharmaceutical composition compriuir.g combining any of
the compounds described herein and a pharmaceutically
acceptable carrier.
Illustrating the invention is a method o£ treating
epilepsy comprising administering to a subject in need
thereof a therapeutically effective amount of any of the
compounds or pharmaceutical compositions described
herein.
Illustrative of the invention is the use of the
compounds described herein in the preparation of a
medicament for treating epilepsy in a subject in need
thereof.
The present invention is further directed to a
process for the preparation of a compound of formula (XX)
wherein
X is selected from CH2 or o;
R3, R4, R5 and R6 are. each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkcne groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or R5 and R6 together may bo a
methylenedioxy group of the formula:

wherein R7 and R8 arc same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohcxyl ring;
or a pharmaceutically acceptable salt thereof;
comprising, reacting a compound of formula (Ij)

wherein
X is selected from CH2 or 0;
Rla is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen) , cycloalkenyl
(wherein the double bond of the cycloalkexiyl group is
directly bound to or one carbon atom removed from the
nitrogen) , heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O) --R9, -C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
Si(R10) (O0-2R11)2, and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloaikyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or uyano;

R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl. group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen),
benzyloxy, heteroaryl-C1alkyl, heterocycloaikyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O)-R9, -C(O) -(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
C(O)0-Si(R17)3, -Si(R10) (O0-1R11)2, -P(=0) (R13)2 and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R2
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R5
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected fro- halogen,
.12
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl , amino,
alkylamino, dialkylamino, nitro or cyano ,-
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is,
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl. or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula


wherein n is an integer from 1 to 3; and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two R15 groups are taken together with
the carbon atoms to which they ar-e bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycioalkyl, aryl or
aralkyl; wherein the alkyl, cycioalkyl or aryl group,
whether alone or as part of an R14 substituent group, in
optionally substituted with one or mere substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, "nitro or cyano;
provided that at least one R14 is selected from the
group consisting of hydrogen and alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula


wherein R20 is lower alkyl;
R3, R4, R5 and R6 arc each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
or a pharmaceutically acceptable salt thereof;
under de-protection conditions, to yield the
corresponding compound of formula (XX).
The present invention is further directed to a
product prepared according to any of the processes
described herein.
Detailed Description of the Invention
The present invention is directed to a compound of
formula (I)

wherein R1, R2, R3, R4, R5, R6 and X are as previously
defined, useful for the treatment of epilepsy.
In an embodiment of the present invention is a
compound of the formula (I)

wherein
X is selected from CH2 or O;
R1 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,
cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaryl-
alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,
alkoxycarbonylalkyl, - (C2-8alkyl)-O-C(O) - (alkyl) , -C(O)-R9,
-C(O)-(alkyl)-O-(alkyl), alkoxycarbonyl, aryloxycarbonyl,
aralkyloxycarbonyl, -Si (R10) (O0-1R11)2, -S02R12 and SEM;
wherein the alkyl, cycloalkyl, aryl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituenr.s independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkyl amino, dialkylaminc, nitro or cyano,-
R2 is selected from the group consisting of hydroxy,
alkyl, alkoxy, alkenyl , alkynyl, cycloalkyl, cycloalkyl
alkyl, cycloalkenyl, aryl, aryloxy, aralkyl, araikyloxy,
heteroaryl, heteroaryl-alkyl, heterocycloalkyl,
heterocycloalkylalkyl, alkoxycarbonylalkyl, -(C2.nalkyl) -
O-C(O)-(alkyl), -C(O)-R9, -C(O)-(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, -
C(O)0-Si(R17)3, -Si(R10) (O0-1R11)2, -SOaR12, --P (=0) (R13) 2 and
SEM;
wherein the alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl or heterocycloalkyl group, whether alone or as
part of the R2 substituent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro or
cyano;
wherein each R9 is independently selected from alkyl,
aryl or aralkyl; wherein the alkyl or aryl group, whether
alone or as part of an R9 substituent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
alkoxycarbonyl, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro 02: cyano;

wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, it
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R12 is independently selected from
alkyl, aryl-, aralkyl or heteroaryl; wherein the alkyl,
aryl or heteroaryl groups, whether alone or as part of a
R1Z substituent group, is optionally substituted with one
or more substituents independently selected from halogen,
trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, nitro,
alkylcarboiiylamino, arylcarbonylamino,
aralkylcarbonylamino, aryl, benzenesulfonyl or phenoxy;
wherein the phenoxy group is optionally substituted with
one or more substituents independently selected from
halogen, alkyl, alkoxy or nitro;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R12 is independently selected from
alkyl, aryl or aralkyl; v/herein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,

alkyl, alkoxy, aryl, aralkyl, amino, alkyiamino,
dialkylamino, nitro or cyano;
alternatively, R1 and R2 are taken together with the
N atom to which they are bound to form a hetcroaryl or
heterocycloalkyl group; wherein the heteroaryl or
heterocycloalkyl group is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, oxo, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro, cyano, -C(-NH)-
amino, -C (=NH) alkylamino or -C(=NH) -dialkylamino; wherein
the aryl substituent is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro, cyano, -C(=NH)-amino, -
C(=NH) -alkylamino or -C(-NH) -dialkylamino; wherein the -
C(=NH)-amino, -C(=NH)-alkylamino or -C(=NH)-dialkylamino
group is bound to a nitrogen or carbon atom on the aryl ,
heteroaryl or heterocycloalkyl; and wherein no more than
one -C(=NH) -amino, -C (=NH) -alkylamino or -C(=NII)-
dialkylamino group is bound to the aryl, heteroary] or
heterocycloalkyl,
alternatively R1 and R2 are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected from
hydrogen, alkyl, cycloalkyl, aryl or aralkyl; wherein the
alkyl, cycloalkyl or aryl group, whether alone or an part
of an R14 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyi, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano,- provided

that at least one R14 is selected from the group
consisting of hydrogen and alkyl;
R3, R4, R5 and Rs are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or R5 and R6 together may bo a
methylenedioxy group of the formula:

wherein R7 and R8 are the same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
provided that when R1 is alkyl, R2 is other than
alkyl;
provided further that when R1 is hydrogen, R2 is
other than alkyl, methylcarbonyl, phenyl, benzyl or
carboxyalkyl ,-
provided further that R1 and R2 when taken together
with the nitrogen atom to which they are bound is other
than imidazolyl;
provided further that when X is O, R2 and R3 are
taken together to form a methylenedioxy group of the
formula:
R4 and R5 are taken together to form a methylenodioxy
group of the formula:


wherein R7 and RB in each instance are each methyl! ,
and R1 is hydrogen then Rz is other than
isopropylsulfonyl, 4- (N-benzyl) -piperidinyl or 4-pyridinyl
or a pharmaceutically acceptable salt thereof.
In an embodiment of the present invention X is O.
In another embodiment of the present invention R3 ... .
R* and R5 and R6 are taken together as methylenedioxy
groups of the formula
wherein R7 and R8, in each instance, are both hydrogen
or are both lower alkyl. Preferably R7 and R8 are both
hydrogen or methyl.
In an embodiment of the present invention is a
compound of formula (I) wherein X is 0, R3 and R4 and R5
and R6 are taken together as methylenedioxy groups of the
formula , wherein R7 and RH, in each instance,
are each lower alkyl, preferably methyl.
In another embodiment of the present invention is a
compound of formula (It)


wherein R1 and R2 are as previously defined.
In an embodiment of the present invention R1 is
selected from the group consisting of hydrogen, lower
alkyl and aralkyl, preferably R1 is hydrogen, ttiethyl or
benzyl. In another embodiment of the present invention R1
is hydrogen or lower alkyl, preferably R1 is hydrogen,
methyl or ethyl. In yet another embodiment of the present
invention, R-1 is hydrogen.
In an embodiment of the present invention R2 is
selected from the group consisting of hydroxy, alky],
benzhydryl, alkoxy, alkenyl, aryl, aralkyl, aralkyloxy,
alkoxycarbonylalkyl, -C(O)-R9, alkoxycarbonyl,
aralkyloxycarbonyl, -C(O)-(alkyl)-O-(alkyl), a nitrogen
containing heteroaryl, a nitrogen containing
heterocycloalkyl, -SO2R12, -C(O)0-Si (R17)3, -Si (R10) (O0
1Rll)2, -P(=O) (R13)2 and SEM;
wherein the alkyl, aralkyl, nitrogen containing
heteroaryl or nitrogen containing het.crocycioalkyl,
whether alone or as part of a substituent group, is
optionally substituted with one or more substituenta
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano.

In another embodiment of the present invention R2 is
selected from the group consisting of hydroxy,
halogcnated alkyl , bernhydryl, alkoxy, aikexiyl, oralkyl
(wherein the aralkyl is optionally substituted with a
substituent selected from alkoxy), aralkyloxy,
alkoxycarbonylalkyl, carboxyalkyl, alkylcarbonyi (wherein
the alkyl is optionally substituted with a substituent
selected from carboxy or alkoxycarbonyl), arylcarbonyl
(wherein the aryl is optionally substituted with a
substituent selected from alkyl, alkoxy, alkoxycarbonyl
or carboxy), aralkycarbonyl, alkoxycarbonyl,
aralkyloxycarbonyl, aikoxyalkylcarbonyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, a nitrogen containing
heteroaryl (preferably the nitrogen containing heteroaryl
is other than 4-pyridyI), a nitrogen containing
heterocycloalkyl aminosulfonyl (wherein the amino group
is optionally substituted with one to two lower alkyl),
alkylsulfonyl (wherein the alkyl group is optional l.y
substituted with one to three substituents independently
selected from halogen), arylsulfonyl (wherein the aryl
group is optionally substituted with one to three
substituents independently selected from alkyl,
trifluoromethyl, trifluoromethoxy, halogen, alkoxy,
alkylcarbonylamino, acetamido, nitro, amino, aikylamino,
dialkylamino or 2-chloro-4-nitrophcnyoxy),
aralkyloulfonyl, biphenylsulfonyl, heteroarylsulfonyl
(wherein the heteroaryl is optionally substituted with
one to two substituents independently selected from
halogen, alkyl, heteroaryl or benzenesulfonyl),
benzhydryl, -Si-(aryl) 3, -C(O)0-Si (aryl) 3, -P (-0) (aryl)2,
-P(=0) (alkoxy) 2 and SEM.

In another embodiment of the present invention R2 is,
selected from, the group consisting of hydroxy,
halogenated alkyl, benzhydryl, alkoxy, alkeryl, alkoxy
substituted aralkyl, aralkylcxy, alkoxycarbonylalkyl,
substituted alkylcarbonyl (wherein the alkyl portion of
the alkylcarbonyl is substituted with a substituent
selected from carboxy or alkoxycarbonyl) , arylcarbonyl
(wherein the aryl is optionally substituted with a
substituent selected from alkyl, alkoxy, alkoxycarbonyl
or carboxy), aralkycarbonyl, alkoxycarbonyl,
aralkyloxycarbonyi, alkoxyalkylcarbonyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, a nitrogen containing
heteroaryl (preferably, the nitrogen containing
heteroaryl is other than 4-pyridyl), a nitrogen
containing heterocycloalkyl, aminosulfonyl (wherein the
amino group is optionally substituted with one to tv/o
lower alkyl), alkylsulfonyl (wherein the alkyl group is
optionally substituted with one to three substituents
independently selected from halogen), arylsulfonyl
(wherein the aryl group is optionally substituted with
one to three substituents independently selected from
methyl, trifluoromethyl, trif luoromethoxy, halogen,
alkoxy, methylcarbonylamino, acetamido, nitro, amino,
alkylamino, dialkylamino or 2-chloro-4-nitrophenyoxy),
aralkylsulfonyl, biphenylsulfonyl, heteroarylsulfonyl
(wherein the heteroaryl is optionally substituted with
one to two substituents independently selected from
halogen, alky!! , heteroaryl or benzenesulfonyl) ,
benzhydryi, -Si - (aryl)3, -C (O)O-Si (aryl)3, -P(-O) (aryl)2.,
-P(-O) (alkoxy) 2 and SEK.
Preferably, R2 is selected from the group comprising
of hydroxy, methoxy, ally], 1-(2 bromo)-ethyl, I-(2
24
ethoxycarbonyl)ethyl, methoxycarbonylmethyl,
methoxycarbony] ethyl, 1 - (methoxycarbonyl} -n-propyl,
carboxymethyl, 1- (3-carboxy) -n-propyl, 1- (2-
carboxy)ethyl, ethoxycarbonyl, t-butoxycarbonyl,
benzyloxycarbonyl, methylcarbonyl, ethylcarbonyl, n-
propylcarbonyl, isobutylcarbonyl, phenylethylcarbonyl,
benzylcarbonyl, phenylcarbonyl, 2 -methoxycarbonylphenyl-
carbonyl, 2-carboxyphenyl-carbonyl, methoxycarbonyl-
ethylcarbonyl, carboxyethylcarbonyl, diethoxy-phosphinyl,
triphenylsilyl, triphenylsilyloxycarbonyl,
trif luoromethylsulfonyl, dimethylaminoethyl, benzyl, 4-
methoxybenzyl, benzyloxy, 3-pyrrolidinyl, SEM,
diphenylphosphinyl, benzhydryl, 2-methoxyphenylcarbonyl,
3-methoxyphenylcarbonyl, 4 -methoxyphenylcarbonyl,
methoxymethylcarbonyl, 2-tolylcarbonyl, 3-tolylcarbonyl,
4-tolylcarbonyl, 5-heptylcarbonyl, aminosulfonyl, 4-
trifluorornethoxyphenylsulfonyl, 1-naphthylsulfonyl, 2-
naphthylsulf onyl, 1- (5-dimethylamino-naphthyl) -sulf onyl,
4-biphenylsulfonyl, 2-thienylsulfonyl, 2-(3-(2-pyridyl)-
thienyl) -sulfonyl, 4-trif luoromethylphenylsulfonyl, 3-
trifluoromethylphenylsulfonyl, 2,6-
difluorophenylsulfonyl, benzylsulf onyl, 4-
methoxyphenylsulfonyl, 4, 5-dibromo-2-thienylsulfor;yl, 2-
benzenesulf oriy.l -5-thienylsulfonyl,
trifluoromethylsulfonyl, 3-trifluoromethylphenylsulfonyl,
2,2, 2-trifluoroethylsulfonyl, phenylsulfonyl, 2,4,6-
trimethylphonyl-sulfonyl, 2-chloro-l-ethylsulfonyl,
isobutylsulfonyl, 1-butyloulfonyl, 4-(2,1,3,-
benzoxadiazolyl)sulfonyl, 4- (2 -chloro-4-nitrophonoxy; -
3 , 5-di.chl.orophenylsulfonyi, 4-bromophenylsul fonyl,
ethylfulfonyl, 8-quinolinylsulfonyl, 3,5-dimethyl-1-
isoxazolylsulfonyl , 4- (2 ,1, 3 -benzothidiazo'l yl) sulfonyl ,

1 -propylsulfony 1, 4 -- methylcarbonylamino-phonyl - sulfonyl,
4 - acetamidophenylsulfonyl and 4 - nitrophenylsulfonyl.
In an embodiment of the present invention R2 is
selected from the group consisting of hydroxy, methoxy,
allyl, 1-(3-methoxycarbonyl)-n-propyl, 1-(2-
carboxy)ethyl, 1-(2-bromo)-ethyl, l-(2-
ethoxycarbonyl)ethyl, methoxycarbonylmethyl, t-
butoxycarbonyl, benzyloxycarbonyl, methylcarbonyl,
ethylcarbonyl, triphenylsilyl, triphenylsilyloxyearbonyl,
trifluoromethylsulfonyl and benzhydryl.
In an embodiment of the present invention R2 is
selected from the group consisting of -C(O)-R9, -C(O)-
(alkyl)-O-(alkyl) and -SO2R12.
In another embodiment of the present invention R2 is -
C(O)-R9; wherein R9 is selected from the group consisting
of alkyl, aryl, (wherein the aryl group is optionally
substituted with a substitent selected from alkyl or
alkoxy) and aralkyl. Preferably, R9 is selected from the
group consisting of methyl, ethyl, n-propyl, isobutyl, 5-
heptyl, phenyl, benzyl, phenylethyl, 2-methoxyphonyl, 3-
methoxyphenyl, 4-methcxyphenyl, 2-tolyl, 3-tolyl and 4-
tolyl
In yet another embodiment of the present invention R2
is -SO2-R12; wherein R12 is selected from the group
consisting of amino, lower alkylamino, di(lower
alkyl)amino, alkyl, (wherein the alkyl group, whether
alone or as part of a substituent group is optionally
substituted with one to three substituents independently
selected from halogen), aryl (wherein the aryl group is

optionally substituted with one to three substituents
independently selected from alkyl, trifluoromethyl,
trifluoromethoxy, halogen, alkoxy, methylcarbonylaminc,
acetamido, nitro, amino, alkylamino, dialkylamino or 2-
chloro-4-nitrophenyoxy) , aralkyl, biphenyl and hetroaryl
(wherein the heteroaryl is optionally substituted with
one to two substituents independently selected from
halogen, alkyl, heteroaryl or benzenesulfonyl).
Preferably, R12 is selected from the group consisting of
trifluoromethyl, 4-trifluoromethoxyphenyl, 1-naphthyl, 2-
naphthyl, 1-(5-dimethylamino-naphthyl), 4-biphenyl, 2
thienyl, 4-trifluoromethylphenyl, 3-
trifluoromethylphenyl, 2,6-difluorophenyl, benzyl, 4-
methoxyphenyl, 4,5-dibromo-2-thienyl, 2-benzenesulfonyl-
5-thienyl, 2-(3-(2-pyridyl)-thienyl), 3-
trifluoromethylphenyl, 2,2,2-trifluoroethyl, phenyl,
2,4,6-trimethylphenyl, 2-chloro-l-ethyl, isobutyl, 1-
butyl, 4-(2,1,3,-benzoxadiazolyl), 4-(2-chloro-4-
nitrophenoxy)-3,5-dichlorophenyl, 4-bromophenyl, ethyl,
8-quinolinyl, 3,5-dimethyl-4-isoxazolyl, 4-(2,1,3-
benzothidiazolyl), 1-propyl, 4-methylcarbonylamino-
phenyl, 4-acetamidophenyl and 4-nitrophenyl.
In an embodiment oE the present invention R1 and R2
are taken together with the nitrogen atom to which they
are bound to form a group selected from heteroaryl or
heterocycloalkyl; wherein the heteroaryl or
heterocycloalkyl group is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, oxo, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro, cyano, -C(=NH)
amino, -C(=NH)alkylamino or -C(=NH)-dialkylamino; whorein
the aryl substituent is optionally substituted with one

or more subatituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro, cyano, -C (=NII)-amino, -
C(=NH)-alkylamino or -C (=NH)--dialkylamino; wherein the -
C (=NH) -amino, -C(=NH)-alkylamino or -C (=NH)-dialkylamino
group is bound to a nitrogen or carbon atom on the aryl,
heteroaryl or heterocycloalkyl; and wherein no more than
one -C(=NH)-amino, -C(=NH)-alkylamino or -C(=NH)-
dialkylamino group is bound to the aryl, heteroaryl or
heterocycloalkyl.
Preferably, R1 and R2 are taken together with the
nitrogen atom to which they are bound to form a
heterocycloalkyl group, a six membered monocyclic
heteroaryl group or a nine to ten membered bicyclic
heteroaryl group, wherein the heterocycloalkyl or
heteroaryl group is optionally substituted as previously
defined. More preferably, R1 and R2 are taken together
with the nitrogen atom to which they are bound to form a
heterocycloalkyl group or a nine to ten membered bicyclic
heteroaryl group, wherein the heterocycloalkyl or
heteroaryl group is optionally substituted as previously
defined. More preferably still, R1 and R2 are taken
together with the nitrogen atom to which they are cound to
form a group selected from morpholinyl, l-(2-
isopropoxyphenyl)-piperazinyl or isoindole-1,3-dione.
In an embodiment of the present invention, R1 and R2
are taken together with the nitrogen atom to which they
are bound to form -N=C(R14)2; wherein R14 is selected from
the group consisting of hydrogen, dialkylamino, cycioalkyl
and aryl; wherein the cycioalkyl or aryl is optionally
substituted with one or more substituents independently

selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro or
cyano. Preferably, R14 is selected from the group
consisting of hydrogen, di (lower alkyl)amino, a three to
eight membered monocyclic cycloalkyl and aryl, more
preferably R14 is selected from the group consisting of
hydrogen, dimethylamino, cyclohexyl and phenyl.
In an embodiment of the present invention, R1 and R2
are taken together with the nitrogen atom to which they
are bound to form -N=C(R14)2; wherein the two R14 groups; are
taken together with the carbon atom to which they are
bound to form a heterocycloalkyl group of the formula

wherein R20 is lower alkyl Preferably, the two R14
groups are taken together with the carbon atom to which
they are bound to form 2- (1-methyl-pyrrclidinyl) .
In an embodiment, the present invention is directed
to a compound of the formula (Ij)

wherein
X is selected from CH2 or O;
R1a is selected from the group consisting oi.
hydrogen, substituted ethyl, alkeny". (wherein the double

bond of the alkenyl group is directly bound to or one
carbon acorn removed from the nitrogen) , cycloalkenyl
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen) , heteroaryl-Cialkyl, heterocycloalkyl-C3alkyl,
alkoxycarbonylC2alkyl, -C(O)-R9, -C(O)-(alkyl)-O- (alkyl),
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
Si(R10) (O0-1R11)2, and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen) ,
benzyloxy, heteroaryl-Cialkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O)-R9, -C(O) - (alkyl) -O- (alkyl),
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
C(O)0-5i(R17)3, -Si(R10) (O0-1R11)2, -P(=0) (R13)2, and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R2

substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or an part
of an R13 substituent group, is optionally substituted

with one or more, substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano,-
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula
wherein n is an integer from 1 to 3,- and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two R15 groups are taken Logether with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;

alternatively R1a and R2a are taken together with the
nitrogen atom to which they are bound to form -N-C (R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycloalkyl, aryl or
arallcyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl;
R3, R4, Rs and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:
wherein R7 and Rd are same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyciohexyl ring;

provided than when R1 is hydrogen, then R2 is other
than methylcarbony] or carboxyethyl;
or a pharmaceutically acceptable salt thereof
In another embodiment of the present invention is a
compound of the; formula (Ik)

wherein
R1a is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen), cycloalkenyl
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen), heteroaryl-Cialkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O)-R9, -C(O)- alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
Si(R10) (O0-1R11)2, and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralky.l , amino,
alkylamino, dialkylamino, nitro or cyano;

R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen),
benzyloxy, heteroaryl-C1alkyl, heterocycloalkyl--C1alkyl,
alkoxycarbonylC2alkyl, -C(O) -R9, -C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
C(O)O-Si(R17)3, -Si(R10) (00-1R11)2, -P(=O)(Rl3)2 and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R2
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, ary3 or
heteroaryl group, whether alone or as part of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl grotip, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more

substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of: an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R13 is independently selected frorr.
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula


wherein n is an integer from 1 to 3; and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two R15 groups are taken together with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycloalkyl, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they arc bound to form a
heterocycloalkyl group of "he formula


wherein R20 is lower alkyl ;
provided than when R1 is hydrogen, then R2 is other
than methylcarbonyl or carboxyethyl ;
or a pharmaceutically acceptable salt thereof.
In an embodiment of the present invention arc
compounds of formula (Ij) and (Ik) wherein the R1a
substituent is a substituent which may be removed under
acidic (acid cleavage) de-protection conditions. In
another embodiment of the present invention are compounds
of formula (Ij) and (Ik) wherein the R1a substituent is a
substituent which may be removed under basic de-protection
conditions. In yet another embodiment of the present
invention are compounds of formula (Ij) and (Tk) wherein
the Rla substituent is a substituent which may be removed
under catalytic reduction conditions.
In an embodiment of the present invention are
compounds of formula (Ij) and (Ik) wherein the R2a
substituent is a substituent which may be removed under
acidic (acid cleavage) de-protection conditions. In
another embodiment of the present invention are compounds
of formula (Ij) and (Ik) wherein the R2a substituent is a
substituent which may be removed under basic de-protection
conditions. In yet another embodiment of the present
invention are compounds of formula (Ij) and (Ik) wherein
the R2a substituent is a substituent which may be removed
under catalytic reduction conditions.

In an embodiment of the present invention are
compounds of formula (Ij) and (Ik) wherein Rla and R2a are
taken together with the nitrogen atom to which they are
bound to form a group which may be removed under de-
protection condidions.
The compounds of formula (Ij) and (Ik) are useful as
intermediates for the preparation of the corresponding
compounds of formula (XX)

wherein X, R3, R4, R5 and R6 are as previously
defined, and the compound of formula (XXa)

respectively.
The present invention is further di.rected to a
process for the preparation of a compound of formula (XX)

wherein X is selected from CH2 or 0;

R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R5 may
be alkene groups joined to form a benzene ring and, when
X is O, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are the same or different and are
selected from hydrogen, lower alky], or are alkyl. and are
joined to form a cyclopentyl or cyclohexyl ring;
comprising reacting a compound of formula (Ij)

wherein
X is selected from CH2 or O;
Rla is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen), cycloalkenyl
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen) , heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbcnylC2alkyl, --C (O) -R9, -C (O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
S i (R10) (O0-1 R12)2, and SEK ;
wherein the subutituention the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

wherein the alky], benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen) ,
benzyloxy, heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O) -R9, -C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl,
C(O)0-Si(R17)3, -Si(R10) (O0-1R31)2, -P(-O) (R13)2 and SBM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as pax-t of the Ra
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R5
substituent group, is optionally substituted with one or-
more substituents independently selected from hologen,

hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy,-
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl? wherein ;;ho alkyl or aryl group,
whether alone or as part of an R ' substituent group, is
optionally substituted with one or more substituents
independently selected from haloyen, hydroxy, carboxy,
42
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively R1a and R2a arc taken together with the
nitrogen atom to which they are bound to form a group of
the formula
wherein n is an integer from 1 to 3; and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two Rla groups are taken together with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycloalkyl, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylandno, nitro or cyano,- provided that at least one

R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
or a pharmaceutically acceptable salt thereof;
under de-protection conditions, to yield the
corresponding compound of formula (XX). The compounds of
formula (XX) are useful for the treatment of epilepsy.
In an embodiment of the present invention in a
process for the preparation of a compound of formula (XX)

wherein
X is selected from CH2 or 0;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is O, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula :

wherein R7 and R8 are same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
or a pharmaceutically acceptable salt thereof,-
comprising, reacting a compound of formula (Ij)

wherein
X is selected from CH2 or 0;
Rla is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen) , cycloalkenyl
(wherein the double bond of the cycloalkenyl group is

directly bound to or one carbon atom removed from the
nitrogen), heteroaryl-C1alkyl, heterocycloalkyl-C3 alkyl,
alkoxycarbonylC2alkyl, -C(O) -R9, -C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, bcnzyloxycarbonyl, -
Si(R10) (O0-1R11)2, and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, di alkyl amino, nitro or cyano,-
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen) ,
benzyloxy, heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonyl C2alkyl, -C(O)-R9, -C(O)-(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, bcnzyloxycarbonyl, -
C(O)0-Si(R17)3, -Si(R10) (O0-1R11)2, -P(=0) (R13)2 and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R2
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,

hydroxy, carboxy, alkyl, alkoxy, aryl , aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R9 is independently selected from alkyl ,
aryl or aralkyl; wherein the alkyl or aryl group, whether
alone or as part of an R9 substituent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
alkoxycarborryl, ary.l , aralkyl, amino, alkylamino,
dialkylamirio, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamirio, nitro or cyano;
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, i.s optionally substituted
with one or more substituents independently selected from

halogen, hydroxy, curboxy, alkyl , alkoxy, aryl, aralkyl ,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula
wherein n is an integer from 1 to 3; and wherein
each Rlb is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two R15 groups arc taken together with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected frori
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, iiii:r;o or cyano;
alternatively R1a and R2a arc taken together with the
nitrogen atom to which they are bound to form -N--C(R14)2;

wherein n each R14 is independently selected from
hydrogen, alkyl, cycloalkyl, aryl or aralkyl; wherein the
alkyl, cycioalkyl or aryl group, whether alone or as part,
of an R14 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
provided that at least one Rl4 is selected from tho
group consisting of hydrogen and alkyl ,-
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or R5 and RG together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
or a pharmaceutically acceptable salt thereof;
under de-protection conditions, to yield the
corresponding compound of formula (XX).
In an embodiment of the present invention is a
process for the preparation of a compound of formula
(XXa)
wherein
R1a is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen) , cycloalkeny.l
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen) , heteroaryl-C1alkyl, heterocycloalkyl--C1alkyl ,
alkoxycarbonylC2alkyl, -C(O)-R9, -C(O)-(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
Si(R10) (O0-1R11)2. and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, hetoroaryl or
heterocycloalkyl group, whether alone or as part oi the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl., alkoxy, aryl, aralkyl , amino,
alkylamino, dialkylamino, nitro or cyario;

R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond ci:
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen),
benzyloxy, heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O)-R9, -C(O)-(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
C(O)0--Si(R17)3, -Si(R10) (00-1R11)2, -P(-O) (R13)2 and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, hoteroaryl or
heterocycloalkyl group, whether alone or as part of the R2
nubstituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl. group, whether alone or as part of an R16 substitiuent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro of cyano;
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independent] y selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula


wherein n is an integer from 1 to 3; and wherein
each R15 in independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two Rla groups are taken together with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form -N=C (R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycloalkyl, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consinting of hydrogen, and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they arc bound to form a
heterocycloaikyl group of the formula


wherein R20 is lower alkyl;
or a pharmaceutically acceptable salt thereof;
under de-protection conditions, to yield the
corresponding compound of formula (XXa). The compounds of
formula (XXa) are useful for the treatment of epilepsy.
The present invention is further directed to a
product prepared by reacting a compound of formula (Ij),
as previously defined, under de-protection conditions. In
an embodiment of the present invention is a product
prepared by reacting a compound of formula (Ik), as
previously defined, under de-protection conditions.
As used herein, "halogen" shall mean chlorine,
bromine, fluorine and iodine.
As used herein, the term "alkyl" whether used alone
or as part of a substituent group, include straight and
branched chains. For example, alkyl radicals include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-
butyl, t-butyl, pentyl and the like. Preferably, the
alkyl group comprises one to eight carbon atoms. Unless
otherwise noted, "lower" when used with alkyl means a
carbon chain composition of 1-4 carbon atoms.
As used herein, the term "alkenyL" shall denote
partially unsaturated straight and branched alkyl chains
containing one or more double bonds, preferably one to
two double bonds. Suiuable example include alkyl,

butenyl, propenyl, and r.he like. Preferably, the double
bond on the alkenyl group is at least one carbon atom
removed from the attachment point.
Similarly, the term "alkynyl" shall denote partially
unsaturated straight and branched alkyl chains containing
one or more triple bonds, preferably one to two triples
bonds, more preferably one triple bond. Suitable
examples include propargyl, -CH2CKaCCH, and the like;
wherein the triple bond on the ail kenyl group is at least
one carbon atom removed from the attachment point.
As used herein, the term "cyeloalkyl" shall mean any
stable 3 to 8 membered monocyclic or 9 to 14 merabered
saturated bicyclic ring system. Suitable examples
include cyclopropyl, cyclobutyl, cyclopentyl, cyclchexyl,
cycloheptyl, cyclooctyl, octabhydroindenyl,
decahydronaphthyl, and the like. The term "cycloalkenyl"
shall mean any stable 3 to 8 tnembered monocyclic,
partially unsaturated ring system containing one or more
double bonds, or any stable 9 to 14 membered, bicyclic,
partially unsaturated (i.e. containing one or more double
bonds) or partially aromatic ring system. Suitable
examples include cyclohexenyl, cyclopentenyl,
cyclopropenyl, cyclohex-1,4-dienyl, tetrahydronaphchyl,
indanyl, and the like.
As used herein, unless otherwise noted, "aryl"
whether used alone or as part of a substituent group,
shall refer to a carbocylic aromatic group such as phenyl,
naphthyl, and the like.

As used herein, unless otherwise noted, "aralkyl"
whether used alone or as part of a aubst.ituent group,
shall mean any lower alkyl group substituted with an aryl.
group such as phenyl, naphthyl and the like. Suitable
examples include, benzyl, phenylethyl, naphthylmethyl, and
the like.
As used herein, unless otherwise noted, "alkoxy"
whether used alone or as part of a substituent group,
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. Similarly, the terms "aryloxy"
and "aralkyloxy" shall denote an oxygen ether radical of
the above described aryl and aralkyl groups, respectively.
As used herein, unless otherwise noted, "heteroaryl"
whether used alone or as part of a substituent group,
shall denote any five or six membered monocyclic aromatic
ring structure containing at least one heteroatom selected
from the group consisting of 0, N and S, optionally
containing one to three additional heteroatoms
independently selected from the group consisting of 0, N
and S; or a nine or ten membered bicyclic aromatic ring
structure containing at least one heteroatom selected from
the group consisting of O, N and S, optionally containing
one to four additional heteroatoms independently selected
from the group consisting of 0, N and S. The heteroaryl
group may be attached at any heteroatom or carbon atom of
the ring such that the result is a stable structure.
Preferably, the heteroaryl group is attached at any carbon
atom of the ring such that the result is a arable
structure.

Examples of suitable hetcroaryl groups include, but
are not limited to, pyrroiyl, furyl, thienyl, oxazolyl,
imidazolyl, purazolyl, isoxazolyl, ioothiazolyl,
triazolyl, thiadiazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl,
indolyl, isoindolinyl, indazolyl, bonzof ury.l,
benzothienyl, bonzimidazolyl, benzthiazolyl,
benzthidiazolyl, benzoxadiazolyl, purinyl, quinolizinyl,
quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxa] inyll , naphthyridinyl,
pteridinyl, and the like.
Particularly preferred heteroaryl groups include
thienyl, 2,1,3-benzoxadiazolyl, 2,1,3-benzothidiazolyl,
quinolinyl and isoxazolyl.
As used herein, the term "heterocycloalkyl" whether
used alone or as part of a substituent group, shall
denote any five to seven membered monocyclic, saturated or
partially unsaturated ring structure containing at least
one heteroatom selected from the group consisting of O, N
and S, optionally containing one to three additional
heteroatoms independently selected from the group
consisting of O, N and S; or a nine to ten membered
saturated, partially unsaturated or partially aromatic
bicyclic ring system containing at least one heteroar.om
selected from the group consisting of 0, N and S,
optionally containing one. to four additional heteroatoms
independently selected from the group consisting of O, N
and S. The heterocycloalkyl group may be attached at: any
heteroatom or carbon atom of the ring such that the result
is a stable structure.
Examples of suitable heterocycloalkyl groups include,
but are not limited to, pyrrolinyl, pyrrolidinyl,

dioxalanyl, imidazolinyl, imidazolidinyl, pyrauolinyl,
pyrazolidinyl, piperidinyl, dioxanyl , morpholinyl,
dithianyl, thiomorpholinyJ , piperazinyl, trithianyl ,
indolinyl , chromenyl, 3,4-methylenedioxyphenyl, 2,3-
dihydrobenzofuryl, 2, 3-dihydro--lH-isoindole, and the like.
Particularly preferred heterocycloa.1 kyl groups
include pyrrolidiny, piperidinyl, morpholinyl,
piperazinyl and 2,3-dihydro-1H-isoindole.
With reference to substituents, the term
"independently" means that when more than one of such
substituents is possible, such substituents may be che
same or different from each other.
When a particular group is "substituted" (e.g.,
phenyl, aryl, aralkyl, heteroaryl), that group may have
one or more substituents, prefereably from one to four
substituents, more preferably from one to three
substituents, more preferably still from one to two
substituents.
As used herein, the symbol "¦¦" shall denote a
bond above the plane of the molecule. Similarly, the
symbol "HHHHH" shall denote a bond below the plane of the
molecule.
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 acid
such as hydrochloric acid, sulfuric acid, fumaric acid,
maleic acid, succinic acid, acetic acid, benzoic acid,
citric acid, tartaric acid, carbonic acid or phosphoric
acid.
Furthermore, where the compounds of the invention
carry an acidic moiety, or wherein R1 or R1a is hydrogen,
suitable pharmaceutically acceptable salts thereof may
include alkali metal salts, e.g., sodium or potassium
salts; alkaline earth metal salts, e.g., calcium ox-
magnesium salts; and salts formed with suitable organic
ligands, e.g., primary, secondary, tertiary or quaternary
ammonium salts, such as morpholinyl, t-butylamino,
choline, and the like.
Representative pharmaceutically acceptable salts
also include the following:
acetate, benzenesulfonate, berizoate, bicarbonate,
bisulfate, bitartrate, borate, calcium edetate,
camsylate, carbonate, clavulanate, citrate, edetate,
edisylate, estolate, osylate, fumarate, gluceptate,
gluconate, glutamate, glycollylarsanilate,
hexylresorcinatc, hydrabamine, hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isothionate,
lactate, lactobionate, laurate, malate, maleate,
tnandelate, mesylate, methylbromide, methylnitx-ate,
methylsulfate, mucate, napsylate, nitrate, N-
methylglucamirie ammonium salt, oleate, pamoate
(embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate,
stearace, sulfate, subacetate, succinate, tannate,
tartrate, teoclate, tosylate, triethiodide, valerate,
bcnzanthine, chloroprocaine, choline, diethanolamine,

ethy.lenediamine, meglumine, procaine, aluminum, calcium,
lithium, magnesium, potassium, sodium and zinc.
The present: invention includes within its scope
prodrugs of the compounds of this invention. In general,
such prodrugs will be functional derivatives of the
compounds which are readily convertible in vivo into the
required compound. Thus, in the methods of treatment, of
the present invention, the term "administering" shall
encompass the treatment of the various disorders
described with the compound specifically disclosed or
with a compound which may not be specifically disclosed,
but which converts to the specified compound in vivo
after administration to the patient. Conventional
procedures for the selection and preparation of suitable
prodrug derivatives are described, for example, in
"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
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. Furthermore, some of the
crystalline forms for the compounds may exist as
polymorphs and as such are intended to be included in the
present invention. In addition, some of the compounds
may form solvates with water (i.e., hydrates) or compounds
organic solvents, and such solvates are also intended to
be encompassed within the scope of this invention.

The term "subject." as used herein, refers to an
animal, preferably a mammal, most preferably a human, who
is 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.
An 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.
Abbreviations used in the specification,
particularly the Schemes and Examples, are as follows:
AcN = Acetonitrile
Benzhydryl = -CH(phenyl)2
CDI = 1,1'-carbonyldiimidazole
DAF = Diacetone fructose
DCC = 1 ,3 -Dicyclchexylcarbodiimide
DCM = Dichloromethane
DIPEA = Diisopropylethylamine
DME = Dimethoxyethane
DMF = Dimethylformami.de
EtOAc = Ethyl acetate

Scheme 1
More particularly, a compound of formula (II), a
known compound (prepared as disclosed in U.S. Patent. No.
4,513,006, Maryanoff, et al. , Issued April 23, 399b) is
reacted with a suitably substituted amine of formula
(III) , a known compound or compound prepared by knows

methods, preferably in amount in the range of about, i te
about 2 equivalents, in an organic solvent such as
acotonitrile, THF, DMK, methylene chloride, and the like,
in the presence of an organic base such as pyridine,
DIPEA, TEA, and the like, to yleld the corresponding
compound of formula (I).
Alternatively, compounds of formula (I) wherein one
of R- or R2 is selected from hydroxy, alkoxy, aryloxy, or
aralkyloxy, may be prepared according to the process
outlined in Scheme 2.

More particularly, a compound of formula (II) is
reacted with a suitably substituted compound of formula
(IV) , wherein one of R1b or R2b is hydroxy, alkoxy,
aryloxy, or aralkyloxy, a known compound or compound
prepared by known methods, preferably in amount in the
range of about 1 to about 2 equivalents, in an organic
solvent such as acetonitrile, THF, DME, and the like, in
the presence of a base such as K2CO3, DIPHA, TEA, and the
like, preferably K2CO3, to yleld the corresponding
compound of formula (Ia).
Compounds of formula (I) wherein one of R1 is
hydrogen and R2 is selected from alkoxycarbonyl,
aryloxycarbonyl or aralkyloxyearbonyl (i.e where R3 or K2

is -C(O)-O-R16, wherein R16 is alkyl, aryl or aralkyl) , may
bo prepared according to the process outlined in Scheme
3,

More particularly, a compound of formula (V), a
known compound or compound prepared by known methods, is
reacted with a suitably substituted compound of formula
(VI), wherein R16 is selected from alkyl, aryl or araikyl,
a known compound or compound prepared by known methods,
in an organic solvent such as acetonitrile, THF, and the
like, in the presence of an inorganic base such as sodium
hydroxide, K2CO3, Na2CO3, CsCO3, and the like or an organic
base such as TEA, DIPEA, pyridine, and the like,
preferably in the presence of an organic base, to yleld
the corresponding compound of formula (Ib).
Compounds of formula (1) wherein both R1 and R2 are
selected from -C(O)0-R16, wherein R16 is as previously
defined, may be prepared by further reacting the compound
of formula (lb) , with a suitably substituted compound of
the formula R16-O-C (O) -CI , or a suitably substituted
symmetric or asymmetric compound of the formula R16-O-
C(O)0-O-R16, in the presence of a base such as TEA, DIPEA,
pyridine, and the like, in an organic solvent such as
acetonitrile, THF, and the like.

Alternatively, compounds of formula (I) may be
prepared directly from the compound of formula (XX).

Compounds of formula (I) wherein one of R1 or R2 is
selected from the group consisting of -C(O)-R9, wherein R9
is as previously defined, may be prepared according to
the process outlined in Scheme 4.

Accordingly, the compound of formula (XX) is reacted
with a suitably substituted symmetric or asymmetric
anhydride, preferably a suitably substituted symmetric
anhydride, a compound of formula (VIII), a known compound
or compound prepared by known methods, wherein R" is as
previously defined, in the presence of an organic base

such as TEA, DIPEA, pyridine, and the like, in an organic
solvent such an TUP, AcN, othyl acetate, DME and the
like, to yleld the corresponding compound of formula
(lc) .
Alternatively, the compound of formula (XX) is
reacted with a suitably substituted acid chloride, a
compound of formula (IX) , wherein R9 is as previously
defined, in the presence of an organic base such as TEA,
BIPEA, pyridine, and the like, in an organic solvent such
as THF, acetonitrile, ethyl acetate, DME and the like, to
yleld the corresponding compound of formula (lc).
One skilled in the art will recognize that in the
process outlined in Scheme 4 above, the acid chloride
compound of formula (IX) may alternatively be substituted
with a suitably substituted acid bromide (i.e a compound
of the formula R3-C(O)-Br) or a suitably substituted acid
fluoride (i.e a compound of the formula R9-C(O)-F) and
reacted with the compound of formula (XX) to yleld the
corresponding compound of formula (lc).
Compounds of formula (I) wherein both R' and R2 are
selected from -C(O)-R9, may be prepared by reacting the
compound of formula (XX) with at least two equivalents of
a suitably substituted acid chloride of formula (IX),
according to the process described above.
Alternatively, for compounds of formula (I) wherein
both R1 and R2 are each selected from -C (O) -RD and are not
the same, may be prepared by reacting the compound of
formula (lc) with a suitably substituted acid chloride of
formula (IX), according to the process described above.

Similarly, compounds of formula (T) wherein one of R9
or R2 is selected from the group consisting of -SO2-R12,
wherein RiZ is as previously defined, may be prepared
according to the process outlined in Scheme 4, with
selection and substitution of a suitably substituted
symmetric or asymmetric sulfonic anhydride (R12-SO2-0-SO2-
R12) for the symmetric or asymmetric anhydride of formula
(VIII) or selection and substitution of a suitably
substituted sulfonyl chloride (R-2-SO2-Cl) for the acid
chloride of formula (IX). One skilled in the art will
further recognize that a suitably substituted sulfonyl
bromide (R12-SOz-Br) may be used in place of the suitably
substituted sulfonyl chloride to yleld the desired
product.
Similarly, compounds of formula (I) wherein one of R1
or R2 is selected from -SO2-R12 and R12 is selected from
the group consisting of amino, alkylamino and
dialkylamino, may be prepared by reacting a suitably
substituted compound of formula (XX) with sulfuryl
chloride (SO2Cl2) and then reacting with a suitably
substituted amine, alkylamine or dialkylamine.
Compounds of formula (I) wherein one or both of R1 or
Rz is SEM, may be prepared by reacting the compound of
formula (XX) with SEM-Cl, in the presence of a base such
as sodium hydride, n-butyl lithium, lithium
diisopropylamide, and the like, in an organic solvent
such as THE, DME, acetonitrilc, ethyl acetate, and the
like. Wherein one of R1 or R2 is SEM, the SEM-Cl reagent
is present in an amount equal to about I equivalent.
Wherein when both of R1 and R2 are SEM, the SEM-CI reagent
is present in an amount greater than 1. equivalent,

preferably in an amount equal to or greater than about 2
equivalents.
Compounds of formula (I) wherein R1 is -P(O)(R14)2,
wherein R13 is as previously defined may be prepared
according to the process outlined in Scheme 5.

Accordingly, a suitably substituted compound of
formula (lb'), prepared as described in Scheme 2, is
reacted with a suitably substituted compound of formula
(XI) , 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
toluene, xylene, benzene, and the like, at a reduced
temperature, to yleld the corresponding compound of
formula (XIT) , which is heated at, elevated temperature,
preferably at a temperature of greater than or equal to

about 80°C, to yleld the corresponding compound of formula
(Id).
One skilled in the art will recognize that in the
process as outlined in Scheme 5 above, a suitably
substituted compound of the formula Br-P(R13)2 may be
substittited for the compound of formula (XI) and reacted
with the compound of formula (Ib'), to yleld the
corresponding compound of formula (XII), which is then
further reacted to yleld the corresponding compound of
formula (Id).
Compounds of formula (I) wherein R1 and R2 are taken
together with the N atom to which they are bound to form
a group of the formula -N=C(R14)2, and wherein at least
one R14 is selected from the group consisting of hydrogen
and alkyl; may be prepared according to the process
outlined in Scheme 6.

Accordingly, a suitably substituted compound of
formula (XX), a known compound, is reacted with a
suitably substituted compound of formula (XIII) , a known
compound, or compound prepared by known methods, in an
organic solvent such as MeOH, THF, AcN, and the like,

preferably in the presence of a catalytic amount of an
acid such as acetic acid, p-toluenesulfonic acid, HCl,
and the like, to yleld the corresponding compound of
formula (le).
Similarly, compounds of formula (I) wherein R1 and K2
are taken together with the nitrogen atom to which they
are bound to form -N=C(R14)2 wherein one R14 is
dialkylamino, may be prepared by reacting a suitably
substituted compound of formula (XX) with a suitably
substituted compound of the formula

a known compound or compound prepared by known
methods, in an organic solvent such as methylene
chloride, diethyl ether, THF, and the like.
Similarly, compounds of formula (T) wherein R1 and R2
are taken together with the nitrogen atom to which they
are bound to form -N=C(R14)2 and wherein two R14 groups are
taken together with the carbon atom to which they are
bound to form a heteroeycloalkyl group of the formula

may be prepared by reacting a suitably substituted
compound of formula (XX) with a suitably substituted
compound of the formula


a known compound or compound prepared by known
methods, in the presence of base such as sodium hydride,
sodium methoxide, sodium ethoxide, and the like, in an
organic solvent such as methylene chloride, diethyl
ether, THF, and the like.
Compounds of formula (I) wherein R1 and R2 are taken
together with the nitrogen atom to which they are bound
to form a group of the formula

may be prepared according to the process outlined in
Scheme 7.

Accordingly, a compound of formula (XX), a known
compound or compound prepared by known methods, is
reacted with a suitably substituted compound of formula
(XIV) , wherein W is -OH, -Cl, -Br or -F, a known compound
or compound prepared by known methods, in the presence of
a coupling agent such as DCC, CDI, HBTU, and the like, in
the presence of an organic base such as DIPEA, TEA,
pyridine, and the like, in an organic solvent such as
DCM, THF, DMF, and the like, or a mixture thereof, to
yleld the corresponding compound of formula (If). When
in the compound of formula (XIV) W is Cl, Br or F, the
organic base is an organic tertiary amine base such as
TEA, DIPEA, pyridine, and the like.
The compound of formula (If) is reacted with a base
such as NaOK, KOH, TBAH, and the like, in a polar organic
solvent such as acetone, methanol, DMF, THF, and the
like, to yleld the corresponding compound of formula
(xg) -
The compound of formula (Ig) is subjected to ring
closure, in the presence of a coupling agent, such as CDI,
DCC, HBTU, and the like, in the presence of an organic

base such as DIPEA, TEA, pyridine, and the like, in an
organic solvent such as THF, DM-/, AcST, and the like, to
yleld the corresponding compound ot formula (Ih).
The compounds of formula (XX) may be prepared
according to the process outlined in Scheme 8.

Accordingly, the compound of formula (Ij), prepared
as in any of the Schemes described above, is reacted
under de-protection conditions (for example as described
in T.W. Greene & P.G.M. Wuts, Protective Groups in
Organic Synthesis, John Wiley & Sons, 1991), to yleld the
corresponding compound of formula (XX).
For compounds of formula (Ij) wherein Rla its selected
from the group consisting of hydrogen, benzyl,
heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl and
benzyloxycarbonyl; and wherein R2a is selected from the
group consisting of benzyl, hetercaryl-C1alkyl,
heterocycloalkyl-C1alkyl and benzyloxycarbonyl , the
compound of formula (Ij) is subjected to catalytic
reduction, to yleld the corresponding compound of formula
(XX). More particularly, the compound of formula (Ij) is
treated with a reducing agent such as H2 gas, preferably
hydrogen gas at a pressure of about 1 to about 70 psi,
preferably about 50 psi, in the presence of a catalyst
such as 10% Pd on carbon, Pt on carbon, and the like, in
an organic solvent such as ethanol, methanol, and the
like, to yleld the corresponding compound of formula
(XX).
Alternatively, for compounds of formula (Ij) wherein
R3a is selected from the group consisting of hydrogen,
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl,
Si(R10) (O0-1R11)2 and SEM; and wherein R2a is selected from
the group consisting of substituted ethyl, alkenyl
(wherein the double bond of the alkenyl group is directly
bound to or one carbon atom removed from the nitrogen),
cycloalkenyl (wherein the double bond of the cycloalkenyl
group is directly bound to or one carbon atom removed
from the nitrogen), alkoxycarbonyl, aryloxycarbonyl,
benzyloxycarbonyl, -C (O) O-Si (R17) 3, -Si (R10) (O0-1R11) 2, -
P(=0) (R13)2 and SEM; or wherein Rla and R2a are taken
together with the nitrogen atom to which they are bound
to form a group of the formula -N-C(R14) 2; the compound of
formula (lj) is subjected to acid cleavage, to yleld the
corresponding compound of formula (XX). More
particularly, the compound of formula (Ij) is reacted
with an acid such as hydrochloric acid, sulfuric acid,
trifluaoroacetic acid, and the like, in a polar solvent
such as acetone, THF, DCM, and the like, preferably
acetone, to yleld the corresponding compound of formula
(XX) .

Alternatively still, for compounds of formula (Ij)
wherein Rla is selected from the group consisting of
hydrogen, alkoxycarbonylC2alkyl and --C(O) -R9, --C(O)-
(alkyl)-O-(alkyl); and R2a is selected from the group
consisting of carboxyethyl, alkoxycarbonylC2alkyl and
C(O)-R9, -C(O)-(alkyl)-O-(alkyl); the compound of formula
(I) is subjected to basic cleavage, to yleld the.
corresponding compound of formula (XX) . More
particularly, the compound of formula (Ij) is reacted
with a base such as sodium hydroxide, potassium
hydroxide, TJ3AH, and the like, in an organic solvent such
as, THF, DMF, and the like, to yleld the corresponding
compound of formula (XX).
Compounds of formula (Ij) wherein Rla and R2a are
taken together to form a group of the formula

may be reacted under de-protention conditions, to
yleld the corresponding compound of formula (XX). Fox-
example, the compound of formula (Ij) is reacted with a
reagent such as hydrazine, methylhydrazinc or
phenylhydrazine, in an organic solvent such as a lower
alcohol (such as ethanol, methanol, isoproanol, and the
like), THF, DMF, and the like.
One skilled in the art will recognize that wherein
R3a and R2a are independently groups which may not be
removed under the same conditions (for example, wherein
the Rla group may be removed by acid cleavage and the R2a

group may be removed by basic cleavage), the compound of
formula (Ij) may be subjected to the individual de-
protection conditions required for the Rla and R2a groups,
in a sequential or simultaneous manner, to yleld the
corresponding compound of formula (XX).
In a preferred embodiment of the present invention
is a process for the preparation of a compound of formula
(XXa) comprising reacting a compound of formula (Ik)
under de-protection conditions (for example as described
in T.W. Greene & P.G.M. Wuts, Protective Groups in
Organic Synthesis, John Wiley & Sons, 1991).
In an embodiment of the present invention, the
compound of formula (Ij) is de-protected by subjecting
the compound of formula (Ij) to catalytic reduction,
according to the procedure described above. In another
embodiment of: the present invention, the compound of
formula (Ij) is de-protected by subjecting the compound
of formula (Ij) to acidic cleavage, according to the
procedure described above. In yet another embodiment of
the present invention, the compound of formula (Ij) is
de-protected by subjecting the compound of formula (Ij)
to basic cleavage, according to the procedure described
above. In yet another embodiment of the present
invention, the compound of formula (Ij) is de-protected
by reacting the compound of formula (Ij) with a reagent
such as hydrazine, methylhydrazine or phenylhydrazine,
according to the procedure described above.
In an embodiment of the present invention, the
compound of formula (Ik) is de-protected by subjecting
the compound of formula (Ik) to catalytic reducetion,

according to the procedure described above. In another
embodiment of the present invention, the compound of
formula (Ik) is de-protected by subjecting the compound
of formula (Ik) to acidic cleavage, according to the
procedure described above. In yet another embodiment of
the present invention, the compound of formula (Ik) is
de-protected by subjecting the compound of formula (Ik)
to basic cleavage, according to the procedure described
above. In yet another embodiment of the present
invention, the compound of formula (Ik) is de-procected
by reacting the compound of formula (Ik) with a reagent
such as hydrazine, methylhydrazine or phenyl hydrazinc,
according to the procedure described above.
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-1-tartaric acid
followed by fractional crystallization and regeneration
of the free base. The compounds may also be resolved by
formacion of diastereomeric esters or amides, followed by
chromatographic separation and removal of the chiral
auxiliary. Alternatively, the compounds may be resolved
using a ehiral HPLC column.

During any of the processes Cor preparation of the
compounds of the present invention, it may be necessary
and/or desirable to protect sensitive or reactive groups
on any of the molecules concerned. This may be achieved
by means of conventional protecting groups, such as those
described in Protective Groups in Organic Chemistry, ed.
J.F.W. McOmie, Plenum Press, 1973; and 7.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.
One skilled in the. art will further recognize that
wherein a reaction step of the present invention may be
carried out in a variety of suitable solvents, said
reaction step may also be carried out in a mixture of the
suitable solvents.
The present invention also provides pharmaceutical
compositions comprising one or more compounds of this
invention in association with a pharmaceutically
acceptable carrier. Preferably these compositions are in
unit dosage forms such as tablets, pills, capsules,
powders, granules, sterile parenteral solutions or
suspensions, metered aerosol or liquid sprays, drops,
ampoules, autoinjeetor 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 tor 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 preforrnulation
composition containing a homogeneous mixture of a
compound of the present invention, or a pharmaceutically
acceptable salt thereof. When referring to these
preforrnulation 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 about 5 to about
2000 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, aqucous
solutions, suitably flavoured syrups, aqueous or oil
suspensions, and flavoured emulsions with edible oils
such as cottonseed oil, sesame oil, coconut oil or peanut
oil, as well as elixirs and similar pharmaceutical
vehicles. Suitable dispersing or suspending agents for
aqueous suspensions, include synthetic and natural gums
such as tragacanth, acacia, alginate, dextran, sodium
carboxymethylcellulose, methylcelluloso, polyvinyl -
pyrrolidone or gelatin.
The method of treating epilepsy 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 1 mg and about 2000 mg, preferably about 5
mg to about 1000 mg, more preferably about 10 mg to about
500 mg of the compound, 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, sodium acetate,
sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar,
bentonite, xanthan gum and the like.
The liquid forms may include 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 solutionis are desired. Isotonic
preparations which generally contain suitable
preservatives are employed when intravenous-, administration
is desired.
The compound of the present invention can also be
administered in the form of liposome delivery systems,
such as small unilamellar vesicles, largo unilamellar
vesicles, and multilamellar vesicles. Liposomes can be
formed from a variety of phospholipids, such as
cholesterol, stearylamine or phophatidylcholines.
Compounds of the present invention may also be
delivered by the use of monoclonal antibodies as
individual carriers to which the compound molecules are
coupled. The compounds of the present invention may also
be coupled with soluble polymers as targetable drug
carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamidephenol,
polyhydroxyethylaspartamidephenol, or polyethyl-
eneoxidepolylysine substituted with palmitoyl residue.
Furthermore, the compounds of the present invention may be
coupled to a class of biodegradable polymers useful in
achieving controlled release of a drug, for example,
polylactic acid, polyepsilon caprolactone, polyhydroxy
butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross-linked or
amphipathic block copolymers of hydrogels.
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 is required.

The daily dosage of the products may be varied over a
wide range from 5 to 1,000 mg per adult human per day.
For oral administration, the compositions are preferably
provided in the form of tablets containing, 5.0, 10.0,
15.0, 25.0, 50.0, 100, 250 and 500 milligrams of the
active ingredient for the symptomatic adjustment of the
dosage to the patient to be treated. An effective amount
of the drug is ordinarily supplied at a dosage level of
from about 0.01 mg/kg to about 50 mg/kg of body weight par
day. Preferably, the range is from about. 0.1 mg/kg to
about 25 mg/kg of body weight per day, more preferably
from about 0.2 mg/kg to about 10 mg/kg, more preferably
from about 0.5 mg/kg to about 10 mg/kg of body weight per
day. 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 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.
The following examples describe the invention in
greater detail and are intended to illustrate the
invention, but not to limit it.
Example 1
N-allyl-2,3:4,5-bis-O-(l-methylethylidene)-ß-D-
fructopyranose sulfamate (Compound #2)

A 500 mil three-necked reaction flask equipped with a
thermometer, stirring bar, addition funnel and N2 outlet:
was charged with allyl amine (2.1 mL, 20 mmol),
tetrahydrofuran {85 mL) and triethylamine (4.7 mL, 33.5
mmol). The addition funnel was charged with 2,2,7,7-
Letramethyl-tetrahydro-bis[1,3]dioxolo[4,b-b;4' 5' -
d]pyran-3a-ylmethyl ester chlorosulfuric acid (10.0 g, 28
mmol) and tetrahydrofuran (20 mL) which was slowly added
(over 10 minutes) at room temperature. Upon complete
addition, the reaction was warmed to 50°C and stirred for
4 h. The resulting suspension was filtered and
concentrated to yleld a crude oil. The oil was taken up
in ethyl acetate (200 mL) and washed with saturated NH4C1
(1 x 50 mL) and brine (1 x 50 mL). After phase
separation, the organic layer was dried over Na2SO4 (150
g), then filtered and concentrated under vacuum to yleld
a light yellow oil (9.3 g). The oil was applied to
silica gel and eluted with ethyl acetate and hexane (30%)
to yleld the title compound. Upon standing the compound
slowly crystallized to yleld a low melting white solid,
m.p. 51-52°C
1H NMR (300 MHz, CDCl3) d 5.99-5.80 (1H, m) , 5.30
(1H, d, J = 17.5 Hz), 5.24 (HI, d, J = 10.2 Hz), 4.63
(1H, dd, J = 8.3, 2.5 Hz), 4.35 (1H, d, J= 2.7 Hz), 4.27
(IK, s) , 4.19 (2H, dd, J = 12.9, 10.5 Hz), 3.93 (1H, dd,
J= 13.0, 1.9 Hz), 3.83-3.74 (3H, m), 1.56 (3H, s), 1.49
(3H, s), 1.44 (3H, s), 3.36 (3H, s).
Elemental Analysis: (T = Theoretical, F = Found)

T: C, 47.48; H 6.64; N, 3.69; O, 33.73; S, 8.45
F: C, 47.52; H 6.77
Compounds #3-6, 8, 21-27, 37-39 and 45 were
similarly prepared according to the above described
procedure with appropriate selection and substitution of
a suitably substituted amine for the allyl amine
described above.

A 250 mL three-necked reaction flask equipped with a
thermometer, stirring bar, addition funnel and N2 outlet
was charged with hydoxylamine hydrochloride (2.0 g, 29
mmol), tetrahydrofuran (65 mL), water (1.7 mL) and
potassium carbonate (3.8 g, 27 mmol). 2,2,7,7-
Tetramethyl-tetrahydro-bis [1,3] dioxolo[4 , 5-b,-4 ' b' -
d]pyran-3a-ylmethyl ester chlorosulfuric acid (9.3 g, 26
mmol) in tetrahydrofuran (20 mL) was slowly added (over
10 minutes) via addition funnel at room temperature.
Upon complete addition the suspension was stirred for 12
h. The reaction mixture was filtered and concentrated to
yleld the title product as a white solid.
The product was further purified by
recrystallization from tertiary butyl methyl ether /
hexane to yleld a white solid.
m.p. 45-48°C

1H NMR (300 MHz, CDCl3) d 7.10 (1H, s) , 7.05 (IK, s) ,
4.62 (III, dd, J = 8.0, 2.5 Hz), 4.35 (1H, d, J = 2.6 hz) ,
4.25 (III, d, J= 7.6 Hz), 3.93 (1H, dd, J= 13.0, 1.0
Hz), 3.78 (1H, d, J = 12.9 Hz), 3.69 (211, q, J = 17.4,
12.0 Hz), 1.55 (3H, s) , 1.49 (3H, s) , 1.40 (3H, s) , 1.36
(3H, s) .
Compounds #10-3 2 were similarly prepared according
to the above described procedure with appropriate
selection and substitution of a suitably substituted
amine for the hydoxylamine hydrochloride described above.

A 100 mL reaction flask equipped with a stirring bar
and N2 outlet was charged with chlorosulfonyl isocyanoate
(1.85 mL, 23 mmol) and dichloromethane (10 mL). At room
temperature tertiary butyl alcohol (2.03 mL, 21 mmol) was
slowly added and the solution stirred for 3 0 min. The
reaction was then concentrated and the residue taken up
in AcN (20 mL). DAF(5.5 g, 21 mmol) in pyridine (2.6 mL,
32 mmol) was then added via addition funnel and the
reaction was stirred overnight. The material was then
concentrated to dryness to yleld an oil. The oil was
taken up in DCM (100 mL) and washed with 0.5N HCl (2 x 50
mL) and brine (1 x 50 mL). After phase separation, the

organic layer was dried over Na2SO4 (150 g) , filtered and
concentrated under vacxium to yleld a light yellow oil
(10.5 g). The oil was applied to silica gel and eluted
with ethyl acetate and hexane (30 %) to yleld the title
compound as a white powder.
m.p. 88-90°C
1H NMR (300 MHz, CDCl3) d 4.60 (1H, d, J = 7.7 Hz),
4.45-4.34 (2H, m) , 4.30-4.19 (2H, m) , 3.93 (1H, d, J =
12.8 Hz), 3.75 (1H, d, J = 13.0 Hz}, 1.60-1.38 (18H, m) ,
1.33 (3H, s)
Elemental Analysis: (T - Theoretical, F = Found)
T: C, 46.46; H, 6.65; N, 3.19; O, 36.41; S, 7.30
F: C, 46.78; H, 6.89; N, 3.15
Compound #13 was similarly prepared according to the
procedure described above with substitution of triphenyl
silynol for tertiary butyl alcohol to yleld a white
solid.
A 250 mL reaction flask equipped with a stirring
bar, thermocouple and N2 outlet was charged with
chlorosulfonyl isocyanoate (10.0 mL, 115 mmol) and
dichloromethane (20 mL). After cooling the reaction
flask to 0°C benzyl alcohol (11.9 mL, 115 mmol) was added
via addition funnel over 3 0 min. The internal
temperature was kept below 10°C. After complete addition,
the reaction mixture was warmed to room temperature,
stirred for 15 min, then concentrated under vacuum to
yleld a white solid. The white solid was triturated in
petroleum ether (100 mL) . The solid was collected by
filtration, washed with petroleum ether (2 x 50 mL) and
dried under vacuum to yleld the final product as a fine
white powder.
Step B:
A 100 mL reaction flask equipped with a stirring bar
and N2 outlet was charged with
[ t [ (chlorosulfonyl)amino]carbonyl] oxyl-benzene (5.0 g, 21
mmol) and acetonitrile (20 mL) . Diacetone fructose (5.2
g, 20 mmol) in pyridine (2.4 mL, 30 mmol) was then added
via addition funnel and the reaction was stirred
overnight. The material was then concentrated to dryness
to yleld an oil. The oil was taken up in DCM (100 mL)
and washed with 0. 5N HCl (2 x 50 mL) and brine (1 x 50
mL) . After phase separation, the organic layer was dried
over Na2SO4 (150 g) , filtered and concentrated under
vacuum to yleld a sticky white solid (9.3 g). The
material was applied to silica gel and eluted with ethyl
acetate and hexane (50 %) to yleld the title compound as
a viscous oil.
1H NMR (300 MHz, CDCl3) d 8.58 (IK, g) , 7.45-7.30
(5H, m) , 5.21 (1H, s) , 4.58-4.50 (.1H, m) , 4.42 (III, dd, J

= 10.6, 3.0 Hz), 4.35-4.17 (3H, m) , 3.87 (1H, d, J = 13.4.
Hz), 3.74 (1H, d, J= 13.2Hz), 1.51 (3H, s), 1.43 (3H,
s) , 1.36 (3H, a), 1.32 (3H, s)
Elemental Analysis: (T = Theoretical, F = Found)
T: C, 50.73; H, 5.75; N, 2.96; O, 33.79; S, 6.77
F: C, 50.97; H, 6.10; N, 2.67

A 200 ml. three-necked reaction flask equipped with a
stirring bar, addition funnel and N2 outlet was charged
with topiramate (3.0 g, 9 mmol), triethylaniine (1.5 ml.,
11 mmol), tetrahydrofuran (88 mL) , propionic anhydride
(3,4 mL, 27 mmol) and a catalytic amount of 1,1-
dimethylamino pyridine (0.5 g, 4 mmol). The reaction
mixture was stirred at room temperature for 16 h, after
which time the reaction was quenched with water (200 mL)
and ethyl acetate (150 mL) . The organic layer was washed
with brine (1 x 100 mL) , dried over Na2SO4 (75 g) ,
filtered and concentrated to yleld the title compound as
a viscous oil.
1H NMR (300 MHz, CDCl3) d 4.61 (III, dd, J = 8.0, 2.6
Hz), 4.39 (1H, d, J = 10.7), 4.33-4.20 (3H, m) , 3.90 (1H,
d, J = 13.4 Hz), 3.76 (1H, d, J = 13.4), 2.54-2.34 (2H,
m) , 1.54 (311, s) , 1.47 (3K, s) , J.42 (311, s) , 1.34 (3I-I,
s), 1.16 (3H, t, J = 7.2 HZ)

Elemental Analysis: (T = Theoretical, F = Found)
T: C, 45.56; H, 6.37; N, 3.54; 0, 36.42; S, 8.11
F: C, 45.28; H, 6.47; N, 3.26
Compound #29 was similarly prepared according to the
procedure described above with substitution of acetic
anhydride for propionic anhydride, to yleld a yellow oil.
Compounds #4 9-61 were similarly prepared according
to the procedure described above with appropriate
selection and substitution of a suitably substituted acid
chloride for the propionic anhydride.

A 200 mL three-necked reaction flask equipped with a
stirring bar, addition funnel and N2 outlet was charged
with sodium hydride (0.2 g, 8 mmol) and tetrahydrofuran
(70 mL). A tetrahydrofuran (15 mL) solution of N-acetyl-
2,3:4, 5-bis-O-(1-methylethylidine)-p-D-fructopyranose
sulfamate (3.2 g, 8 mmol) was added slowly via addition
funnel. The mixture was allowed to stir at room
temperature for 1 h, after which Lime the solvent was
removed under reduced pressure. The solid was triturated
with hexane to yleld the product as a solid.

A sample of the solid product was recrystailized
from acetone and filtered to yleld the title product, as a
sodium salt, as a fine white powdex".
1H NMR (3 00 MHz, CDCl3) d 4.54 (1H, dd, J = 8.0, 2.7
Hz), 4.35 (III, d, J =2.7 Hz), 4.21 (1H, d, J = 8 . 2 Hz),
3.89-3.68 (3H, m) , 3.56 (1H, d, J= 13.3 Hz), 1.70 (3H,
s) , 1.43 (3H, s), 1.34 (3H, s), 1.27 (3H, s)
Elemental Analysis: (T = Theoretical, F = Found)
T: C, 41.69; H, 5.50; N, 3.47; Na, 5.70; O, 355.70;
S, 7.95
F: C, 41.56; H, 5.89; N, 2.94; Na, 5.93
Compounds #16, 17, 19 and 20 were similarly prepax-ed
according to the procedure described above.

A 100 mL reaction flask equipped with a stirring bar
and N2 outlet was charged with topiramate (3.0 g, 9 mmol),
pyridine (0.8 mL, 10 mmol) and tetrahydrofuran (10 mL) .
At room temperature, N-trifluorornethane sulfonyl chloride
(0.94 mL, 9 mmol) was added dropwise and stirred for 2.5
h. The x-eaction was quenched by addition of 1.0 N HCl
(50 mL) and extracted with ethyl acetate (100 mL) . After
phase separation, the organic layer was washed with brine
(1 x 50 mL), dried over Na2SO4 (100 g) , filtered and

concentrated under vacuum to yleld a sticky white solid
(3.0 g) . The solid was recrystallazed from hexane /
ether to yleld the title compound as a white powder,
m.p. 126°C
1H NMR (300 MHz, CDCl3) d 4.63 (1H, dd, J = 8.0, 2.7
Hz), 4.36-4.2 (4H, m) , 3.93 (1H, d, J = 13.0, 1.9 Hz),
3.80 (1H, d, J = 13.0Hz), 1.56 (3H, s), 1.51 (3H, s),
1.44 (3H, s), 1.37 (3H, s)
Elemental Analysis: (T = Theoretical, F = Hound)
T: C, 33.12; H, 4.28; N, 2.97; 0, 33.94; S, 13.60;
F, 12.09
F: C, 33.25; H, 4.18; N, 3.06
Compounds #44 and 62-91 were similarly prepared
according to the procedure described above with
appropriate selection and substitution of a suitably
substituted chloride for the N-trifluoromethane sulfonyl
chloride.

A 50 mL three-necked reaction flask equipped with a
stirring bar and N2 outlet was charged with N-
trifluorosulfonyl-2, 3 :4, 5-bis-O- (l-methylethylidine) -ß- D-

fructopyranose sulfamate (0.4 g, 1 mmol), tetrahydrofuran
(10 mL) , followed by addition of morphol.ine (0.07 mL, 1
mmol). After stirring for 12 h at room temperature the
reaction was concentrated and the resulting solid
recrystallized from hexane / ethyl acetate to yleld the
title product as a water-soluble salt, as an off white
solid.
1H NMR (300 MHz, CDCl3) d 4.70 (8H, s) , 4.43-4.37
(2H, m) , 4.16 (2H, d, J = 3.6 Hz), 3.93 (HI, d, J = 13.7
Hz), 3.83 (1H, t, J = 5.0 Hz), 3.74 (1H, d, J = 13.7 Hz) ,


1.52 (3H, s) , 1.44 (3H, s) , 1.33 (311, s) , 1.33 (311, s)
Compound #32 was similarly prepared according to the
procedure described above with substitution of t -
butylamine for morpholine, to yleld a white solid.







A 100 mL three-necked reaction flask equipped with a
stirring bar and N2 outlet was charged with topiramato
(1.0 g, 3 mmol), diisopropylethyl amine (0.6 ml., 4 mmol)
and tetrahydrofuran (30 mL) . At room temperature 2-
(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (0.55 m.L,
3 mmol) was added dropwise and stirred for 14 h. The
reaction was quenched by addition of saturated ammonium
chloride (50 mL) and extracted with ethyl acetate (100

mL). After phase separation, the organic layer was
washed brine (1 x 50 mL) , then dried over Na2SO4 (50 g) ,
filtered and concentrated under vacuum to yleld a thick
oil. The oil material was applied to silica gel and
eluted with ethyl acetate and hexane (30 %) to yleld the
title product as the major product, as an oil.
1H NMR (300 MHz, CDCl3) d 4.76 (4H, s) , 4.61 (III, dd,
J = 8.0, 2.7 Hz), 4.38 (1H, d, J =3.6 Hz), 4.27-4.24
(1H=m), 4.22 (1H, s) , 4.14-4.10 (1 H, m) , 3.91 (IH, dd,
J = 13.0, 2.0 Hz), 3.75 (III, d, J = 12.8 Hz), 3.66-3.57
(4H, m), 1.55 (3H, s), 1.48 (3K, s) , 1.41 (3K, s) , 1.32
(3H, s), 0.01 (18 H, s)
Elemental Analysis: (T - Theoretical, F = Found)
T: C, 48.05; H, 8.23; N, 2.33; O, 26.67; S, 5.35;
Si, 9.36
P: C, 48.33; H, 8.15; N, 2.12

A 50 mL reaction flask equipped with a stirring bar
and N2 outlet was charged with N-hydroxyl topiramate
derivative (2.1 g, 6 mmol), triethylamine (0.9 mL, 7
mmol) and toluene (16 mL). The mixture was cooled to 0°C,
chlorodiphenylphosphine (1.17 mL, 7 mmol) was added
dropwise and the reaction mixture was stirred at. room
temperature for 1 h. The suspension wan filtered through
Celite and the filtrate warmed to 80°C for 14 h. The

vessel was cooled and the reaction mixture concentrated
to dryness, resulting in a white solid which was
recrystallized from tertiary butyl methyl ether to yleld
the title product as a white solid.
m.p. 137-138 °C
1H NMR (300 MHz, CDCl3) d 7.52-7.39 (4H, m) , 7.17-
7.00 (6H, m) , 4.22 (1H, dd, J= 7.9, 2.5 Hz), 3.90-3.86
(1H, m) , 3.84 (1H, s) , 3.68 (2H, dd, J =-. 16.1, 9.9 Hz),
3.49 (1H, dd, J" = 13.0, 1.8 Hz), 3.24 (3H, d, J = 13.0
Hz), 1.11 (3H, s), 0.98 (3H, s), 0.96 (3H, s) , 0.89 (3H,
s)
Elemental Analysis: (T = Theoretical, F = Found)
T: C, 53.43; H, 5.60; N, 2.60; O, 26.69; P, 5.74;
S, 5.94
F: C, 53.72; H, 5.42; N, 2.33

A 50 mL reaction flask equipped with a stirring bar
and N2 outlet was charged with methylbutyrate, 2,3:4,5-
bis-O- (1-methylethylidene) -P-D-fructopyranose sulfamnte
(0.79 g, 2 mmol) and acetone (6 ml.). 1. ON sodium
hydroxide (1.9 mL, 1.9 mmol) was added to the solution
and the reaction mixture was stirred at room temperature
for 15 min. The acetone was removed under vacuum. Ethyl
acetate. (50 mL) was then added and the pH adjusted to

about pH 3, with 1.0 N HCl. The layers were separated,
the organic layer was dried over Na2SO4 (25 g) , filtered
and concentrated to yleld the title compound as a thick
oil.
1H NMR (300 MHZ, CDCl3) d 5.30 (1H, s), 4.63-4.55
(1H, m) , 4.35-4.28 (1H, m) , 4.23 (1H, d, J = 7.6 Hz),
4.32 (2H, q, J = 20.4, 11.4 Hz), 3.89 (1H, d, J= 2.2.8
Hz), 3.74 (1H, d, J = 12.7 Hz), 3.3 9 (2H, q, J = 12.3,
5.7 Hz), 2.41 (2.H, t, J = 7.1 Hz), 1.89 (211, t, J = 7.1
Hz), 1.53 (3H, s), 1.45 (3H, s), 1.40 (3H, s), 1.33 (3H,
s)
Elemental Analysis: (T = Theoretical, F = Found)
T: C, 45.17; H, 6.40; N, 3.29; O, 37.61; S, 7.54
F: C, 44.95; H, 6.22; N, 3.05
Compounds #35 and 36 were similarly prepared
according to the procedure described above with
appropriate selection and substitution of a suitably
substituted ester for the methyl butyrate.

A 100 mL reaction flask equipped with a stirring
bar, N2 outlet and Dean-Stark, trap was charged with
2,3:4, 5-bis-O- (l-methylethvlidine) -ß-D-fructopyrananose
sulfamate (3.39 g, 10 mmol) and toluene (50 mL).

Benzaldehyde (1.1 ml, 11 mmol) and 10 drops of acetic
acid were added and the reaction was warmed to reflux
overnight. The reaction was then cooled and concentrated
to yleld a thick oil. (Note: The reaction mixture was
filtered through Celite prior to concentration on the
rotoevaporator to remove any solid particles). The oil
was then taken up in EtOAc (150 mL) and washed with NaHCO3
(2 x 50 mL) . The organics were dried and then filtered
through a plug of silica gel (10 g). The eluent was
concentrated to yleld the title product as a crude oil.
HPLC/MS/ES+ [M+l]+ mass = 428.0
Compound #46 was similarly prepared according to the
procedure described above.

A 300 mL reaction flask equipped with a stirring
bar, N2 outlet and addition funnel was charged with mono-
methyl phthalate (5.6 g, 31 mmol) dichloromethane (100
mL) and a drop of DIPEA. The reaction mixture was cooled
to 0°C. To the reacion mixture was then added HOC (6.7 g,
32 mmol) and dichloromethane (25 mL) , slowly via the
addition funnel. The resulting solution was then stirred

for 30 minutes at 0°C. To the reaction mixture was then
added 2,3:4, 5-bis-O- (1-methylethylidine) - ß-D-
fructopyranose sulfamate (10.0 g, 2 9 mmol) as a solution
of dichloromethane and DIPEA (5.7 mL, 32 mmol). The
reaction was allowed to slowly warm to room temperature,
with continuing stirring (12 h) . The reaction mixture
was then concentrated to a thick oil. The oil was taken
up in DCM (100 ml.) and then washed with 0. 5N HCl (2 x 50
mL) and brine (1 x 50 mL) . The organic layer was
separated and dried over Na2SO4 (150 g) , filtered and
concentrated under vacuum to yleld a light yellow oil.
The oil was applied to silica gel and eluted with
EtOAc/hexane (60 %) to yleld the title compound as an
oil.

A 100 mL reaction flask equipped with a stirring bar
and N2 outlet was charged with compound prepared as in
Example 13, (4.0 g, 8 mmol) and acetone (200 mL) . NaOH
(1.0 M, 20 ml, 20 mmol) was added at room temperature and
the reaction was stirred overnight. The reaction was
then concentrated and the residual oil taken up in EtCAc
(250 mL) . After extraction the layers were separated.
The aqueous layer was adjusted to about pH 1 with 1.0N

HCl (25 mL) . The product was extracted with EtOAc (2 00
mL) and the organic layer dried over Na2SO4 (150 g) ,
filtered and concentrated under vacuum to yleld the title
compound as a light yellow oil.
Compounds #42 and 43 were similarly prepared
according to the procedure described in Examples 13 and
14 above.

A 100 mL round bottom flask was charged with the
compound prepared as in Example 15 (1.2 g, 2.2 mmol) and
DMP (25 mL) . The reaction vessel was then charged with
CDI (0.5 g, 3 mmol) and the reaction mixture stirred for
one hour at room temperature. To the reaction mixture
was then added DIPEA (0.51 mL, 3 mmol) and the reaction
continued overnight. The reaction mixture was treated
with silica gel (50 g) and filtered through a plug of
Celite. Toluene (3 x 50 mL) was used to wash the pad of
Celite and silica gel. The filtrate was concentrated to
yleld the title compound as a light yellow oil.
HPLC/MS (ES+) [M+Na]+ = 492.1; [M+K]' - 500.2 m/z
Example 16

A 250 mL hydrogenation vessel was charged with N-
phenoxycarbonyl-2,3 :4,5-bis-Q- (1-tnethylethylidene) -p-D-
fructopyranose sulfamate (prepared as in Example 4)
{l.Og, 2.1 mmol), ethanol (21 mL) and palladium on carbon
(O.lg, 10% w/w, nominally wet). The vessel was subject
to 50 psi H2 using a Parr hydrogenationator at room
temperature. After 5 hours the reaction was purged with
N2 and filtered through a plug of Celite. The filtrate
was concentrated to a thick oil . The oil was treated
with ethanol (15 mL) and water (1 mL) , and the resulting
cloudy mixture was warmed (50°C) and hot filtered to
remove insoluble material. The filtrate was cooled to 0°C
and allowed to crystallize overnight. The solid was
collected by filtration, then dried under vacuum to yleld
the title product as a white solid.
m.p. 126°C
Example 17
2,3:4, 5-bis-0 (1-methylethylidine)-ß-D-fructopyranose
sulfamate (also known as Topiramate)
A 20 ml flask was charged with the compound prepared
as in Example 12 (0.18g, 0.42 mmol) and acetone (5 mL) .
At room temperature a catalytic amount of 2.ON KC1 (0.2
mL, 0.2 mmol) was added to the reaction mixture and t.he
resulting light yellow solution was stirred at room
temperature. GC and TLC were used to monitor the
progress of the reaction. After 1.5 hours the reaction
was complete. The reaction mixture was then diluted with
EtOAc (1 x 50 mL) and water (5 mL), the organic layer wan
separated, dried (Na2SO4) , filtered and concentrated. The
product was isolated as a white solid after
crystallization from EtOH.
1HNMR of the solid was consistent with topiramate,

A 20 mL reaction flask, equipped with a stirring bar
and N2 outlet was charged with N-{2-
methoxycarbonylphenyl)carbonyl-2,3:4,5-bis-O- (1 -

methylethylidine) -ß-D-fructopyranose sulfamate, the
compound prepared as in Example 13 (0.3 g, 0.6 mrr.ol) and
DMF (6 mL). NaOH (3.0 M, 1.2 ml, 3.6 mmol) was added at
room temperature. The reaction was warmed to 80°C and
continued overnight (about 12 hrs). Th reaction mixture
was then cooled to room temperature. 1. ON IIC'J. (10 mT;}
was added, followed by dilution with EtOAc (75 ml,) . The
layers were separated and the organic layer was dried
over Na2SO4 (10 g), filtered and concentrated to yleld the
title compound as a thick oil.
XHNMR of the oil was consistent with topiramato.

To a cooled (-60°C) mixture of topiramate (39.02 g,
0.114 mol) and pyridine (18.19 g, 0.23 mol) in TH? (300
mL) was added sulfuryl chloride (31.04 g, 0.23 mol),
dropwise, over a 10 minute period while maintaining the
temperature below -60°C. After 30 minutes, the ice bath
was removed and the mixture poured into a 1L glass lined
autoclave. The reactor was pressurized with anhydrous
ammonia to 24 psi, ambient temperature, and maintained
overnight. The following morning the resulting dark
brown mixture wan concentrated under reduced pressure; and
the resulting reddish-brown residue (53.04 g) dissolved
in distilled water and extracted with CH2Cl2 (4 x .100 mL) .
The aqucous layer was concentrated under reduced

pressure to yleld the title compound as a brittle, tan
colored foam.
Three separate samples of this foam (6.0 g in 30-40
mL of water, 4.6 g in MeOH and 2.0 g dissolved in the
solvent system) were chromatographed on the Waters Prep
500 using a 10C column, eluting with MeOH:AcN:0.5 M NaCl
(15:35:50). The cleanest fractions containing product
were combined and concentrated under reduced pressure to
yleld the product as a tan colored solid.
MS MH+ = 418

N-Methylpyrrolidione (130.01 g, 1.31 mol) and
dimethyl sulfate (153.94 g, 115.5 mL, 1.22 mol) were
heated on a steam bath, for one hour. The resulting black
solution was added to a mixture containing topiramate
(104.5 g, 0.31 mol) and sodium methoxide (66.5 g, 1.22
mol) in methylene chloride (660 mL),and then heated at
reflux on a steam bath for 4 hr. The reaction mixture
was washed with 3 N NaOH (4 x 100 mTi) , the layers
separated and the aqueous layer extracted with CH2Cl2 (4 x
100 mL). The combined organic layer was dried over
sodium sulfate, filtered and concentrated under reduced
pressure to yleld a yellow residue that crystallized on
standing. The mixture was filtered and washed with

hexane to yleld a yellow, crystalline solid. The crude
solid was slurried in distilled water and heated on the
steam bath. Ethanol was added until a clear solution wan
obtained. The hot solution was allowed to cool
overnight, with stirring. A white precipitate was
observed. The mixture was filtered, washed with cold
water and dried to yleld the title compounds as a white,
crystalline solid.
MS MH+ =42 0

To a stirred solution of N, N-dimethylformamide
(26.20 g, 0.358 mol) in diethyl ether (672 mL) was added
oxalyl chloride (45.48 g, 0.358 mol), dropwise, over a 3b
minute period. A white solid started to precipitate out
of solution immediately. The mixture was stirred for 1
hr after the addition was complete then concentrated
under reduced pressure to remove the solvent. To this
solid was added topiramatc (105.54 g, 0.311 mol)
dissolved in methylene chloride (800 mL). The yellow
solution was stirred at ambient temperature, under argon,
for 3 hr then washed with 1 N NaOH (4 x 100 mL). The
aqueous layer was extracted with methylene chloride (4 x
100 mL). The combined organic layer was dried over
sodium sulfate, filtered and concentrated under reduced

pressure to yleld a thick, yellow residue. The residue
was slurried in distilled water (100 mL) while warming on
a steam bath, followed by the addition of ethanol (10-15
mL) until a clear solution was obtained. The heat was
removed and the solution allowed to cool to ambient
temperature, overnight, with stirring. A solid
precipitated out of solution. The mixture was filtered
and washed with cold water to yleld the title produce as
a white solid.
MS MH+ = 394.44

A mixture of toplramate (1.5 gm, 4.4 mmol), 5-
(pyrid-2-yl) thien-2-yl-sulphonyl chloride (2.4gm, 9mntol) ,
DMAP (0.5 gm), TEA (1.9ml, 13 mmol) was stirred in
dichloromethane (100 mL) for 5 hours. The solvent was
" removed under vacuum to yleld a residue. Ethyl acocate
(200 mL) was added to the residue. The solution war, then
washed with a saturated NaCl solution. The organic: layer
was dried over sodium sulfate and the solvent removed
under vacuum to yleld a crude oil. The crude oil was
purified on a column (eluting with 5%MeOH/CH2Cl2) to yleld
the title compound as a solid.

1H NMR (300 MHz, CDCl3) : d1.23 (s, 311), 81.32 (s,
3H) , 81.39 Cs, 3H) , 81.42 (s, 3H) , 83.G8 (d, 1H,
J=12.3MHz), 83.81 (d, 1H, J=12.3MKz), 84.10-4.25 (m, 4H) ,
84.47(dd 1H, J=2.46MHz, J= 7.88MHz), 87.14 (t, 1H,
J=7.2MHz), 87.36 (d, 1H, J=3.93MHz), 87.54 (d, 1H,
J=7.71MHz), 87.59 (d 1H J=7.71MIIz ), 87.67 (d, 1H,
J=3.99MHz), 88.49(d 1H, J=4.6MHz).

A 100 ml round bottom flask was charged with sodium
hydride (0.1 g, 4 mmol) and THF (20 mL). The resulting
suspension was slowly treated with a solution of N-
(benzyloxy-carbonyl) -2 , 3 :4, 5-bis-O- (1-methylethylidene)
ß-D-fructopyrnnose sulfamate (1.8 g, 4 mmol) (prepared as
in Example 4) in THF (10 mL). After addition was
complete the reaction was stirred for an additional 30
minutes. The solvent was concentrated under vacuum to
yleld a white solid, which was treated with with 95%
ethanol (40 mL) to yleld the title compound as a white
solid.
M.P. >250°C.
H4i NMR (300 MHz, DMSO) d 7.45-7.20 (LSH, m) , 4.B6 (2H,
s) , 4.55 (1H, dd, J = 8.1, 2.4 Hz), 4.38 (111, d, J = 2.8

Hz), 4.20 (1H, d, J = 8.1 Hz), 3.84 (2H, q, J = 20.2,
10.5 Hz), 3.73 (1H, d, J = 13.3 Hz), 3.56 (1H, d, J =
12.9 Hz), 3.44 (3H, s) , 1.34 (311, s) , 1.33 (311, s) , 1.25
(3H, s)
Following the procedures described above,
representative compounds of the instant invention were
prepared, as listed in Table 1, 2 and 3. For compounds
which were prepared as salts, the Rl is replaced with the
salt cation.
Molecular weights for representative compounds
listed in Tables 1, 2 and 3 were measured on an Agilent
1100 HPLC/MSD Mass Spectrometer, with results as listed
in Table 4.
Example 24 & 25
In Vivo Testing, Maximal Electoshock Seizure
Anticonvulsant activity was determined using the
standard MES model for generalized tonic-clonic seizures
(Swinyard EA, Woodhead JH, White HS, franklin MR, In:
Levy RH, Mattson RH, Meldrum BS, Penry JK, Dreifuss FE
eds. Antiepileptic drugs. New York: Raven Press,
1989:85-102).
An electric stimulus of 0.2 sec duration, 60Hz, 50mA
in mice, 150mA in rats, was delivered via corneal
electrodes primed with an electrolyte solution containing
an anesthetic agent (0.5% tetracaine hydrochloride in
0.9% saline).
Mice or rats were randomly selected into control and
test groups. The animals were dosed with vehicle or test
compound, at varylng concentrations. Mice were subjected
to the electrical stimulus at 30 minutes and 4 hours
following administration of test compound. Rats were
subjected to electrical stimulus at time intervals
between 15 minutes and 4 hours following administration
of test compound. Abolition of the hind limb tonic

extensor component was an indication of the test
compound's ability to inhibit MES-induced seizure spread.
The EDSO (the calculated dose required to block the
hindlimb tonic-extensor component of the maximal
electroshock seizure in 50% of the animals tested) was
calculated. A probit analysis (Finney DJ. Probit
Analysis. Cambridge, England: Cambridge University Press,
1971) was used to calculate the ED50.
Following the mouse procedure described above,
representative compounds of the instant invention were
tested for biological activity in the mouse, with results
as listed in Table 5. Mouse activity is listed as number
of mice active / total number of mice tested @ time after
administration of the test compound.
Following the rat procedure described above;,
representative compounds of the instant invention were
tested for biological activity in the rat, with results
as listed in Table 6 and 7. Rat activity is listed as
number of rats active / total number of rats tested ©
time after administration of the test compound.
While the foregoing specification teaches the
principles of the present invention, with examples
provided for the purpose of illustration, it will be
understood that the practice of the invention encompasses
all of the usual variations, adaptations and/or
modifications as come within the scope of the following
claims and their equivalents.
We Claim:
1. A compound of the formula (I)

wherein
X is selected from CH2 or 0;
R1 is selected from the group consisting of hydrogen,
, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl -alkyl,
cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaryl-
alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,
alkoxycarbonylalkyl, - (CVaalkyl)-O-C(O) - (alkyl) , -C(O)-R9,
-C(O)-(alkyl)-O- (alkyl), alkoxycarbonyl, aryloxycarbonyl,
aralkyloxycarbonyl, -Si (R10) (00-1-R11)2, -SO2R12 and SEM,-
wherein the alkyl, cycloalkyl, aryl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylatnino, dialkylamino, nitro or cyano;
R2 is selected from the group consisting of hydroxy,
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyl-
alkyl, cycloalkenyl, aryl, aryloxy, aralkyl, aralkyloxy,
heteroaryl, heteroaryl-alkyl, heterocycloalkyl,
heterocycloalkylalkyl, alkoxycarbonylalkyl, -(C2-8alkyl)-
0-C(O)--(alkyl) , -C(O)-R9, -C(O) - (alkyl)-O-(alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,
C(O)0-Si(R17)3, -Si(R10) (00-1R21)2, -SO2R12, -P(-O)(R11), and
SEM;

wherein the alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl or heterocycloalkyl group, whether alone or as
part of the R2 substituent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro or
cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R30 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is;
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;

wherein each R12 is independently selected from
amino, alkylamino, dialkylamino, alkyl, aryl, aralkyl or
heteroaryl; wherein the alkyl, aryl or heteroaryl groups,
whether alone or as part of an RIa substituent group, is
optionally substituted with one or more substituents
independently selected from alkyl, halogen,
trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, nitro,
amino, alkylamino, dialkylamino, alkylcarbonylamino,
arylcarbonylamino, aralkylcarbonylamino, aryl,
heteroaryl, benzenesulfonyl or phenoxy; wherein the
phenoxy group is optionally substituted with one or more
substituents independently selected from halogen, alkyl,
alkoxy or nitro;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent: group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively, R1 and R2 are taken together with the
N atom to which they are bound to form a heteroaryl or
heterocycloalkyl group; wherein the heteroaryl or

heterocycloalkyl group is optionally substituted with one
or more substituents independennly selected from halogen,
hydroxy, carboxy, oxo, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro, cyano, -C(=NK)-
amino, -C(=NH) alkylamino or -e the aryl substituent is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro, cyano, -C(-NH) -amino,
C{=NH)-alkylamino or -C(=NH) -dialkylamino; wherein the -
C{=NH)-amino, -C(-NH)-alkylamino or -C(=NH)-dialkylamino
group is bound to a nitrogen or carbon atom on the aryl,
heteroaryl or heterocycloalkyl; and wherein no more than
one -C(=NH) -amino, -C(-NH)-alkylamino or -C(=NH)-
dialkylamino group is bound to the aryl, heteroaryl or
heterocycloalkyl;
alternatively Ra and R2 are taken together with the
nitrogen atom to which they are bound to form -N=C{R14) 2;
wherein each R14 is independently selected from
hydrogen, alkyl, cycloalkyl, dialkylamino, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula


wherein R20 is lower alkyl;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CII2, R5 and Rc may
be alkene groups joined to form a benzene ring and, when
X is O, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are the same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
provided that when R1 is alkyl, R2 is other than
alkyl;
provided further that when R1 ia hydrogen, R2 is
other than alkyl, methylcarbonyl, phenyl, benzyl or
carboxyalkyl,-
provided further that R1 and R2 when taken together
with the nitrogen atom to which they are bound is other
than imidazolyl;
provided further that when X is 0, Rz and R3 are
taken together to form a methylenedioxy group of. the
formula:

R4 and R5 are taken together no form a methylenedioxy
group of the formula:

wherein R7 and R8 in each instance are each methyl,
and R1 is hydrogen then R2 is other than
isopropylsulfonyl, 4-(N-benzyl)-piperidinyl or 4-pyridyl;
or a pharmaceutical^ acceptable salt thereof.
2. A compound as in Claim 1 of the formula (It)

wherein
R1 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,
cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaryl
alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,
alkoxycarbonylalkyl, - (Ca-ealkyl) -O-C(O) - (alkyl) , -C(O) -R9,
-C(O) -(alkyl)-O-(alkyl), alkoxycarbonyl, aryloxycarbonyl,
aralkyloxycarbonyl, -Si (R10) (O0-1R11) 2, -SO2R12 and SEM;
wherein the alkyl, cycloalkyl, aryl, hcteroaryl or
heterocycloalkyl group, whether alone or as part of the P1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;

R2 is selected from the group consisting of hydroxy,
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyl-
alkyl, cycloalkenyl, aryl, aryloxy, aralkyl, aralkyloxy,
heteroaryl, heteroaryl-alkyl, heterocycloalkyl,
heterocycloalkylalkyl, alkoxycarbonylalkyl, - (C2-8alkyl)-
O-C(O)-(alkyl), -C(O)-R9, -C(O)-(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, -
C(O)0-Si(R1"')3, -Si(R10) (O0-1R")a, -SO2R12, -P(=0) (R13) 2 and
SEM;
wherein the alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl or heterocycloalkyl group, whether alone or as
part of the R2 substituent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro or
cyano ,-
wherein each R3 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R12 is independently selected from
amino, alkylamino, dialkylamino, alkyl, aryl, aralkyl or
heteroaryl; wherein the alkyl, aryl or hoteroaryl groiips,
whether alone or as part of an R12 substituent group, is
optionally substituted with one or more substituents
independently selected from alkyl, halogen,
trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, nitro,
amino, alkylamino, dialkylamino, alkylcarbonylamino,
arylcarbonylamino, aralkylcarbonylamino, aryl,
heteroaryl, benzenesulfonyl or phenoxy; wherein the
phenoxy group is optionally substituted with one or more
substituents independently selected from halogen, alkyl,
alkoxy or nitro;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected "from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is

optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano?
alternatively, R1 and R2 are taken together with the
N atom to which they are bound to form a heteroaryl or
heterocycloalkyl group; wherein the heteroaryl or
heterocycloalkyl group is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, oxo, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro, cyano, -C(=NH)-
amino, -C(=NH) alkylamino or -C(=NH)-dialkylamino; wherein
the aryl substituent is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro, cyano, -C(-=NH)-amino, -
C(=NH)-alkylamino or -C C(=NH)-amino, -C(=NH)-alkylamino or -C(-NH)-dialkylamino
group is bound to a nitrogen or carbon atom on the aryl,
heteroaryl or heterocycloalkyl; and wherein no more than
one -C(=NH)-amino, -C (=NH)-alkylamino or ~C(=NH)-
dialkylamino group is bound to the aryl, heteroaryl or
heterocycloalkyl;
alternatively R1 and R2 are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected from
hydrogen, alkyl, cycloalkyl, dialkylamino, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,

alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least; one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl;
provided that when R1 is alkyl, R2 is other than
alkyl;
provided further that when R1 is hydrogen, R2 is
other than alkyl, methylcarbonyl, phenyl, benzyl or
carboxyalkyl;
provided further that R1 and R2 when taken together
with the nitrogen atom to which they are bound is other
than imidazolyl;
provided further that when R1 is hydrogen then R2 is
other than isopropylsulfonyl, 4-(N-benzyl)-piperidinyl or
4-pyridyl;
or a pharmaceutically acceptable salt thereof.
3. A compounds as in Claim 1 wherein
R1 is selected from the group consisting of hydrogen,
lower alkyl and aralkyl;
Rz is selected from the group consisting of hydroxy,
alkyl, benzhydryl, alkoxy, alkenyl, aryl, aralkyl,
aralkyloxy, alkoxycarbonylalkyl., C(O)-R9, alkoxycarbonyl,
aralkyloxycarbonyl, -C(O) - (alkyl) -C- (alkyl) , a nitrogen

containing hetcroaryl, a nitrogen containing
heterocycloalkyl, -SO2R12, -C(O)O-Sl(R27)3, -Si(R10)(O0-
1R11)2, -P(=0) (R13)2 and SEM;
wherein the alkyl, aralkyl, nitrogen containing
heteroaryl or nitrogen containing heterocycloalkyl,
whether alone or as part of a substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
provided that when R1 is lower alkyl, R2 is other
than alkyl;
provided further that when R1 is hydrogen, R2 is
other than alkyl, methylcarbonyl, phenyl, benzyl or
carboxyalkyl ,-
provided further that when R1 is hydrogen then R2 is
other than isopropylsulfonyl, 4-(N-benzyl)-piperidinyl or
4-pyridyl ,-
or a pharmaceutically acceptable salt thereof.
4. A compound as in Claim 3 wherein R2 is selected from
the group consisting of -C(O)-R9, -C(O)-(alkyl)-O-(alkyl)
and -SO2R12.
5. A compound as in Claim 1 wherein
R1 and R2 are taken together with the nitrogen atom to
which they are bound to form a group selected from
heteroaryl or heterocycloalkyl;
wherein the heteroaryl or heterocycloalkyl group is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
oxo, alkyl, alkoxy, ary.L, aralkyl, amino, alkylamino,
dialkylamino, nitro, cyano, -C(=NH)-amino,

C(=NH)alkylamino or -C(=NH)-dialkylamino; wherein the
aryl substituent is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro, cyano, -C(=NH)-amino, -
C(=NH)-alkylamino or -C(=NH) -dialkylamino; wherein the -
C(=NH) -amino, -C(=NH)-alkylamino or -C(=NH) -dialkylamino
group is bound to a nitrogen or carbon atom on the aryl,
heteroaryl or heterocycloalkyl; and wherein no more than
one -C(=NH)-amino, -C (=NH)-alkylamino or -C(=NH)-
dialkylamino group is bound to the aryl, heteroaryl or
heterocycloalkyl;
provided that R1 and R2 when taken together with the
nitrogen atom to which they are bound is other than
imidazolyl ,-
or a pharmaceutically acceptable salt thereof.
6. A compound as in Claim 5 wherein R1 and R2 are taken
together with the N atom to which they are bound to form
a group selected from morpholinyl or 1-(2-isopropoxy~
phenyl)-piperazinyl, isosindole-1,3-dione; or a
pharmaceutically acceptable salt thereof.
7. A compound as in Claim 3 wherein
R1 and R2 are taken together with the nitrogen atom to
which they are bound to form -N=C(R14)2;
wherein R14 is selected from the group consisting of
hydrogen, dialkylamino, cycloalkyl and aryl; wherein the
cycloalkyl or aryl is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, axalkyl, amino,
alkylamino, dialkylamino, nitro or cyano;

alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl;
or a pharmaceutically acceptable salt thereof.
8. A compound as in Claim 7 wherein R14 is selected from
the group consisting of hydrogen, di(lower alkyl)amino,
aryl and cycloalkyl; or a pharmaceutically acceptable
salt thereof.
9. A compound as in Claim 8, wherein R14 is selected
from the group consisting of dimethylamino, eyclohexyl
and phenyl; or a pharmaceutically acceptable salt
thereof.
10. A compound as in Claim 7, wherein two R14 group are
taken together with the carbon atom to which they are
bound to form 2-(1-methyl-pyrrolidinyl).
11. A compound as in Claim 3 wherein
R1 is selected from the group consisting of hydrogen,
alkyl, aralkyl and SEM;
R2 is selected from the group consisting of hydroxy,
halogenated alkyl, benzhydryl, alkoxy, alkenyl, ax-alkyl
(wherein the aralkyl is optionally substituted with a
substituent selected from alkoxy) , aralkyloxy,
alkoxycarbonylalkyl, carboxyalkyl , alkyl carbonyl (wherein
the alkyl is optionally substituted wiuh a substituent

selected from carboxy or alkoxycarbonyl), arylcarbonyl
(wherein the aryl is optionally substituted with a
substituent selected from alkyl, alkoxy, alkoxycarbonyl
or carboxy), aralkycarbonyl, alkoxycarbonyl,
aralkyloxycarbonyl, alkoxyalkylcarbonyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, a nitrogen containing
heteroaryl, a nitrogen containing heterocycloalkyl ,
aminosulfonyl (wherein the amino group is optionally
substituted with one to two lower alkyl), alkylsulfonyl
(wherein the alkyl group is optionally substituted with
one to three substituents independently selected from
halogen), arylsulfonyl (wherein the aryl group is
optionally substituted with one to three substituents
independently selected from alkyl, trifluoromethyl,
trifluoromethoxy, halogen, alkoxy, alkylcarbonylamino,
acetamido, nitro, amino, alkylamino, dialkylamino or 2-
chloro-4-nitrophenyoxy), aralkylsulfonyl,
biphenylsulfonyl, heteroarylsulfonyl (wherein the
heteroaryl is optionally substituted with one to two
substituents independently selected from halogen, alkyl,
heteroaryl or benzenesulfonyl), benzhydryl, -Si-(aryl)3, -
C(O)0-Si(aryl)3, -P(=0)(aryl)2, -P(=O) (alkoxy)2 and SEM;
provided that when R1 is hydrogen, then R2 is other
than methylcarbonyl, phenyl, benzyl or carboxyalkyl;
provided further that when R1 is hydrogen, R2 is
other than isopropylsulfonyl or 4-pyridyl;
or a pharmaceutically acceptable salt thereof.
12. A compound as in Claim 11 wherein
R1 is selected from the group consisting of hydrogen,
methyl, ethyl, benzyl and SRM;
R2 is selected from the group consisting of hydroxy,
tnethoxy, allyl, 1~(2-bromo)-ethyl, l-{2-

ethoxycarbonyl)ethyl, methoxycarbonylmethyl,
methoxycarbonylethyl, 1-(methoxycarbonyl)-n-propyl,
carboxymethyl, 1- (3-carboxy) -n-propyl, 1- (2-
carboxy)ethyl, ethoxycarbonyl, t-butoxycarbonyl,
benzyloxycarbonyl, methylcarbonyl, ethylcarbonyl, n-
propylcarbonyl, isobutylcarbonyl, phenylethylcarbonyl,
benzylcarbonyl, phenylcarbonyl, 2-methoxycarbonylphenyl-
carbonyl, 2-carboxyphenyl-carbonyl, methoxycarbonyl-
ethylcarbonyl, carboxyethylcarbonyl, diethoxy-phosphinyl,
triphenylsilyl, triphenylsilyloxycarbonyl,
trifluoromethylsulfonyl, dimethylaminoethyl, benzyl, 4-
methoxybenzyl, benzyloxy, 3-pyrrolidinyl, 4-pyridyl, 4-
(N-benzyl)-piperidinyl, SEM, diphenylphosphinyl,
benzhydryl, 2-methoxyphenylcarbonyl, 3-
methoxyphenylcarbonyl, 4-methoxyphenylcarbonyl,
methoxymethylcarbonyl, 2-tolylcarbonyl, 3-tolylcarbonyl,
4-tolylcarbonyl, 5-heptylcarbonyl, aminosulfonyl, 4-
trifluoromethoxyphenylsulfonyl, l~naphthylsulfonyl, 2-
naphthylsulfonyl, 1-(5-dimethyl amino)-naphthyl-sulfonyl,
4-biphenylsulfonyl, 2-thienylsulfonyl, 2-(3-(2-pyridyl)-
thienyl)-sulfonyl, 4-trifluoromethylphenylsulfonyl, 3-
trifluoromethylphenylsulfonyl, 2,6-
difluorophenylsulfonyl, benzylsulfonyl, 4-
methoxyphenylsulfonyl, 4,b-dibromo-2-thienylsulfonyl, 2-
benzenesulfonyl-5-thienylsulfonyl,
trifluoromethylsulfonyl, 3-trifluoromethylphenylsulfonyl,
2,2,2-trifluoroethylsulfonyl, phenylsulfonyl, 2,4,6-
trimethylphenyl-sulfonyl, 2-chloro-l-ethylsulfonyl,
isopropylsulfonyl, isobutylsulfonyl, l-butylsulfonyl, 4-
(2,1,3,-benzoxadiazolyl)sulfonyl, 4-(2-chloro-4-
nitrophenoxy)-3,5-dichlorophenylsulfonyl, 4-
bromophenylsulfonyl, ethylsulfonyl, 8-quinolinylsulfonyl,
3,5-dimethyl-4-isoxazolylsulfonyl, 4 -(2,1,3-

benzothidiazolyl)sulfonyl, 1-propylsulfonyl, 4-
methylcarbonylaminophenyl-sulfonyl, 4 -
acetamidophenylsulfronyl and 4-nitrophenylsulfonyl;
provided that when R1 is hydrogen, then R2 is other
than methylcarbonyl, phenyl, benzyl or carboxyraethyl;
provided further that when R1 is hydrogen, R2 is
other than isopropylsulfonyl 4- (N-benzyl) -piperidinyl or
4-pyridyl;
or a pharmaceutically acceptable salt thereof.
13. A compound as in Claim 12 wherein
R1 is selected from the group consisting of hydrogen
and methyl;
R2 is selected from the group consisting of hydroxy,
methoxy, allyl, 1-(3-methoxycarbonyl)-n-propyl, l-(2-
carboxy)ethyl, 1-(2-bromo)-ethyl, l-{2-
ethoxycarbonyl)ethyl, methoxycarbonylmethyl, t-
butoxycarbonyl, benzyloxycarbonyl, methylcarbonyl,
ethylcarbony 1, triphenylsilyl, triphenylsilyloxycarbonyl,
trifluoromethylsulfonyl and benzhydryl;
alternatively R1 and R2 are taken together with the
nitrogen atom to which they are bound to form l--(2-
isopropoxyphenyl) -piperidinyl,-
provided that when R1 is hydrogen, then R2 is other
than methylcarbonyl;
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of
Claim 1.

15. A pharmaceutical composition made by mixing a
compound of Claim 1 and a pharmaceutlcally acceptable
carrier.
16. A process for making a pharmaceutical composition
comprising mixing a compound of Claim 1 and a
pharmaceutically acceptable carrier.
17. A method of treating epilepsy, in a subject in need
thereof comprising administering to the subject a
therapeutically effective amount of the compound of Claim
1.
18. A process for the preparation of a compound of
formula (XX)
wherein
X is selected from CH2 or O;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are same or different and are.
hydrogen, lower alkyl or are alkyl and are joined r.o form
a cyclopentyl or cyclohexyl ring;

comprising, reacting a compound of formula (Ij)

wherein
X is selected from CH2 or o;
Rla is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen), cycloalkenyl
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen), heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O)-R9, -C(O) -(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, bcnzyloxycarbonyl, -
Si(R10) (O0-1R11)2, and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the

double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen),
benzyloxy, heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C (O) -R9, -C (O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl,-
C(O)0-Si(R17)3, -Si(R10) (O0-1R11)2, -P(=0) (R13)2 and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R2
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 in independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;

wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part,
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano,-
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula
wherein n is an integer from 1 to 3; and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two R15 groups are taken together with
the carbon atoms to which they are bound to form a phenyl,
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycloalkyl, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl ,-

R3, R*, R5 and R6 are each independently selected from
hydrogen or lower alkyl, and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is O, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are same or different and are
hydrogen, lower alkyl or are alkyl and arc joined to form
a cyclopentyl or cyclohexyl ring;
or a pharmaceutically acceptable salt thereof;
under de-protection conditions.
19. The process as in Claim 18, wherein the de-
protection conditions are catalytic reduction.
20. The process as in Claim 18, wherein the de-
protection conditions are acid cleavage.
21. The process as in Claim 18, wherein the de-
protection conditions are basic cleavage.
22. The process as in Claim 18, wherein the compound of
formula (Ij) is reacted with hydrazine, methylhydrazine
or phenylhydrazine.
23. A process as in Claim 18, -wherein the compound of
formula (XX) is a compound of formula (XXa).


24. A process for the preparation of a compound of
formula (XXa)
comprising reacting a compound of formula (Ik)

wherein
Rla is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen) , cycloalkenyl
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen) , heteroaryl-CNalkyl, hor.erocycloalkyl - C1alkyl,
alkoxycarbonylC2alkyl, -C (O) -R9, --C (O) - (alkyl) -O- (alkyl),

alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
Si(R10) (O0-1R11)2, and SEM,-
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano,-
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of: the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen),
benzyloxy, heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonyl C2alkyl, -C(O) -R9, -C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
C(O)0-Si(R17)3, -Si(R10) (O0-1R11)2, -P(=0)(R13)2 and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R'!
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;

wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part; of an R9
substituent group, is optionally substituted with one ox-
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano,-
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula
wherein n is an integer from 1 to 3; and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano ,-
alternatively two R15 groups are taken together with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively Rla and R2a are taken together with the
nitrogen atom to which they are bound Lo form -N-C(R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycloalkyl, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,

whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl;
or a pharmaceutically acceptable salt thereof;
under de-protection conditions.
25. The process as in Claim 24, wherein the de-
protection conditions are catalytic reduction.
26. The process as in Claim 24, wherein the de-
protection conditions are acid cleavage.
27. The process as in Claim 24, wherein the do-
protection conditions are basic cleavage.
28. The process as in Claim 24, wherein the compound of
formula (Ik) is reacted with hydrazine, methylhydrazine
or phneylhydraz ine.
29. A compound as in Claim 1 of the formula (Ij)
145
wnerein
X is selected from CH2 or 0;
Rla is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or ono
carbon atom removed from the nitrogen), eycloalkenyl
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen), heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O) -R9, --C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl,-
Si(R10) (O0-1R11)2, and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
R1l is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group in directly bound to or ono carbon atom
removed from the nitrogen), eycloalkenyl {wherein the
double bond of the eycloalkenyl group is directly bound

to or one carbon atom removed from the nitrogen) ,
benzyloxy, heteroaryl-C1alkyl, hetorocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C(O) -R9, -C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
C(O)0-Si(R17)3, -Si(R10) (O0-1R11)2, -P(=0) (R13)2 and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R2
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,

whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R11 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an Ri7 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively R1a and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula

wherein n is an integer from 1 to 3; and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two R15 groups are taken together with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively R1a and R2a are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycloalkyl, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl;
R3, R4, R5 and Rh are each independently selected trom
hydrogen or Lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when

X is O, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are same or different and arc
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
provided further that when R1 is hydrogen, R7" is
other than methylcarbonyl or carboxyethyl;
or a pharmaceutically acceptable salt thereof.
30. A compound as in Claim 29 of the formula (Ik)

31. A product prepared by reacting a compound of formula
(Ij)
wherein
X is selected from CH2 or O;
R1a is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double

bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen), cycloalkenyl
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen), heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl, -C (O) -R9, -C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl,
Si (R10) (O0-1R11)2, and SEM;
wherein the substituents on the ethyl group arc one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group is directly bound
to or one carbon atom removed from the nitrogen),
benzyloxy, heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonylC2alkyl , -C (O) -R9, -C (O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
C(O)O-Si(R17)3, -Si(R10) (O0-lR11)2, -P(=0) (R13)a and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R2

substituent group, is optionally substituted w.i th one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R9 is independently selected from alkyl,
aryl, aralkyl or heteroaryl; wherein the alkyl, aryl or
heteroaryl group, whether alone or as part of an R9
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, alkoxycarbonyl, aryl,
aralkyl, amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted

with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, aikoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 aubstituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively R1a and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula
wherein n is an integer from 1 to 3; and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, aikoxy,
aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two R15 groups are taken togethex- with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, aikoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively R1a and R2a are taker, together with the
nitrogen atom to which they are bound to form -N=C(R14)2;
wherein each R14 is independently selected from
hydrogen, dialkylamino, alkyl, cycloalkyl, aryl or
aralkyl; wherein the alkyl, cycloalkyl or aryl group,
whether alone or as part of an R14 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano; provided that at least one
R14 is selected from the group consisting of hydrogen and
alkyl;
alternatively, two R14 groups are taken together with
the carbon atom to which they are bound to form a
heterocycloalkyl group of the formula

wherein R20 is lower alkyl;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is O, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are same or different and are
hydrogen, lower alkyl or arc alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;

or a pharmaceutically acceptable salt thereof;
under de-protection conditions.
32. A product as in Claim 31, wherein the compound of
formula (Ij) is a compound of formula (Ik)

33. A compound of the formula (I)

wherein
X is selected from CE2 or o;
R1 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,
cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaryl-
alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,
alkoxycarbonylalkyl, - (C2-8alkyl) -O--C (O) - (alkyl) , -C (O) -R9,
-C(O)-(alkyl)-O-(alkyl), alkoxycarbonyl, aryloxycarbonyl,
aralkyloxycarbonyl, -Si (R10) (C0-1R11)2, -SO2R12 and SKM,-
wherein the alkyl, cycloalkyl, aryl, heteroaryl cr
heterocycloalkyl group, whether alone or as part ot the R1
substitucnt group, is optionally substituted with one or
more substituents independently selected from halogen,

hydroxy, carboxy, alkyl, alkoxy, aryl, arulkyl, amino,
alkylatnino, dialkylamino, nitro or cyano;
R2 is selected from the group consisting or hydroxy,
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyl-
alkyl, cyeloalkenyl, aryl, aryloxy, araikyl, aralkyloxy,
heteroaryl, heteroaryl-alkyl, heterocycloalkyl,
heteroeycloalkylalkyl, alkoxycarbonylalkyl, - (C3-8alkyl) -
0-C(O)-(alkyl), -C(O)-R9, -C(O)-(alkyl)-O-(alkyl),
alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, -
C(O)0-Si(R17)3, -Si(R10) (00-1R11)2, -SOaR12, -P (=0) (R13)2, and
SEM;
wherein the alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl or heterocycloalkyl group, whether alone or as
part of the R2 substituent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
aryl, araikyl, amino, alkylatnino, dialkylamino, nitro or
cyano;
wherein each R9 is independently selected from alkyl,
aryl or araikyl; wherein the alkyl or aryl group, whether
alone or as part of an R9 substituent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
alkoxycarbonyl, aryl, araikyl, amine:, alkylamino,
dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or araikyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substituent
group, is optionally substituted with one or more
substituents independently selected from halogen,

hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R11 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each Ri2 is independently selected from
alkyl, aryl, aralkyl or heteroaryl; wherein the alkyl,
aryl or heteroaryl groups, whether alone or as part, of an
R12 substituent group, is optionally substituted with one
or more substituents independently selected from halogen,
trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, nitro,
alkylcarbonylamino, arylcarbonylamino,
aralkylcarbonylamino, aryl, benzenesulfonyl or phenoxy,-
wherein the phenoxy group is optionally substituted with
one or more substituents independently selected from
halogen, alkyl, alkoxy or nitro;
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy;
wherein the alkyl or aryl group, whether alone or as part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,

whether alone or as part of an R17 substituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively, R1 and R2 are taken together with the
N atom to which they are bound to form a heteroaryl or
heterocycloalkyl group; wherein the hoteroaryl or
heterocycloalkyl group is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, oxo, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro, cyano, -C(=NH)-
amino, -C(=NH)alkylamino or -C(-NH)-dialkylamino; wherein
the aryl substituent is optionally substituted with one
or more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro, cyano, -C(-NH)-amino,
C(=NH)-alkylamino or -C(=NH)-dialkylamino; wherein the -
C(=NH) -amino, -C (=NH)-alkylamino or -C (=NH)-dialkylamino
group is bound to a nitrogen or carbon atom on the aryl,
heteroaryl or heterocycloalkyl; and wherein no more than
one -C{=NH)-amino, -C(=NH)-alkylamino or -C(=NH)-
dialkylamino group is bound to the aryl, heteroaryl or
heterocycloalkyl;
alternatively R1 and R2 are taken together wi t.h the
nitrogen atom to which they are bound to form -N=C (R14)2;
wherein each R14 is independently selected from
hydrogen, alkyl, cycloalkyl, aryl or aralkyl; wherein the
alkyl, cycloalkyl or aryl group, whether alone or as part
of an R14 substituent group, is optionally substituted
with one or more substituents independently selected from

halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano,- provided
that at least one R14 is selected from the group
consisting of hydrogen and alkyl;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is O, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula-.
wherein R7 and R8 are the same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
provided that when R1 is alkyl, R2 is other than
alkyl;
provided further that when R1 is hydrogen, R2 is
other than alkyl , methylcarbonyl, phenyl, benzyl or
carboxyalkyl ,-
provided further that R1 and R2 when taken together
with the nitrogen atom to which they are bound is other
than imidazolyl;
provided further that when X is O, R2 and R3 are
taken together to form a methylenedioxy group of the
formula:

R4 and R5 are taken together to form a raethylenedioxy
group of the formula:
wherein R7 and R8 in each instance are each methyl,
and R1 is hydrogen then R2 is other than
isopropylsulfonyl, 4-(N-benzyl)-piporidiriyl or 4-pyridyl ;
or a pharmaceutically acceptable salt thereof.
34. A process for the preparation of a compound of
formula (XX)

wherein
X is selected from CH2 or O;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2 , R5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or R5 and R6 together may be a
methylenedioxy group of the formula:

wherein R7 and R8 are same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
or a pharmaceutically acceptable salt, thereof;
comprising, reacting a con-pound of formula (Ij)

wherein
X is selected from CH2 Or 0;
Rla is selected from the group consisting of
hydrogen, substituted ethyl, alkenyl (wherein the double
bond of the alkenyl group is directly bound to or one
carbon atom removed from the nitrogen), cycloalkenyl
(wherein the double bond of the cycloalkenyl group is
directly bound to or one carbon atom removed from the
nitrogen), heteroaryl-Cialkyl, heterocycloalkyl-Cialkyl,
alkoxycarbonylC2alkyl, -C(O) -R9, - C(O) - (alkyl) -O- (alkyl) ,
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
Si(R10) (O0-1R11), and SEM;
wherein the substituents on the ethyl group arc one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R1
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
R2a is selected from the group consisting of
substituted ethyl, alkenyl (wherein the double bond of
the alkenyl group is directly bound to or one carbon atom
removed from the nitrogen), cycloalkenyl (wherein the
double bond of the cycloalkenyl group in directly bound

to or one carbon atom removed from the nitrogen),
benzyloxy, heteroaryl-C1alkyl, heterocycloalkyl-C1alkyl,
alkoxycarbonyl C2alkyl, -C(O)-R9, -C(O)-(alkyl)-C-(alky!),
alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, -
C(O)0-Si(R17)3, -Si(R10) (O0-1R11)2, -P (=0) (R13) 2 and SEM;
wherein the substituents on the ethyl group are one
or more substituents independently selected from halogen,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
wherein the alkyl, benzyl, heteroaryl or
heterocycloalkyl group, whether alone or as part of the R2
substituent group, is optionally substituted with one or
more substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitx~o or cyano;
wherein each R9 is independently selected from alkyl,
aryl or aralkyl; wherein the alkyl or aryl group, whether
alone or as part of an R9 substitutent group, is optionally
substituted with one or more substituents independently
selected from halogen, hydroxy, carboxy, alkyl, alkoxy,
alkoxycarbonyl, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
wherein each R10 is independently selected from
hydrogen, alkyl, aryl or aralkyl; wherein the alkyl or
aryl group, whether alone or as part of an R10 substir.uent
group, is optionally substituted with one or more
substituents independently selected from halogen,
hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano;
wherein each R11 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,

whether alone or as part of an R11 substituont group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, alkoxycarbonyl, aryl, aralkyl, amino,
alkylamino, dialkylamino, nitro or cyano,-
wherein each R13 is independently selected from
alkyl, alkoxy, aryl, aryloxy, aralkyl or aralkyloxy,-
wherein the alkyl or aryl group, whether alone or an part
of an R13 substituent group, is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
wherein each R17 is independently selected from
alkyl, aryl or aralkyl; wherein the alkyl or aryl group,
whether alone or as part of an R17 subutituent group, is
optionally substituted with one or more substituents
independently selected from halogen, hydroxy, carboxy,
alkyl, alkoxy, aryl, aralkyl, amino, alkylamino,
dialkylamino, nitro or cyano;
alternatively R1a and R2a are taken together with the
nitrogen atom to which they are bound to form a group of
the formula
wherein n is an integer from 1 to 3,- and wherein
each R15 is independently selected from the group
consisting of halogen, hydroxy, carboxy, alkyl, alkoxy,

aryl, aralkyl, amino, alkylamino, dialkylamino, nitro and
cyano;
alternatively two R15 groups are taken together with
the carbon atoms to which they are bound to form a phenyl
ring; wherein the phenyl ring is optionally substituted
with one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
alternatively R1a and R2a are taken together with the
nitrogen atom to which they are bound to form -N=C(R14)2,-
wherein each R14 is independently selected from
hydrogen, alkyl, cycloalkyl, aryl or aralkyl; wherein the
alkyl, cycloalkyl or aryl group, whether alone, or an part
of an R14 substituent group, is optionally substituted
v/ith one or more substituents independently selected from
halogen, hydroxy, carboxy, alkyl, alkoxy, aryl, aralkyl,
amino, alkylamino, dialkylamino, nitro or cyano;
provided that at least one R14 is selected from the
group consisting of hydrogen and alkyl;
R3, R4, R5 and R6 are each independently selected from
hydrogen or lower alkyl and, when X is CH2, H5 and R6 may
be alkene groups joined to form a benzene ring and, when
X is 0, R3 and R4 and/or RD and Rs together may be a
methylenedidxy group of the formula:

wherein R7 and R8 are same or different and are
hydrogen, lower alkyl or are alkyl and are joined to form
a cyclopentyl or cyclohexyl ring;
or a pharmaceutically acceptable salt thereof;

under de-protection conditions, to yield the
corresponding compound of formula (XX) .

The present invention is directed to novel compounds of the formula (I) wherein X, R1, R2, R3, R4, R5 and R6
are as described in the specification, processes for the preparation of and pharmaceutical compositions comprising said derivatives
The compounds of the present invention are useful for the treatment of epilepsy. The invention is further directed to a process for the
preparation of compounds of formula (XX), wherein X, R3, R4, R5 and R6 are as described in the specification.

Documents:

1718-kolnp-2004-abstract.pdf

1718-KOLNP-2004-ASSIGNMENT-1.1.pdf

1718-KOLNP-2004-ASSIGNMENT.pdf

1718-kolnp-2004-claims 1.1.pdf

1718-kolnp-2004-claims.pdf

1718-KOLNP-2004-CORRESPONDENCE-1.1.pdf

1718-KOLNP-2004-CORRESPONDENCE.pdf

1718-kolnp-2004-description (complete) 1.1.pdf

1718-kolnp-2004-description (complete).pdf

1718-kolnp-2004-examination report reply recieved 1.1.pdf

1718-kolnp-2004-examination report.pdf

1718-kolnp-2004-form 1 1.1.pdf

1718-KOLNP-2004-FORM 1.pdf

1718-kolnp-2004-form 18.pdf

1718-kolnp-2004-form 2 1.1.pdf

1718-KOLNP-2004-FORM 2.pdf

1718-kolnp-2004-form 3 1.1.pdf

1718-kolnp-2004-form 3.pdf

1718-KOLNP-2004-FORM 5.pdf

1718-KOLNP-2004-FORM 6.pdf

1718-kolnp-2004-intenational publication.pdf

1718-kolnp-2004-international search report.pdf

1718-kolnp-2004-others 1.1.pdf

1718-kolnp-2004-pa 1.1.pdf

1718-KOLNP-2004-PA.pdf

1718-kolnp-2004-pct request form.pdf

1718-kolnp-2004-petition under rule 137-1.1.pdf

1718-kolnp-2004-petition under rule 137.pdf

1718-kolnp-2004-specification.pdf


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Patent Number 256469
Indian Patent Application Number 1718/KOLNP/2004
PG Journal Number 25/2013
Publication Date 21-Jun-2013
Grant Date 20-Jun-2013
Date of Filing 11-Nov-2004
Name of Patentee JANSSEN PHARMACEUTICAL N.V.
Applicant Address TURNHOUTSEWEG 30, B-2340 BEERSE, BELGIUM
Inventors:
# Inventor's Name Inventor's Address
1 AHMED ABDEL-MAGID 1383 JASPER DRIVE, AMBLER, PA 19002
2 STEVEN MEHRMAN 29 MEADOW LANE, LANSDALE, PA 19446
3 KIRK SORGI 2543 RED GATE DRIVE, DOYLESTOWN, PA 18901
4 FRANK VILLANI 2 PINEWOOD LANE, PERKASIE, PA 18944
5 CHERYL P. KORDIK 102 SUMMER RIDGE DRIVE, LANSDALE, PA 19446
6 ALLEN B. REITZ 109 GREENBRIAR ROAD, LANSDALE, PA 19446
7 BRUCE ELIOT MARYANOFF 4029 DEVONSHIRE DRIVE, PO BOX 239, NEW HOPE, PA 18938
8 CYNTHIA MARYANOFF 4029 DEVONSHIRE DRIVE, PO BOX 239, NEW HOPE, PA 18938
PCT International Classification Number C07H
PCT International Application Number PCT/US2003/14796
PCT International Filing date 2003-05-09
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/378,017 2002-05-13 U.S.A.