BACKGROUND OF THE INVENTION
The present invention is drawn, to methods for preparing cyclic carbamate and
thiocarbamate compounds.
Methods for preparing cyanopyrrole-containing cyclic carbamate and
thiocarbamate biaryls have been described in US Patent Nos. 6,509,334; 6,566,358;
6,436,929; 6,407,101; and 6,562,857. Such compounds are useful as progesterone
receptor (PR) modulators, which are pharmaceutically useful for a variety of
indications including contraception; the treatment and/or prevention of dysfunctional
bleeding, uterine myometrial fibroids, uterine leiomyomata, endometriosis, benign
prostatic hypertrophy, polycystic ovary syndrome, carcinomas, and adenocarcinomas;
the synchronization of the estrus in livestock; and the stimulation of food intake.
Current methods for preparing cyclocarbamate compounds substituted at the
6-position with bromine substituents entail at least three steps and utilize expensive
reagents, including 1,1-carbonyldiimidazole and 1,1-thiocarbonyldiirnidazole.
Conversion of the cyclocarbamate to the cyclothiocarbamate further requires a
fourth step utilizing a thionating agent. Such methods typically form a variety of
impurities, including pyrrole thioamide impurities. These methods also entail many
steps, are expensive, and are troublesome.
What is needed in the art are more efficient methods for preparing
cyclocarbamate and cyclothiocarbamate compounds.
SUMMARY OF THE INVENTION
In one aspect, a method for producing 6-(cyanopyrrole)-cyclocarbamate or
cyclothiocarbamate compounds is provided and includes the steps of (a) reacting a
cyanopyrrole with a coupling agent; (b) reacting the product of (a) with an
anthranilate or nitroester thereof; (c) reacting the product of (b) with an

organometallic nucleophile; and (d) converting the product of (d) to the 6-
(cyanopyrrole)-cyclocarbamate or cyclothiocarbamate compound.
In another aspect, a method for producing 6-(cyanopyrrole)-cyclocarbamate or
6-(cyanopyrrole)-cyclocarbamate compounds is provided and includes the steps of (a)
reacting a cyanopyrrole with a coupling agent; (b) reacting the product of (a) with an
anthranilic alcohol or nitro alcohol thereof; and (c) converting the product of (b) to the
6-(cyanopyrrole)-cyclocarbamate or 6-(cyanopyrrole)-cyclothiocafbamate compound.
In a further aspect, a method for producing 6-(cyanopyrrole)-cyclocarbamate
or 6-(cyanopyrrole)-cyclocarbamate compounds is provided and includes the steps of
(a) reacting a cyanopyrrole with a coupling agent; (b) reacting the product of (a) with
an anthranilic ketone or nitro ketone thereof; and (c) converting the product of (b) to
the 6-(cyanopyrrole)-cycIocarbamate or 6-(cyanopyrrole)-cyclothiocarbamate
compound.
In yet another aspect, a method for producing 6-(cyanopyrrole)-
cyclothiocarbamate compounds is provided and includes the steps of (a) reacting a
cyanopyrrole with a coupling agent; (b) reacting the product of (a) with a
bromoanthranilate or bromoanthranilate nitroester; (c) reacting the product of (b) with
an organometallic nucleophile; and (d) converting the product of (c) to the 6-
(cyanopyrrole)-cyclothiocarbamate.
In still a further aspect, a method for producing 6-(cyanopyrrole)-
cyclothiocarbamate compounds is provided and includes the steps of (a) reacting a
cyanopyrrole with a coupling agent; (b) reacting the product of (a) with a
bromoanthranilic alcohol or bromoanthranilic alcohol nitro alcohol; and (c)
converting the product of (b) to 6-(cyanopyrrole)-cyclothiocafbamate.
In another aspect, a method for producing 6-(cyanopyrrole)-
cyclothiocarbarnate compounds is provided and includes the steps of (a) reacting a
cyanopyrrole with a coupling agent; (b) reacting the product of (a) with a
bromoanthranilic ketone or bromoanthranilic nitro ketone; and (c) converting the
product of (b) to 6-(cyanopyrrole)-cyclothiocarbamate.
In still a further aspect, a method for producing cyanopyrrole anthranilates or
rdtroesters thereof is provided and includes the steps of (a) reacting a cyanopyrrole
with a coupling agent; and (b) reacting the product of (a) with an anthranilate.

In another aspect, a method for producing a cyanopyrrole anthranilic alcohol
or nitro alcohol thereof is provided and includes the steps of (a) reacting a
cyanopyrrole with a coupling agent; (b) reacting the product of (a) with an anthranilic
alcohol or nitro alcohol thereof; and (c) reacting the product of (b) with an
organometallic nucleophile.
In yet a further aspect, a method for producing a cyanopyrrole anthranilic
ketone or nitro ketone thereof is provided and includes the steps of (a) reacting a
cyanopyrrole with a coupling agent; (b) reacting the product of (a) with an anthranilic
ketone or nitro ketone thereof; and (c) reacting the product of (b) with an
organometallic nucleophile.
In yet a further aspect, compounds of the following formulas are provided:

Other aspects and advantages of the present invention are described further in
the following detailed description of the preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methods for producing cyclocarbamate and
cyclothiocarbamate compounds and cyanopyrrole-containing compounds, and
derivatives thereof. Specifically, the present invention provides more efficient
methods for preparing cyclocarbamate and cyclothiocarbamate compounds and
cyanopyrrole-containing compounds.
The method of the present invention typically includes (a) reacting an
optionally substituted cyanopyrrole with a coupling agent; (b) reacting the product of
(a) with an anthranilate, anthranilate nitroester, anthranilic ketone, or anthranilic nitro
ketone; (c) converting the product of (b) to the corresponding alcohol; and (d)
forming the cyclocarbamate or cyclothiocarbamate. Step (c) can be omitted if step (b)
includes reacting the product of (a) with an anthranilic alcohol or nitro alcohol
thereof. See, Scheme 1, where Q, Z, M, M', and L are denned below.


I. Definitions
The term "coupling agent" as used herein refers to a compound that directly or
indirectly promotes the coupling of two or more chemical compounds (depicted as M-
M' in the above-noted Scheme 1). A variety of coupling agents is known to those of
skill in the art and includes magnesium, zinc, silicon, tin, or boron compounds.
Desirably, the coupling agent is a trialkylborate such as tri-isopropylborate, zinc
halide such as zinc chloride or zinc bromide, or a magnesium halide such as
magnesium chloride or magnesium bromide. See, International Patent Publication
No. WO 03/105860.

The term "coupling group" as used herein refers to a substituent that results
from a coupling agent and becomes attached thereto the cyanopyrrole compound
(depicted as M' in the above-noted Scheme 1). This group can be displaced upon
reaction with other reagents, such as the anthranilate and nitroesters thereof and
anthranilic alcohols and nitro alcohols thereof as set forth above in Scheme 1 and
below the description thereof. The particular coupling group utilized in the present
invention is dependent upon the specific reaction being performed and can readily be
determined by one of skill in the art. Common coupling groups include, without
limitation, magnesium, zinc, silicon, tin, or boron substituents. In one embodiment,
the coupling groups are boron moieties including boronate salts, borinate salts,
boronic acids, borinic acids, boronic esters, borinic esters such as the ester noted
below, and trihaloborate salts such as trifluoroborate salts (BF3-), zinc halides,
magnesium moieties, diazonium salts (N2+), tosylates (OTs), mesylates (OMs), and
copper moieties. In a further embodiment, the coupling groups are boron moieties
including boronic acids, borinic acids, boronic esters, borinic acids such as the borate
ester noted below, trihaloborate salts such as trifluoroborate salts (BF3"), zinc halides,
or magnesium moieties.

The term "catalyst" as used herein refers to a compound that promotes the
coupling of 2 compounds. Typically, the catalyst contains a transition metal and one
or more ligands attached thereto. A variety of transition metals can be used in the
present invention and includes Pd and Ni metals, among others. Several ligands can
be bound to the transition metal and include, without limitation, acetate, hydroxyl,
nitrile, halide, and phosphine substituents. Many transition metal complexes
containing such ligands that can be used as the catalysts are commercially available

and include those recited on the Strem website. In one embodiment, the catalyst is
tetrakis(triphenylphosphine)palladium.
The term "ligand" as used herein refers to a substituent that is bound to a
transition metal.
The term "alkyl" is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups having 1 to about 10 carbon atoms, and
desirably about 1 to about 8 carbon atoms. The term "alkenyl" is used herein, to refer
to both straight- and branched-chain alkyl groups having one or more carbon-carbon
double bonds and containing about 2 to about 10 carbon atoms. In one embodiment,
the term alkenyl refers to an alkyl group having 1 or 2 carbon-carbon double bonds
and having 2 to about 6 carbon atoms. The term "alkynyl" group is used herein to
refer to both straight- and branched-chain alkyl groups having one or more carbon-
carbon triple bond and having 2 to about 8 carbon atoms. In one embodiment, the
term alkynyl refers to an alkyl group having 1 or 2 carbon-carbon triple bonds and
having 2 to about 6 carbon atoms.
The terms "substituted alkyl" refers to an group having one or more
substituents including, without limitation, halogen, CN, OH, NO2, amino, aryl,
heterocyclic, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, and arylthio, which groups
can be optionally substituted. These substituents can be attached to any carbon of an
alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable
chemical moiety.
The term "aryl" as used herein refers to an aromatic system e.g., of 6 to 14
carbon atoms, which can include a single ring or multiple aromatic rings fused or
linked together where at least one part of the fused or linked rings forms the
conjugated aromatic system. In one embodiment, the aryl groups include phenyl,
naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl,
fiuorenyl, and carbazolyl.
The term "substituted aryl" refers to an aryl group which is substituted with
one or more substituents including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl,
alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl, alkylcarboxy, aminoalkyl,
and arylthio, which groups can be optionally substituted. In one embodiment, a
substituted aryl group is substituted with 1 to about 4 substituents.

The term "heterocyclic" as used herein refers to a stable 4- to 7-membered
monocyclic or 9-15 membered multicyclic heterocyclic ring which is saturated,
partially unsaturated, or wholly unsaturated. The heterocyclic ring has carbon atoms
and one or more heteroatoms including nitrogen, oxygen, and sulfur atoms. In one
embodiment, the heterocyclic ring has 1 to about 4 heteroatoms in the backbone of the
ring. In another embodiment, when the heterocyclic ring contains nitrogen or sulfur
atoms in the backbone of the ring, the nitrogen or sulfur atoms can be oxidized. The
term "heterocyclic" also refers to multicyclic rings in which a heterocyclic ring is
fused to anarylring, e.g., of 9-15 ring members. In yet another embodiment, the
heterocyclic ring can be attached to the aryl ring through a heteroatom or carbon atom
provided the resultant heterocyclic ring structure is chemically stable.
A variety of heterocyclic groups are known in fee art and include, without
limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing
rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and
combinations thereof. Oxygen-containing rings include, but are not limited to, furyl,
tetrahydrofuranyl, pyranyl, pyronyl, and dioxinyl rings. Nitrogen-containing rings
include, without limitation, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl,
piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl,
azepinyl, triazinyl, pyrrolidinyl, and azepinyl rings. Sulfur-containing rings include,
without limitation, thienyl and dithiolyl rings. Mixed heteroatom containing rings
include, but are not limited to, oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl,
oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxazinyl, oxathiazrnyl, morpholinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, and diazepinyl rings.
Fused heteroatom-containing rings include, but are not limited to, benzofuranyl,
thionapthene, indolyl, benazazolyl, purindinyl, pyranopyrrolyl, isoindazolyl,
indoxazinyl, benzoxazolyl, anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl,
benzodiazonyl, napthylridinyl, benzotluenyl, pyridopyridinyl, benzoxazinyl,
xanthenyl, acridinyl, and purinyl rings.
The term "substituted heterocyclic" as used herein refers to a heterocyclic
group having one or more substituents including halogen, CN, OH, NO2, amino,
alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl,
alkylcarboxy, aminoalkyl, and arylthio, which groups can be optionally substituted.

Preferably, a substituted heterocyclic group is substituted with 1 to about 4
substituents.
The term "arninoalkyl" as used herein refers to both secondary and tertiary
amines where the point of attachment is through the nitrogen-atom and the alkyl
groups are optionally substituted. The alkyl groups can be the same or different.
The term "halogen" as used herein refers to CI, Br, F, or I groups.
The term "alkoxy" as used herein refers to the O(alkyl) group, where the point
of attachment is through the oxygen-atom and the alkyl group is optionally
substituted.
The term "aryloxy" as used herein refers to the 0(aryl) group, where the point
of attachment is through the oxygen-atom and the aryl group is optionally substituted.
The term "arylthio" as used herein refers to the S(aryl) group, where the point
of attachment is through the sulfur-atom and the aryl group can be optionally
substituted.
The term "alkylcarbonyl" as used herein refers to the C(O)(alkyl) group,
where the point of attachment is through the carbon-atom of the carbonyl moiety and
the alkyl group is optionally substituted.
The term "alkylcarboxy" as used herein refers to the C(O)O(alkyl) group,
where the point of attachment is through the carbon-atom of the carboxy moiety and
the alkyl group is optionally substituted.
The term "leaving group" as used herein refers to a substituent that is present
on a chemical compound and can be displaced (the term L as used herein refers to a
leaving group). The particular leaving group utilized in the present invention is
dependent upon the specific reaction being performed and can readily be determined
by one of skill in the art. Common leaving groups include, without limitation, halides
and sulfonates (OSO2R1). In one embodiment, the leaving group is a halide such as
-bromine, chlorine, or iodine, and more preferably is bromine.
The term "strong non-nucleophilic base" as used herein refers to a compound
that abstracts a hydrogen atom from a molecular complex. In one embodiment, the
strong non-nucleophilic Base does not interact with any other substituents on the
molecular complex or the reagents utilized in the reaction. In another embodiment,
the strong non-nucleophilic base is lithium di-isopropyl amide (LDA). A number of

strong non-nucleophilic bases are known to those of skill in the art and include di-
isopropyl amine salts. See, e.g., the strong non-nucleophilic bases commercially
available at http://www.fmclithium.com (the FMC Lithium website).
The term "organometallic nucleophile" as used herein refers to a compound
that reacts with a compound having an acidic hydrogen atom. A number of
organometallic nucleophiles are known in the art and include Grignard agents and
lithium agents such as alkyl lithium agents. In one embodiment, the organometallic
nucleophile is a Grignard agent such as R'MgX, wherein R' is an alkyl such as a
methyl group or R' is an aryl group, such as a phenol, and X is a halogen such as
bromine or chlorine. In a further embodiment, the Grignard agent is
methylmagnesium bromide which is typically utilized as a solution (e.g., 1.4 M
solution) in a mixture of toluene and THF at reduced temperatures. In one
embodiment, the Grignard agent is a 80:20 to 70:30 mixture of toluene:THF, or about
a 75:25 mixture of toluene:THF. Reduced temperatures typically range from -7° to -
0°C, but lower or higher temperatures can be utilized depending on the reaction being
performed and conditions of the reaction. In another embodiment, the organometallic
nucleophile is an alkyl lithium agent such as methyl lithium, ethyl lithium, propyl
lithium or butyl lithium.
The term "purified" or "pure" as used herein refers to a compound that
contains less than about 10% impurities. In one embodiment, the term "purified" or
"pure" refers to a compound that contains less than about 5% impurities, less than
about 2% impurities, or less than about 1% impurities. The term "purified" or "pure"
can also refer to a compound that contains about 0% impurities.
By the term "dry" or "drying" is meant a procedure by which entrapped
solvents, including organic solvents, or water, or volatile solids are removed.
The term "boronate" or "boronate salf' as used herein refers to a compound
having a -B(0-substituent)3 group attached thereto, wherein the substituent forms a
stable bond to an O-atom attached to the boron atom and a countercation (denoted by
the term CC+ as used herein) is present to form the stable compound. In one
embodiment, the counteraction is a Group I or II alkali or alkaline earth metal
including lithium, sodium, potassium, cesium, magnesium calcium, strontium, or
barium, among others.

The term "borinate" or "borinate salt" as used herein refers to a compound
having a -B(O-substituent)2- group attached thereto, wherein the substituent forms a
stable bond to an O-atom attached to the boron atom and a countercation (denoted by
the term CC+ as used herein and defined above) is present to form the stable
compound.
The term "boronic ester" as used herein refers to a compound having a
-B(O-substituent)2 group attached thereto, wherein the substituent forms a stable bond
to an O-atom attached to the boron atom.
The term "borinic ester" as used herein refers to a compound having a
-B(O-substituent)- group attached thereto, wherein the substituent forms a stable bond
to an O-atom attached to the boron atom.
The term "boronic acid" as used herein refers to a compound having a
-B(OH)2 group attached thereto.
The term "borinic acid" as used herein refers to a compound having a -B(OH)-
group attached thereto.
II. Methods of the Invention
The method of the present invention is drawn to preparing cyclocarbamate and
cyclothiocarbamate compounds, preferably containing cyanopyrrole substituents, and
derivatives thereof. In one embodiment, 2-cyanopyrrole containing cyclocarbamate
and cyclothiocarbamate compounds are prepared according to the present invention.
In another embodiment, compounds having the following structures are prepared
according to the present invention:

wherein:
Z are the same or different and are H, C1 to C6 alkyl, substituted C1 to C6
alkyl, or CORA. RA is selected from among H, C1 to C6 alkyl, substituted C1 to C6

alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted
C1 to C6 aminoalkyl.
Q are the same or different and are selected from among H, OH, NH2, CN,
halogen, C1 to C6 alkyl, suhstituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to
C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to C6 alkoxy, substituted
C1 to C6 alkoxy, C1 to C6 aminoalkyl, substituted C1 to C6 aminoalkyl, or CORB. RB
is selected from among H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy,
substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl.
In a further embodiment, compounds of the following formula are prepared
according to the present invention.

5-(4,4-dirnethyl-2-oxo-1,4-dihydro-2H-benzooxazin-6-yl)-l -methyl-1H-
pyrrole-2-carbonitrile and 5-(4,4-dirnethyl-2-thioxo-1,4-dihydro-2H-benzooxazin-6-
yl)-l-methyl-1H-pyrrole-2-carbonitrile can therefore be prepared according to the
present invention.
In one embodiment, a cyanopyrrole of the following structure is reacted with a
coupling agent as defined above. The CN group of the following structure can be
bound to any carbon-atom of the flve-membered ring, including the 2-, 3-, 4-, or 5-
position of the ring.

In a further embodiment, the cyanopyrrole utilized with the coupling agent is a
2-cyanopyrrole, or a 2-cyanopyrrole having the following structure, where Q and Z
are defined above. In yet another embodiment, the cyanopyrrole is 1-methylpyrrole-
2-carbonitrile.


Upon reaction of the cyanopyrrole with the coupling agent, a compound of the
following structure is formed, where Q and Z are defined above.

In one embodiment, the following 2-cyanopyrrole borate salts, or derivatives
thereof, are prepared upon reaction of the cyanopyrrole with the coupling agent In
these compounds, CC+ denotes a counter-cation (countercation) from the strong non-
nucleophilic base that interacts with the base molecule to form a stable compound and
Q, Z, and CC are as defined above.

In another embodiment, the following 2-cyanopyrrole borate salts, or
derivatives thereof, are prepared upon reaction of the cyanopyrrole with the coupling
agent.


In a further embodiment, the following boronic acids, borinic acids,
cyanopyrrole boronic acids, and cyanopyrrole borinic acids are prepared. Such
boronic and borinic acids are typically isolated in situ and utilized in further reactions.
The boronic and borinic acids are prepared using the borate salt as described above
and hydrolyzing the borate salt. See, Scheme 2, where substituents Q, Z, and CC+ are
defined above. In another embodiment, hydrolyzing is accomplished using water
which may contain other agents including mineral acids such as hydrochloric acid. In
still a further embodiment, the boronic acid is (5-Cyano-l-methyl-1H-pyrrol-2-yl)-
boronic acid.

In yet a further embodiment, the following cyanopyrrole boronic and borinic
acids are prepared according to the present invention, where Q and Z are defined
above.

In still another embodiment, the following cyanopyrrole boronic and borinic
acids are prepared according to the present invention.


In yet another embodiment, the trifluoroborate salts and cyanopyrrole
trifluoroborate salts are prepared by combining a fluoride agent with a borate salt as
described above. A number of fluoride agents can be utilized to prepare the
trifluoroborate salts and include reagents such as hydrogen fluoride, or derivatives
thereof including potassium hydrogen fluoride, among others. One of skill in the art
would readily be able to determine a suitable fluoride agent to utilize in the present
invention.
In still a further embodiment, the following trifluroborate salt can be prepared
according to the present invention.

Additional compounds can be added to promote reaction between the
cyanopyrrole and coupling agent and include strong non-nucleophilic bases including
LDA. One of skill in the art would readily be able to select other additional agents for
use in the coupling reaction.
Subsequent to the reaction between the cyanopyrrole and coupling agent, the
product of the same is reacted with an optionally substituted anthranilate, anthranilate
nitro ester, anthranilic alcohol, anthranilic nitro alcohols, anthranilic ketone, or
anthranilic nitro ketone.
(i) Coupling the Cyanopyrrole with an Anthranilate or Nitro Ester Thereof
The product of the reaction between the cyanopyrrole and coupling
agent can be reacted with an optionally substituted anthranilate or nitroester thereof to
form a cyanopyrrole substituted anthranilate. Desirably, the anthranilate or nitroester
thereof is optionally substituted with a leaving group (L) and can have the following
structures.


wherein:
Q are the same or different and are H, OH, NH2, CN, halogen, C1 to C6 alkyl,
substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6
alkynyl, substituted C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1
to C6 aminoalkyl, substituted C1 to C6 aminoalkyl, or CORB;
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted
C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
Rc is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2
to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to C6 aminoalkyl, or
substituted C1 to C6 aminoalkyl;
L is halogen or OSO2R1; and
R1 is CF3, C1 to C6 alkyl, or substituted C1 to C6 alkyl.
Desirably, L is a halogen or alkyl sulfonate leaving group and the anthraralate
is further substituted with amino or nitro groups.
In a further embodiment, the anthranilate or nitroester thereof has the
following structure:

wherein, L, Q, and Rc are defined above.
In another embodiment, the anthranilate is bromoanthranilate or methyl-2-
arnino-5-bromo benzoate.
The cyanopyrrole-substituted anthranilate or nitroester thereof prepared
according to the present invention typically has the following structure:

wherein:
Z is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;

RA is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted
C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 atninoalkyl;
Q are the same or different and are H, OH, NH2, CN, halogen, C1 to C6 alkyl,
substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6
alkynyl, substituted C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1
to C6 aminoalkyl, substituted C1 to C6 aminoalkyl, or CORB;
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted
. C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; and
Rc is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2
to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to C6 aminoalkyl, or
substituted C1 to C6 aminoalkyl.
Desirably, the cyanopyrrole-substituted anthrardlate or nitroester thereof
prepared according to the present invention is a compound of the following structure

In a further embodiment, 2-amino-5-(5-cyano-1-methyl-1H-pyrrol-2-yl)
benzoic acid methyl ester is prepared according to the present invention.

The cyanopyrrole substituted anthranilate and anthranilate nitroester can be
converted to a cyanopyrrole substituted anthranilic alcohol ornitro alcohol thereof
using an organometallic nucleophile such as a Grignard reagent or lithium reagent.
Without wishing to be bound by theory, the inventors have discovered that the
organometallic nucleophile utilized in the present invention preferentially adds to the
ester group of the cyanopyrrole-substituted anthranilate or nitroester thereof and not
the undesirable cyano group of the pyrrole.

(ii) Coupling the Cyanopyrrole with an Anthranilic Ketone or Nitre
Ketone Thereof
Alternatively, the product of the reaction between the cyanopyrrole and
coupling agent is reacted with an optionally substituted anthranilic ketone or nitro
ketone thereof to form a cyanopyrrole substituted anthranilic ketone. In one
embodiment, the anthranilic ketone or nitro ketone thereof utilized in the present
invention is optionally substituted with a leaving group (L) and can have the
following structures:

In a further embodiment, the anthranilic ketone or nitro ketone thereof
has the following structure:

In another embodiment, the anthranilic ketone or nitro ketone thereof
contains a halogen or alkyl sulfonate leaving group. In still another embodiment, the
anthranilic ketone is bromoanthranilic ketone or l-(2-amino-5-bromo-phenyl)-
ethanone.
Typically, the cyanopyrrole-substituted anthranilic ketone or nitro
ketone thereof prepared according to the present invention is a compound of the
following structure:

Desirably, the cyanopyrrole-substituted anthranilic ketone or nitro
ketone thereof prepared according to the present invention is a compound of the
following structure


In a further embodiment, 2-ammo-5-(5-cyano-l-methyI-1H-pyrrol-2-
yl)-phenyl-ethanone is prepared according to the present invention.
The cyanopyrrole substituted anthranilic ketone and anthranilic nitro
ketone thereof can then be converted to a cyanopyrrole substituted anthranilic alcohol
or nitro alcohol thereof using an organometallic nucleophile such as a Grignard
reagent or lithium reagent as described above.
(iii) Coupling the Cyanopyrrole with an Anthranilic Alcohol or Nitro
Alcohol Thereof
An anthranilic alcohol or nitro alcohol thereof is alternatively utilized
in place of the anthranilate, anthranilate nitroester, anthranilic ketone, or anthranilic
nitro ketone to form the cyanopyrrole substituted anthranilic alcohol or nitro alcohol
thereof. By doing so, conversion of the cyanopyrrole substituted anthranilate or
nitroester thereof to the corresponding cyanopyrrole anthranilic alcohol or nitro
alcohol thereof can be avoided.
This method includes reacting an anthranilic alcohol or nitro alcohol
thereof with the product of the reaction between the cyanopyrrole and coupling agent,
The anthranilic alcohol or nitro alcohol thereof is substituted with a leaving group (L)
such as a halogen or alkyl sulfonate group and optionally substituted with other
substituents such as amino or nitro groups. In one embodiment, this reaction is
performed in the presence of a catalyst, such as
tetrakis(triphenylphosphine)palladium, among others.
In a further embodiment, the anthranilic alcohol or nitro alcohol
thereof has the following structure, where Z and Q are defined above.


In another embodiment, the anthranilic alcohol or nitro alcohol thereof
has the following structure, where Z and Q are defined above.

In still a further embodiment, the anthranilic alcohol is
bromoanthranilic alcohol which is described in detail in International Patent
Publication No. WO 00/66570.
Typically, the cyanopyrrole-substituted anthranilic alcohol or nitro
alcohol thereof of the following structure is prepared according to the present
invention:

wherein:
Z are the same or different and are selected from among H, C1 to C6
alkyl, substituted C1 to C6 alkyl, or CORA. RA is selected from among H, C1 to C6
alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, or substituted C1 to C6 aminoalkyl. Q are the same or different and are
selected from among H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted C1 to C6
alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2
to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl,
substituted C1 to C6 aminoalkyl, or CORB. RB is selected from among H, C1 to C6
alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, or substituted C1 to C6 aminoalkyl.

Desirably, the cyanopyrrole-substituted anthranilic alcohol or nitro
alcohol thereof of the following structure is prepared according to the present
invention:

In a further embodiment, the following cyanopyrrole-substituted
anthranilic alcohol is 5-[4-amrno-3-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-methyl-
1 H-pyrrole-2-carbonitrile.

Prior to cyclizing the anthranilate nitro ester, anthranilic nitro alcohol, or
anthranilic nitro ketone, the same must independently be converted to the
corresponding anthranilate, anthranilic alcohol, or anthranilic ketone, respectively, by
reduction. One of skill in the art would readily be able to select suitable reducing
agent to carry out these reductions. A number of reducing agents useful for this
purpose are known and include, without limitation, those set forth in R.C. Larock,
"Comprehensive Organic Transformations", VCH Publishers, Inc., New York, New
York, 1989, which is hereby incorporated by reference.
The cyanopyrrole substituted anthranilic alcohol can thereby be converted to
the cyanopyrrole substituted cyclocarbamate or cyclothiocarbamate compound.
Typically, this is performed using a cyclizing agent. A variety of cyclizing agents are
known to those of skill in the art and include, without limitation, phosgene,
thiophosgene, triphosgene, 1,1'-carbonyldiimidazoIe (CDI), 1,1'-
tbiocarbonyldiimidazole (TCDI), carbon disulfide at elevated temperatures such as
80°C, or carbon disulfide in the presence of a base such as ethanolic KOH, NaOH,
imidazole, tertiary bases such as triethylamine or rriphenylphosphine, polycarbonate,

chloroformates such as trichloromethylchloroformate, or trichloromethanesulfenyl
chloride.
In one embodiment, the present invention provides a method for producing 6-
(cyanopyrrole)-cyclocarbamate or cyclothiocarbamate compounds including the steps
of (a) reacting a cyanopyrrole with a coupling agent; (b) reacting the product of (a) to
form a cyanopyrrole substituted anthranilic alcohol or nitro alcohol thereof; (c)
reducing the anthranilic nitro alcohol to the anthranilic alcohol; and (d) converting the
cyanopyrrole substituted alcohol to the 6-(cyanopyrrole)-cyclocarbamate or
cyclothiocarbamate compound.
In another embodiment, the present invention provides a method for producing
6-(cyanopyrrole)-cyclocarbamate or 6-(cyanopyrrole)-cyclothiocarbamate compounds
including the steps of (a) reacting a cyanopyrrole with a coupling agent; (b) reacting
the product of (a) with an anthranilate or nitroester thereof; (c) reacting the product of
(b) with an organometallic nucleophile; and (d) converting fhe product of (c) to 1he 6-
(cyanopyrrole)-cyclocarbamate or 6(cyanopyrrole)-cyclothiocarbamate compound.
In another embodiment, the present invention provides a method for producing
6-(cyanopyrrole)-cyclocarbarnate or 6-(cyanopyrrole)-cyclothiocafbamate compounds
including the steps of (a) reacting a cyanopyrrole with a coupling agent; (b) reacting
the product of (a) with an anthranilate or nitroester thereof; (c) reacting the product of
(b) with an organometallic nucleophile; (d) optionally reducing the cyanopyrrole
anthranilate nitro ester to the cyanopyrrole anthranilate; and (e) converting the
cyanopyrrole anthranilate to the 6-(cyanopyrrole)-cyclocafbamate or 6(cyanopyrrole)-
cyclothiocarbamate compound.
In a further embodiment, the present invention provides a method for
producing 6-(cyanopyrrole)-cyclocarbamate or 6-(cyanopyrrole)-cyclothiocarbamate
compounds including the steps of (a) reacting a cyanopyrrole with a coupling agent;
(b) reacting the product of (a) with an anthranilic alcohol or nitro alcohol thereof; and
(c) converting the product of (b) to the 6-(cyanopyrrole)-cyclocarbamate or
6(cyanopyrrole)-cyclothiocarbamate compound.
In yet another embodiment, the present invention provides a method for
producing 6-(cyanopyrrole)-cyclocarbamate or 6-(cyanopyrrole)-cyclothiocarbamate
compounds including the steps of (a) reacting a cyanopyrrole with a coupling agent;

(b) reacting the product of (a) with an anthranilic alcohol or nitro alcohol thereof; (c)
reducing the cyanopyrrol anthranilic nitro alcohol to the cyanopyrrole anthranilic
alcohol; and (d) converting the cyanopyrrole anthranilic alcohol to the 6-
(cyanopyrrole)-cyclocarbamate or 6(cyanopyrrole)-cyclothiocarbamate compound.
In a further embodiment, the present invention provides a method for
producing 6-(cyanopyrrole)-cyclocarbamate or 6-(cyanopyrrole)-cyclotbiocarbamate
compounds including the steps of (a) reacting a cyanopyrrole with a coupling agent;
(b) reacting the product of (a) with an anthranilic ketone or nitro ketone thereof; and
(c) converting the product of (b) to the 6-(cyanopyrrole)-cyclocarbamate or
6(cyanopyrrole)-cyclothiocarbamate compound.
In still another embodiment, the present invention provides a method for
producing 6-(cyanopyrrole)-cyclocarbarnate or 6-(cyanopyrrole)-cyclothiocarbamate
compounds including the steps of (a) reacting a cyanopyrrole with a coupling agent;
(b) reacting the product of (a) with an anthranilic ketone or nitro ketone thereof; (c)
reducing the cyanopyrrole anthranilic nitro ketone to the cyanopyrrole anthranilic
ketone; and (d) converting the anthranilic ketone to the 6-(cyanopyrrole)-
cyclocarbamate or 6(cyanopyrrole)-cyclothiocarbamate compound.
In yet another embodiment, the present invention provides a method for
producing 6-(cyanopyrrole)-cyclothiocarbarnate compounds including the steps of: (a)
reacting a cyanopyrrole with a coupling agent; (b) reacting the product of (a) with
bromoanthranilate or nitroester thereof; (c) reacting the product of (b) with an
organometallic nucleophile; and (d) converting the product of (c) to the 6-
(cyanopyrrole)-cyclotlriocarbamate compound.
In still another embodiment, the present invention provides a method for
producing 6-(cyanopyrrole)-cyclothiocarbamate compounds including the steps of (a)
reacting a cyanopyrrole with a coupling agent; (b) reacting the product of (a) with
bromoanthranilic alcohol or nitro alcohol thereof; and (c) converting the product of
(b) to the 6-(cyanopyrrole)-cyclothiocarbamate compound.
In another embodiment, the present invention provides a method for producing
6-(cyanopyrrole)-cyclothiocarbamate compounds including the steps of (a) reacting a
cyanopyrrole with a coupling agent; (b) reacting the product of (a) with

bromoanthranilic ketone or nitro ketone thereof; and (c) converting the product of (b)
to the 6-(cyanopyrrole)-cyclothiocarbamate compound.
In yet another embodiment, the present invention provides a method for
producing cyanopyrrole anthranilates including the steps of (a) reacting a
cyanopyrrole with a coupling agent; and (b) reacting the product of (a) with an
anthranilate or nitroester thereof.
In another embodiment, the present invention provides a method for producing
a cyanopyrrole anthranilic alcohol or nitro alcohol thereof including the steps of (a)
reacting a cyanopyrrole with a coupling agent; (b) reacting the product of (a) with an
anthranilate, anthraniliate nitroester, anthranilic ketone, or antrhanilic nitro ketone;
and (c) reacting the product of (b) with an organometallic nucleophile.
In still another embodiment, the present invention provides method for
producing 6-(cyanopyrrole)-cyclocarbarnate and cyclothiocarbamate compounds
according to Scheme 3, where substituents R and CC+ are defined above.


III. Compounds of the Invention
The present invention also provides novel compounds that can be prepared
according to the present invention. In one embodiment, 2-amino-5-(5-cyano~l-
methyl-1H-pyrrol-2-yl) benzoic acid methyl ester and 5-[4-amino-3-(l-hydroxy-l-
methyl-ethyl)-phenyl]-1-methyl-1H-pyrroIe-2-carbonitrile can be prepared according
to the methods described above.
Such compounds can be utilized in situ in solution, isolated as raw materials
and utilized without further purification, or isolated and purified to obtain pure
compounds. Purification can include utilizing techniques known to those of skill in
the art, including chromatography, such as thin layer chromatography (TLC) and
liquid chromatography (LC) including high performance liquid chromatography
(HPLC), extraction, recrystallization, washing, and drying.

IV. Methods of Using the Compounds of the Invention
The compounds of this invention, including intermediates thereof, are
modulators of the progesterone receptor (PR), including antagonists and agonists, as
described in US Patent Nos. 6,509,334; 6,566,358; 6,436,929; 6,407,101; and
6,562,857. The compounds of the invention act as PR modulators in functional
models, either/or in-vitro and in-vivo. These compounds are useful for contraception,
in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate
cancer, and in preparing medicaments therefor, and hormone replacement therapy
including peri- and post-menopausal hormone replacement therapy.
The compounds of the present invention are used in the form of salts derived
from pharmaceutically or physiologically acceptable acids or bases. These salts
include, but are not limited to, the following salts with mineral or inorganic acids such
as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and organic acids such
as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts
with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or
magnesium in the form of esters, carbamates and other conventional "pro-drug"
forms, which, when administered in such form, convert to the active moiety in vivo.
This invention includes pharmaceutical compositions comprising one or more
compounds of this invention and a pharmaceutically acceptable carrier or excipient
The invention also includes methods of treatment which comprise administering to a
mammal a pharmaceutically effective amount of one or more compounds as described
above as modulators of the progesterone receptor, or use of compounds of the
invention in the preparation of medicaments useful in treating the above conditions.
The compounds of the present invention, used alone or in combination, are
utilized in methods of contraception and the treatment and/or prevention of benign
and malignant neoplastic disease. Specific uses of the compounds and pharmaceutical
compositions of invention include the treatment and/or prevention, or preparation of
medicaments useful therefor, of dysfunctional bleeding, uterine myometrial fibroids,
uterine leiomyomata, endometriosis, benign prostatic hypertrophy, polycystic ovary
syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast,
colon, prostate, pituitary, meningioma and other hormone-dependent tumors.

Additional uses of the compounds of the present invention include the
synchronization of the estras in livestock and the stimulation of food intake.
When the compounds are employed for the above utilities, they are combined
with one or more pharmaceutically acceptable carriers or excipients, for example,
solvents, diluents and the like, and are administered orally in such forms as tablets,
capsules, dispersible powders, granules, or suspensions containing, for example, from
about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10
to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol,
and the like, or parenterally in the form of sterile injectable solutions or suspensions
containing from about 0.05 to 5% suspending agent in an isotonic medium. Such
pharmaceutical preparations contain, for example, from about 25 to about 90% of the
active ingredient in combination with the carrier, more usually between about 5% and
60% by weight
The effective dosage of active ingredient employed varies depending on the
particular compound employed, the mode of administration and the severity of the
condition being treated. However, in one embodiment, satisfactory results are
obtained when the compounds of the invention are administered at a daily dosage of
from about 0.5 to about 500 mg/kg of animal body weight, or administered in divided
doses two to four times a day, or in a sustained release form. For most large
mammals, the total daily dosage is from about 1 to 100 mg, or about 2 to 80 mg.
Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the
active compound in intimate admixture with a solid or liquid pharmaceutically
acceptable carrier. This dosage regimen is adjusted to provide the optimal therapeutic
response. For example, several divided doses are administered daily or the dose is
proportionally reduced as indicated by the exigencies of me therapeutic situation.
These active compounds are administered orally as well as by intravenous,
intramuscular, or subcutaneous routes. Solid carriers include starch, lactose,
dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid
carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible
oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active
ingredient and the particular form of administration desired. Adjuvants customarily
employed in the preparation of pharmaceutical compositions are advantageously

included, such as flavoring agents, coloring agents, preserving agents, and
antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
In one embodiment, solid pharmaceutical compositions are used for ease of
preparation and administration. In a further embodiment, tablets and hard-filled or
liquid-filled capsules are used. In still another embodiment, compounds are
administered orally.
In other embodiments, these active compounds are administered parenterally
or intraperitoneally. In a further embodiment, solutions or suspensions of these active
compounds as a free base or pharmacologically acceptable salt are prepared in water
suitably mixed with a surfactant such as hydroxypropylcellulose. In other
embodiments, dispersions are prepared, such as in glycerol, liquid polyethylene
glycols and mixtures thereof in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous preparation of
sterile injectable solutions or dispersions. In all cases, the form is sterile and fluid to
the extent that easy syringe ability exits. It is stable under conditions of manufacture
and storage and is preserved against the contaminating action of microorganisms such
as bacterial and fungi. The carrier is a solvent or dispersion medium containing, for
example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene
glycol), suitable mixtures thereof, and vegetable oil.
The following examples are provided to illustrate the invention and do not
limit the scope thereof. One skilled in the art will appreciate that although specific
reagents and conditions are outlined in the following examples, modifications can be
made which are meant to be encompassed by the spirit and scope of the invention.
EXAMPLES
EXAMPLE 1 - PREPARATION OF 2-AMINO-5-(5-CYANO-1-METHYL-1H-
PYRROL-2-YL) BENZOIC ACID METHYL ESTER
l-Methylpyrrole-2-carbonitrile (0.106 g, 1.0 mmol), triisopropyl borate (270
µL, 1.2 mmol) and tetrahydrofuran (THF - 4 mL) were mixed in a 50-mL flask

equipped with nitrogen inlet, magnetic stirrer, and temperature controller. After
cooling the solution to -3°C, 2M LDA solution (0.6 mL, 1.2 mmol) was added
dropwise and the mixture was allowed to warm up to ambient temperature. Toluene (5
mL) was added followed by tetrakis(triphenylphosphine)palladium (25 mg), ethanol
(1.6 mL), potassium carbonate (0.326 g), water (2 mL), and methyl bromoanthranilate
(0.225 g, 0.98 mmol). The reaction mixture was heated to a gentle reflux for 7 h, then
cooled and quenched with 5% hydrochloric acid (HC1), 10% ammonium chloride. It
was extracted twice with ethyl acetate. The combined organic phase was washed with
brine, dried over magnesium sulfate, filtered, and evaporated to give a dark, very
viscous oil (0.307 g), containing 2-amino-5-(5-cyano-l-mefhyl-1H-pyrrole-2-yl)
benzoic acid methyl ester.
EXAMPLE 2 - PREPARATION OF 5-[4-AMlNO-3-(1-HYDROXY-1-METHYL-
ETHYL)-PHENYL]-1-METHYL-1H-PYRROLE-2-CARBONiTRlLE
In a similar preparation, starting with 1-memylpyrrole-2-carbonitrile (0.104 g,
0.98 mmol), bromoanthranilic alcohol (0.245 g, 1.1 mmol) was coupled in the
presence of tetrakis(triphenylphosphine)palladium (32 mg). After standard work up
and evaporation, a glassy mass (0.198 g, about 93% yield), containing
cyanopyrroleaniline alcohol, was obtained.
EXAMPLE 3 - PREPARATION OF 6-BROMO-4,4-DIMETHYL-2-THIOXO-1,4-
DIHYDRO-BENZOXAZINE
2-(2-Amino-5-bromophenyl)-propan-2-ol (1.028 g, 4.4 mmol) was dissolved
in THF (12 mL) and TCDI (1.087 g, 6.1 mmol) was added as solid to form a hazy
solution. After stirring the mixture for 140 min., it was transferred into a separately
funnel containing 5% HC1. After separation of the phases, the aqueous phase was
extracted twice with 1:1 ethyl acetate/THF. The combined organic extracts were
washed with brine and dried over MgS04. Filtration and evaporation gave 1.081 g
(89% yield) of the product.

EXAMPLE 4 - PREPARATION OF (4,4-DIMETHYL-2-THIOXO-1,4-
DIHYDRO-2H-3,1-BENZOXAZIN-6-YL)-1H-PYRROLE-2-CARBONITRILE
AND (4,4-DIMETHYL-2-OXO-1,4-DIHYDRO-2H-3,1-BENZOXAZIN-6-YL)-1 H-
PYRROLE-2-CARBONITRILE
5-[4-amino-3-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-methyl-1H-pyrrole-2-
carbonitrile prepared according to Example 2 is dissolved in THF and TCDI or CDI is
added. Extraction using an aqueous dilute hydrochloride solution gives an about
quantitative yield of (4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-
1H-pyrrole-2-carbonitrile and (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-
yl)-1H-pyrrole-2-carbonitrile, respectively.
EXAMPLE 5 - SELECTIVE ADDITION OF METHYL GRIGNARD TO
METHYL ANTHRANILATE IN THE PRESENCE OF 1-METHYL-1H-
PYRROLE-2-CARBONITRILE
1-Methylpyrrole-2-carbonitrile (0.302 g, 2.85 mmol) was dissolved in THF (6
mL). Methyl anthranilate (0.425 g, 2.81 mmol) was added, followed by the addition
of 1.4M solution of methylmagnesium bromide in toluene/THF 75/25 (4 mL, 5.6
mmol, 2 eq.) at about -7 °C. After standard work up and evaporation, the product
(0.695 g) was isolated as a 1:1 mixture of l-methyl-1H-pyrrole-2-carbonitrile and 2-
(2-aminophenyl)propan-2-ol.
All publications identified in this specification are incorporated herein by
reference. While the invention has been described with reference to specific
embodiments, it will be appreciated that modifications can be made without departing
from the spirit of the invention. Such modifications are intended to fall within the
scope of the appended claims.

WE CLAIM :
1. A method for producing 6-(cyanopyrrole)-cyclocarbamate or cyclothiocarbamate
compounds comprising the steps of:
(a) reacting a cyanopyrrole with a coupling agent;
(b) converting the product of (a) to a cyanopyrrole substituted anthranilic alcohol or nitro
alcohol thereof; and
(c) reducing the anthranilic nitro alcohol to the cyanopyrrole substituted anthranilic
alcohol; and
(d) converting the cyanopyrrole substituted anthranilic alcohol to said 6-(cyanopyrrole)-
cyclocarbamate or cyclothiocarbamate compound.

2. The method as claimed in claim 1, wherein the cyanopyrrole substituted anthranilic
alcohol is formed by reacting the product of (a) with an anthranilic alcohol.
3. The method as claimed in claim 1, wherein the cyanopyrrole substituted anthranilic
alcohol is formed by:
(i) reacting the product of (a) with an anthranilate or nitroester thereof to form a
cyanopyrrole substituted anthranilate or nitroester thereof; and
(ii) reacting the cyanopyrrole substituted anthranilate or nitroester thereof with an
organometallic nucleophile.
4. The method as claimed in claim 3, wherein the anthranilate is a bromoanthranilate.
5. The method as claimed in claim 1, wherein the cyanopyrrole substituted anthranilic
alcohol is formed by:
(i) reacting the product of (a) with an anthranilic ketone or nitro ketone thereof to form a
cyanopyrrole substituted anthranilic ketone or nitro ketone thereof; and
(ii) reacting the cyanopyrrole substituted anthranilic ketone or nitro ketone thereof with
an organometallic nucleophile.

6. The method as claimed in any of claims 1 to 5, wherein step (d) is performed using
phosgene, thiophosgene, triphosgene, l,l'-carbonyldiimidazole (CDI), 1,1'-
thiocarbonyldiimidazole (TCDI), carbon disulfide, or carbon disulfide in the presence of a base.
7. The method as claimed in any of claims 1 to 6, wherein said cyanopyrrole is:

wherein:
Z is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;
RA is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
Q is H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6
alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to
C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, substituted C1 to C6
aminoalkyl, or CORB; and
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl.
8. The method as claimed in any of claims 1 to 7, wherein said cyanopyrrole is 1-methyl-2-
cyanopyrrole.
9. The method as claimed in any of claims 1 to 8, wherein said coupling agent is a trialkyl
borate.
10. The method as claimed in any of claims 1 to 9, wherein said trialkyl borate is triisopropyl
borate.

11. The method as claimed in any of claims 1 to 10, wherein said step (a) further comprises
lithium diisopropyl amide.
12. The method as claimed in any of claims 2, 6 to 11, wherein said anthranilic alcohol or
nitro alcohol thereof is:

wherein:
Z are the same or different and are H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;
Q are the same or different and are H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted
C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl,
substituted C1 to C6 aminoalkyl, or CORB;
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
Rc is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6
alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to C6 aminoalkyl, or
substituted C1 to Cg aminoalkyl;
L is halogen or OSO2R1; and
R1 is H, C1 to C6 alkyl, or substituted C1 to C6 alkyl.
13. The method as claimed in any of claims 2, 6 to 12, wherein said anthranilic alcohol is
substituted with a leaving group.
14. The method as claimed in any of claims 3 or 6 to 13, wherein said anthranilate or
nitroester thereof is:


wherein:
Q are the same or different and are H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted
C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl,
substituted C1 to C6 aminoalkyl, or CORB;
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
Rc is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6
alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to C6 aminoalkyl, or
substituted C1 to C6 aminoalkyl;
L is halogen or OSO2R1; and
R1 is H, C1 to C6 alkyl, or substituted C1 to C6 alkyl.
15. The method as claimed in any of claims 3 or 6 to 14, wherein said anthranilate or
nitroester thereof is substituted with a leaving group.
16. The method as claimed in claim 12 or claim 14, wherein said leaving group is a halogen
or alkyl sulfonate group.
17. The method as claimed in any of claims 3 or 6 to 16, wherein said anthranilate is 4-
bromo-methylanthranilate.
18. The method as claimed in any of claims 2, 6 to 16, wherein said anthranilic alcohol is
bromoanthranilic alcohol.

19. The method as claimed in any of claims 2, 6 to 16, wherein said anthranilic alcohol is 4-
bromo-methylanthranilic alcohol.
20. The method as claimed in any of claims 5 or 6 to 13, wherein said anthranilic ketone or
nitro ketone thereof is:

wherein:
Q are the same or different and are H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted
C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl,
substituted C1 to C6 aminoalkyl, or CORB;
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
L is halogen or OSO2R1; and
R1 is H, C1 to C6 alkyl, or substituted C1 to C6 alkyl.
21. The method as claimed in claim 20, wherein said anthranilic ketone is 1-(2-amino-5-
bromo-phenyl)-ethanone.
22. The method as claimed in any of claims 3 to 21, wherein said organometallic nucleophile
is an organolithium agent or Grignard agent.
23. The method as claimed in any of claims 1 to 22, wherein step (b) is performed in the
presence of a catalyst.
24. The method as claimed in claim 23, wherein said catalyst is tetrakis(triphenylphosphine)

palladium.
25. The method as claimed in any of claims 1 to 24, wherein the product of step (a) is:

wherein:
M' is a boron, zinc, magnesium or silicon containing coupling group;
Z is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;
RA is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
Q is H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6
alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to
C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, substituted C1 to C6
aminoalkyl, or CORB; and
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl.
26. The method as claimed in any of claims 1 to 25, wherein the product of step (a) is:

27. The method as claimed in any of claims 1 to 25, wherein the product of step (a) is (5-
cyano-l-methyl-1H-pyrrol-2-yl)boronic acid.
28. The method as claimed in any of claims 1 to 25, wherein the product of step (a) is:


wherein, R is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, and substituted aryl.
29. The method as claimed in any of claims 1 to 28, wherein the product of step (b) is:

wherein:
Z are the same or different and are H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;
RA is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
Q are the same or different and are H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted
C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl,
substituted C1 to C6 aminoalkyl, or CORB; and
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl.
30. The method as claimed in any of claims 1 to 29, wherein said anthranilic alcohol is 5-[4-
amino-3 -(1 -hydroxy-1 -methyl-ethyl)-phenyl] -1 -methyl-1H-pyrrole-2-carbonitrile.
31. The method as claimed in any of claims 1 to 30, wherein said 6-(cyanopyrrole)-
cyclocarbamate compound is:


wherein:
Z are the same or different and are H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;
RA is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
Q are the same or different and are H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted
C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl,
substituted C1 to C6 aminoalkyl, or CORB; and
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl.
32. The method as claimed in any of claims 1 to 30, wherein said 6-(cyanopyrrole)-
cyclocarbamate compound is 5-(4,4-dimethyl-2-oxo-l,4-dihydro-2H-benzooxazin-6-yl)-1-
methyl-1H-pyrrole-2-carbonitrile, or a pharmaceutically acceptable salt thereof.
33. The method as claimed in any of claims 1 to 29, wherein said 6-(cyanopyrrole)-
cyclothiocarbamate compound is:

wherein:
Z are the same or different and are H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;

RA is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
Q are the same or different and are H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted
C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl,
substituted C1 to C6 aminoalkyl, or CORB; and
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl.
34. The method as claimed in any of claims 1 to 30 or 33, wherein said 6-(cyanopyrrole)-
cyclothiocarbamate compound is 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzooxazin-6-yl)-1-
methyl-1H-pyrrole-2-carbonitrile, or a pharmaceutically acceptable salt thereof.
35. A method for producing 6-(cyanopyrrole)-cyclocarbamate or cyclothiocarbamate
compounds comprising:

(a) reacting a cyanopyrrole, an anthranilate or nitroester thereof, and an organometallic
nucleophile;
(b) reducing the anthranilic nitro alcohol to the anthranilic alcohol; and
(c) converting the anthranilic of steps (a) and (b) to said 6-(cyanopyrrole)cyclocarbamate
or cyclothiocarbamate compound.
36. A method for preparing a 6-(cyanopyrrole)-cyclothiocarbamate or cyclocarbamate
compound of formula:


wherein:
Z are the same or different and are H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;
RA is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
each Q is the same or different and is selected from H, OH, NH2, CN, halogen, C1 to C6
alkyl, substituted Q to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6
alkynyl, substituted C2 to C6 alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to
C6 aminoalkyl, substituted C1 to C6 aminoalkyl, or CORB; and
RB is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; which comprises
a) reacting a cyanopyrrole of formula:

wherein Z and Q are as defined above, with a coupling agent M-M' to give a compound
of formula:

wherein Z and Q are as defined above, and M' is a substituent derived from M, and
b) reacting the product of step a) with i) an anthranilate or nitroester thereof of formula:


ii) an anthranilic alcohol or nitro alcohol thereof of formula:

(iii) an anthranilic ketone or nitro ketone there of formula:

in which formulae Q and Z are each as defined above, L is a leaving group and Rc
is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6
alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to C6 aminoalkyl, or
substituted C1 to C6 aminoalkyl;
to give a corresponding compound of formulae A, B, C, D, E, or F;


and where the product is an anthranilate of formula (A), anthranilate nitroester of
formula (B), anthranilic ketone of formula (E), and anthranilic nitro ketone of
formula (F), further reacting the compound of formulae A, B, (E), or (F) with an
organometallic nucleophile such as a Grignard reagent or lithium reagent
containing Z to give a compound of formula (C) or (D);
and where a compound of formula D is obtained reducing the nitro group to give
a compound of formula (C) wherein the NHQ substituent is NH2; and
c) cyclising the anthranilic alcohol of formula (C) prepared in step b) with a carbamate or
thiocarbamate forming reagent such as phosgene, thiophosgene, triphosgene, 1,1'-
carbonyldiimidazole (CDI), 1,1'-thiocarbonyldiimidazole (TCDI), carbon disulfide,
polycarbonate or a chloroformate such as trichloromethylchloroformate, or
trichloromethanesulfenyl chloride to give a compound of formula (I).
37. The method as claimed in claim 36, wherein step (c) is performed using phosgene,
thiophosgene, triphosgene, 1,1'-carbonyldiimidazole (CDI), 1,1'-thiocarbonyldiimidazole
(TCDI), carbon disulfide, or carbon disulfide in the presence of a base.
38. The method as claimed in claim 36 or claim 37, wherein said cyanopyrrole is:

39. The method as claimed in claim 38, wherein said cyanopyrrole is 1-methyl-2-
cyanopyrrole.
40. The method as claimed in any of claims 36 to 39, wherein said coupling agent is a trialkyl
borate.

41. The method as claimed in claim 40, wherein said trialkyl borate is triisopropyl borate.
42. The method as claimed in any of claims 36 to 41, wherein said step (a) further comprises
lithium diisopropyl amide.
43. The method as claimed in claim 36, wherein L is halogen or OSO2R1; and R1 is H, C1 to
C6 alkyl, or substituted C1 to C6 alkyl.
44. The method as claimed in claims 36, wherein Rc is methyl.
45. . The method as claimed in claim 36 or claim 44, wherein L is halogen or OSO2R1; and R1
is H, C1 to C6 alkyl, or substituted C1 to C6 alkyl.
46. The method as claimed in any of claims 36 to 45, wherein said L is bromo.
47. The method as claimed in any one of claims 36 to 46, wherein NHQ is NHMe.
48. The method as claimed in any of claims 36 to 47, wherein said organometallic
nucleophile is an organolithium agent or Grignard agent.
49. The method as claimed in any of claims 36 to 48, wherein step (b) is performed in the
presence of a catalyst.
50. The method as claimed in claim 49, wherein said catalyst is tetrakis(triphenylphosphine)
palladium.
51. The method as claimed in any of claims 36 to 48, wherein the product of step (a) is:


52. The method as claimed in any of claims 36 to 50, wherein the product of step (a) is (5-
cyano-l-methyl-1H-pyrrol-2-yl)boronic acid.
53. The method as claimed in any of claims 36 to 50, wherein the product of step (a) is:

wherein, R is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, and substituted aryl.
54. A compound which is 2-amino-5-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzoic acid methyl
ester.
55. A compound which is 5-[4-amino-3-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-methyl-1H-
pyrrole-2-carbonitrile.
56. A compound which is 2-amino-5-(5-cyano-1-methyl-1H-pyrrol-2-yl)-phenyl-ethanone.

Methods for preparing cyclic carbamates and thiocarbamates containing cyanopyrrole moieties and of the formula
are provided; Formula (I) Z are the same or different and are H, optionally substituted C1 to C6 alky], or CORA; RA is H, optionally
substituted C1 to C6 alkyl, optionally substituted C1 to C6 alkoxy, or optionally substituted C1 to C6 aminoalkyl; Q are the same or
different and are H, OH, NH2, CN, halogen, optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 alkenyl, optionally
substituted C1 to C6 alkynyl, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 aminoalkyl, or CORB; and RB
is H, optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 alkoxy, or optionally substituted C1 to C6 aminoalkyl.
Compounds including 2-amino-5-(5-cyano-1-methyl-1H-pyrrol-2-yl) benzoic acid methyl ester, 5-[4-amino-3-(1-hydroxy-1-methyl-
ethyl)-phenyl]-1-methyl-1H-pyrrole-2-carbonitrile, and 2-amino-5-(5-cyano-1-methyl-1H-pyrrol-2-yl)-phenyl-ethanone, or pharmaceutically
acceptable salts thereof, and the uses thereof are also provided.