Title of Invention

PURIFICATION OF PROGESTERONE RECEPTOR MODULATORS

Abstract Methods for purifying a compound of formula I are provided, wherein A, B, X, Q, and R are defined herein. The methods include mixing the compound of formula I and a. solvent; adding a base to the solvent; and precipitating purified compound of formula, I.
Full Text BACKGROUND OF THE INVENTION
The present invention relates to the production of progesterone receptor
modulators.
The purification'of progesterone receptor (PR) modulators can be achieved by
re-crystallization using organic solvents. However, since many PR modulators have
poor solubilities in organic solvents, recrystallization requires large volumes of the
organic solvents to dissolve the PR modulators, thus making the purification less
economical.
What is needed in the art are alternate methods for purifying progesterone
receptor modulators.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a method for purifying indolone,
indol-thione, indol-ylidene cyanamide, benzoxazinone, benzoxazin-thione,
benzoxazin-ylidene cyanamide, benzothiazinone, benzothiaziae-thione, benzothiazin-
ylidene cyanamide compounds, or derivatives thereof.
In a further aspect, the present invention provides a method for purifying
indol-2-one, indol-2-thione, indol-2-ylidene cyanamide, benzoxazin-2-one,
benzoxazin-2-thione, benzoxazin-2-ylidene cyanamide, benzothiazin-2-one,
benzotluazine-2-thione, benzothiazin-2-ylidene cyanamide compounds, or derivatives
thereof.
In still a further aspect, these compounds are progesterone receptor
modulators.
In another aspect, the invention provides a method for purifying a compound
of formula I:
H
I.
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 the purification of progesterone
receptor modulators, including agonists and antagonists, and their intermediates. In
one embodiment, the pfogesterpne receptor modulators prepared according to the
present invention contain an acidic hydrogen atom. In a further embodiment, the
progesterone receptor modulators prepared according to the present invention contain
an acidic N-H group. In still further embodiments, the compounds are indolone,
indol-thione, indol-ylidene cyanamide, benzoxazinone, benzoxazin-thione,
benzoxazin-ylidene cyanamide, benzothiazinone, benzothiazine-thione, benzothiazin-
ylidene cyanamide compounds, or derivatives thereof, or indol-2-one, indol-2-thione,
indol-2-ylidene cyanamide, benzoxazin-2-one, benzoxazin-2-thione, benzoxazin--
ylidene cyanamide, benzothiazin-2-one, benzothiazine-2-thione, benzothiazin-2-
ylidene cyanamide compounds, or derivatives thereof.
The inventors have found that by treating a crude form of a compound of
formula I with a base to form a basic salt, the basic salt can be converted to a purified
form of the same compound. See, Scheme 1, wherein A, B, T, Q, and R1 are defined
uoiOW.
I. Definitions
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, or 1 to
about 6 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 term "cycloalkyl" is used herein to refer to an alkyl group, as previously
described, that is cyclic in structure and has about 3 to about 10 carbon atoms, about 4
to about 8 carbon atoms, or about 5 to about 8 carbon atoms;
The terms "substituted alkyl", "substituted alkenyl", "substituted alkynyl", and
"substituted cycloalkyl" refer to alkyl, alkenyl, alkynyl, and cycloalkyl groups,
respectively, having one or more substituents the same or different 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 as a group or part of a group refers to an
aromatic system 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 e.g. having 6 to 14 carbon atoms. The aiyl groups can
include, but are not limited to, 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 the same or different 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 10-membered
monocyclic or 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. 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 an aryl ring, e.g., of 6 to 14
carbon atoms. 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 the art and include, without
limitation, oxygen-containing rings, nitrogen-containing rings, sulfor-contoining
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, oxafhiazinyl, morpholinyl,
thiamoipholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, and diazepinyl rings.
Fused heteroatom containing rings include, but are not limited to, benzofuranyl,
thionapthene, inddlyl, benazazolyl, purindinyl, pyranopyrrolyl, isoindazolyl,
indoxazinyl, benzoxazolyl, anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl,
benzodiazonyl, napthylridinyl, benzothienyl, pyridopyridinyl, benzoxazinyl,
xanthenyl, acfidinyl, and purinyl rings.
The term "substituted heterocyclic" as used herein refers to a heterocyclic
group having one or more substituents the same or different including halogen, CN,
OH, NO2, amino, alkyl, cycloalkyl, allcenyl, alkynyl, alkoxy, aryloxy, alkyloxy,
alkylcarbonyl, alkylcarboxy, aminoalkyl, and arylthio, which groups can be optionally
substituted. In one embodiment, a substituted heterocyclic group is substituted with 1
to about 4 substituents.
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 O(aryl) group, where the point
of attachment is through the oxygen-atom and the aryl group is optionally substituted.
The term "alkyloxy" includes hydroxyalkyl and as used herein refers to the
alkylOH group, where the point of attachment is through the alkyl group.
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(0)(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(0)0(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 "aminoalkyl" includes "alkylamino" and 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.
Hie term "thioalkoxy" or "thioalkyl" as used herein refers to the S(alkyl)
group, where the point of attachment is through the sulfur-atom and the alkyl group is
optionally substituted.
The term "halogen" as used herein refers to CI, Br, F, or I groups.
The term "ester" as used herein refers to a C(0)0, where the points of
attachment are through both the Oatom and O-atom. One or both oxygen atoms of
the ester group can be replaced with a sulfur atom, thereby forming a "thioester", i.e.,
a C(0)S, C(S)0 or C(S)S group.
A "base" useful in the invention is a chemical compound having a pKa greater
than 16 that is capable of abstracting an acidic hydrogen atom bound to a molecule.
An "acid" useful in the invention is a chemical compound having a pKa of less
than 16. A number of acids can be utilized according to the present invention and
include water, mineral acids, and organic acids such as hydrochloric acid, acetic acid,
and solutions containing hydrochloric acid or acetic acid, among others. In one
embodiment, the acid is aqueous hydrochloric acid or aqueous acetic acid.
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.
The term "crude" as used herein refers to a compound that contains greater
than about 10% impurities. In one embodiment, the term "crude" refers to a
compound that contains greater than about 5% impurities, greater than about 2%
impurities, or greater than about 1 % impurities. The impurities that can be present in
a crude sample can include unused starting materials or undesirable side products
formed during the reaction to form the crude compound. In one embodiment, such
impurities are present as solids. The impurities can also include solvents that are
present or trapped in the crude compound.
By the term "dry" or "drying" is meant a procedure by which entrapped
solvents, including organic solvents, purifying solvents, solubilizing solvents, or
water, or volatile solids are removed from a sample.
The term "electron withdrawing group" as used herein is meant to describe a
chemical substituent that withdraws electrons from the chemical group to which it is
attached. Examples of electron withdrawing groups include, without limitation, CN,
S03H, C02H, C02R, CHO, COR, N02, NR3+, CF3, or CC13. In one embodiment, the
electron withdrawing group is CN.
II. Method of the invention
The present invention therefore provides methods for purifying indolone,
indol-thione, indol-ylidene cyanamide, benzoxazinone, benzoxazin-thione,
benzoxazin-ylidene cyanamide, benzothiazinone, benzothiazine-thione, benzothiazin-
ylidene cyanamide compounds, or derivatives thereof. In a further embodiment,
indol-2-one, indol-2-thione, indoI-2-ylidene cyanamide, benzoxazin-2-one,
benzoxazin-2-thione, benzoxazin-2-ylidene cyanamide, benzothiazin-2-one,
benzothiazine-2-thione, benzothiazin-2-ylidene cyanamide compounds, or derivatives
thereof, are prepared according to the present invention.
In one embodiment, the present invention provides methods for purifying
compounds of formula I.
wherein, A and B are independently selected from H, Ci to C6 alkyl,
substituted Ci to Ce alkyl, C2 to Cs alkenyl, substituted C% to Cg alkenyl, C2 to Cg
alkynyl, substituted C2 to Q alkynyl, C3 to Cs cycloalkyl, substituted C3 to Cg
cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or
NRBCORA. Alternatively, A and B are joined to form a ring including (i) a
carbon-based 3 to 8 membered saturated spirocyclic ring; (ii) a carbon-based 3 to 8
membered spirocyclic ring containing in its backbone one or more carbon-carbon
double bonds; or (iii) a 3 to 8 membered heterocyclic ring containing in its backbone
one to three heteroatoms selected from the group consisting of 0, S and N. The rings
are optionally substituted by from 1 to 4 groups independently selected from among
fluorine, Ci to C6 alkyl, Ci to C6 alkoxy, Ci to C6 thioalkyl, CF3j OH, CN, NH2,
NH(Ci to C& alkyl), or N(Ci to Cg alkyl)?.. In one embodiment, A and B are Ci to C alkyl or are fused to form a carbon-based saturated spirocyclic ring. RA is selected
from among H, Ci to C3 alkyl, substituted Q to C3 alkyl, aryl, substituted aryl, Ci to
C3 alkoxy, substituted Ci to C3 alkoxy, amino, C\ to C3 aminoalkyl, or substituted Ci
to C3 aminoalkyl. RB is selected from among H, Ci to C3 alkyl, or substituted Ci to
C3 alkyl. T is selected from among O, S, or is absent and Q is selected from among
0,S,orNR3. R3 may be an electron withdrawing group. In one embodiment, R3 is
selected from among Ci to Cg alkyl, substituted Ci to Cq alkyl, aryl, substituted aryl,
CN, C(0)R4, SO2R4, SCN, OR4, SR4, C(0)OR4, C(S)OR4, C(0)SR4, or C(S)SR4 and
R4 is selected from among C\ to Ce alkyl, substituted Ci to Q alkyl, aryl, or
substituted aryl. In another embodiment, R3 is CN.
R1 is located at any position on the ring. In one embodiment, R1 is halogen.
In another embodiment, the halogen is bromine. In still another embodiment, R1 is
selected from among a substituted benzene ring containing the substituents X, Y and
Z as shown below:
wherein, X is selected from among H, halogen, CN, Ci to C3 alkyl, substituted
Ci to C3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Q to C3
alkoxy, substituted Ci to C3 alkoxy, Ci to C3 thioalkoxy, substituted Ci to C3
thioalkoxy, amino, d to C3 aminoalkyl, substituted Ci to C3 aminoalkyl, N02, Ci to
C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3
heteroatoms, S02NH2, C0Rc, OCORc, or NRDCORc; Rc is selected from among H,
Ci to C3 alkyl, substituted Ci to C3 alkyl, aryl, substituted aryl, d to C3 alkoxy,
substituted Ci to C3 alkoxy, Ci to C3 aminoalkyl, or substituted Cj to C3 aminoalkyl;
RD is selected from among H, Ci to C3 alkyl, or substituted d to C3 alkyl; and Y and
Z are independently selected from among H, halogen, CN, NO2, amino, aminoalkyl,
C\ to C3 alkoxy, Ci to C3 alkyl, or Ci to C3 thioalkoxy.
In another embodiment, R1 is a five or six membered heterocyclic ring
comprising 1, 2, or 3 heteroatoms or heteroatom containing groups including 0, S,
SO, SO2 or NR2 and containing one or two substituents independently selected from
among H, halogen, CN, NO2, amino, Ci to C3 alkyl, Ci to C3 alkoxy, Ci to C3
aminoalkyl, S02NH2, CORE, or MRFC0RE; RE is selected from among H, Q to C3
alkyl, substituted Ci to C3 alkyl, aryl, substituted aryl, Q to C3 alkoxy, substituted Ci
to C3 alkoxy, Ci to C3 aminoalkyl, or substituted Ci to C3 aminoalkyl; and RF is
selected from among H, Ci to C3 alkyl, or substituted Ci to C3 alkyl. R2 is absent or
selected from among H, O, or Ci to C4 alkyl. In one embodiment, R1 is a pyrrole ring,
or a pyrrole ring having a cyano substituent
In another embodiment, the following compounds are purified according to
the present invention, where A, B, and Rl are as defined above.
In a farther embodiment, the following compounds are purified according to
the present invention.
In one embodiment, the compounds produced according to the methods
described in US Patent Nos. 6,509,334; 6,566,358; 6,391,907; 6,608,068; 6,466,648;
6,521,657; 6,583,145; 6,436,929; 6,407,101; 6,562,857; 5,171,851; and 5,874,430;
and Singh (J. Med. Chem., 37:248-254 (1994)) are purified according to the method
of the invention.
The compounds of the invention are treated with a base in the presence of a
purifying solvent to form a basic salt. One of skill in the art would readily be able to
select a suitable base according to its basicity and the compound being purified. A
number of bases can be used according to the present invention and include
hydroxides, alkoxides, amines, amidines, ketones, and amino acids such as arginine,
lysine, and betaine, among others. Hydroxides can include, without limitation, 2-
hydroxy-N,N,N4rimethylethatninium hydroxide (choline hydroxide), sodium
hydroxide, potassium hydroxide, lithium hydroxide, zinc hydroxide, calcium
hydroxide, and magnesium hydroxide. Alkoxides can include, without limitation,
potassium, sodium, and lithium, alkoxides such as potassium tert-butoxide, sodium
tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-
pentoxide, and potassium tert-pentoxide. Amines can include dimethylamine,
diethylamine, piperidine, ethylenediamine, ethanolamine, diethanolamine,
triethanolamine, lysine, arginine, morpholine, and tris(hydroxymethyl)aminomethane,
among others. In one embodiment, the amine is diethylamine. Amidines can include
tetramethylguanidine, diazabicycloundecene, or diazabicyclononene, among others.
Ketones can include lower ketones, e.g., of 2 to 7 carbon atoms such as acetone and
methyl ethyl ketone.
The inventors have found that when combined with the crude parent
compound, diethylamine forms a complex as shown in Scheme 2.
Typically, a molar ratio of 1:1 to 3:1, or greater, base to the crude form of the
compound of the invention is utilized. "Where desired, the molar ratio is at least about
1.5:1, at least about 2:1, or at least about 3:1. The base can also serve as the solvent
for the purification. One of skill in art would readily be able to determine the amount
of base required to form the basic salt.
Several purifying solvents can be utilized to form the basic salt and include
alcohols, including lower alcohols such as methanol (MeOH), ethanol (EtOH), and
isopropanol ('PrOH), ethers such as tetrahydrofuran (THF) and 1,2-dimethoxyethane
PME), dimethylsulfoxide (DMSO), dimethylformarnide (DMF), N,N-
dimethylacetamide, N-methylpyrrolidone, drmethylpyrimidone, or combinations
thereof, among others. In one embodiment, the purifying solvent is an alcohol,
including a lower alcohol e.g. of 1 to 6 carbon atoms such as methanol (MeOH),
ethanol (EtOH), and isopropanol ('PrOH), an ether such as tetrahydrofuran (THF).
1,2-dimethoxyethane (DME), or combinations thereof. Water, alone or combined
with water-soluble solvents such as alcohols, acetone, or THF; and aqueous solutions
of hydroxide salts such as sodium hydroxide, can also be utilized as the solvent. As
noted above, the solvent can also be the base utilized to form the basic salt and
includes diethylamine, amidine bases, and dimethylamine, optionally under pressure.
In a further embodiment, a purifying solvent is selected from among MeOH, THF,
and combinations thereof. However, one of skill in the art would readily be able to
select a suitable purifying solvent or mixture containing purifying solvent depending
on the compound to be purified.
The amount of solvent utilized depends upon the scale of the reaction, i.e., the
amount of reagents utilized. One of skill in the art would readily be able to determine
the amount of solvent required to purify the indolone, indol-thione, indol-ylidene
cyanamide, benzoxazin-one, benzoxazin-thione, benzoxazin-ylidene cyanamide,
benzothiazinone, benzothiazine-thione, benzothiazin-ylidene cyanamide compounds,
or derivatives thereof.-
The basic salts prepared according to the invention can be soluble in the
purifying solvent. Any solids can be removed, including unwanted materials that are
still present in the purifying solvent after conversion to the soluble basic salt. For
example, solid residual heavy metals such as palladium, solid inorganic compounds,
and solid organic compounds can be present as impurities and may be removed.
Alternatively, the basic salts of the invention may be insoluble in the purifying
solvent. If insoluble, the filtrate lacking the basic salt, but containing any impurities,
can then be discarded and the basic salt collected using techniques known to those of
skill in the art and thereafter utilized in further reactions or for other purposes. For
example, basic salts with more favorable physical properties than the neutral purified
compounds can be utilized as pharmaceutical entities for administration to a patient.
In one embodiment, solid materials present in a solution, including the
insoluble basic salts of the invention or insoluble rmpurities. can be isolated by
filtration. However, one of skill in the art would readily be able to utilize other
methods to isolate the solid materials and include, without limitation, centrifugation.
The present invention also provides for converting the basic salt to the purified
compound. Methods for converting the basic salt to the purified compound include
treatment of the basic salt with water, an acid, or by heat. In one embodiment, the
diethylamine basic salts are converted to the purified compound by heating a solution
of the same in the purifying solvent such as diethylamine and water.
For conversion of the basic salt that is soluble in the purifying solvent to the
purified compound, the purifying solvent containing the soluble basic salt can be
treated with water or an acid that neutralizes the basic salt and affects precipitation
thereof in the purifying solvent.
If the basic salt is isolated from the purifying solvent as a solid due to its
insolubility in the purifying solvent, the basic salt can be dissolved in a solubilizing
solvent and thereby precipitated from the solubilizing solvent using water, an acid, or
heat. A variety of solubilizing solvents can be used to dissolve basic salts that are not
soluble in the purifying solvents utilized to prepare the same. In one embodiment, the
solubilizing solvents are polar solvents and include, without limitation, acetone,
water, THF, diethylamine, lower alcohols as described above, or combinations
thereof. One of skill in the art would readily be able to select a solubilizing solvent
for use in dissolving the basic salt according to the present invention.
The temperatures utilized to convert the basic salt to the purified compound
must be low enough to avoid decomposition of the basic salt or purified compound
and can be readily determined by one of skill in the art. In one embodiment,
temperatures of less than the boiling point of the organic or solubilizing solvent are
utilized. In another embodiment, the temperature utilized is less than about 100°C.
Once converted to the purified compound, the precipitated purified compound
can be isolated using techniques known to those of skill in the art and include
filtration and centrifugation, among others.
The purified compound can then be farther purified using techniques known to
those of skill in the art and include chromatography, distillation, drying,
recrystallization, or combinations thereof. In one embodiment, the purified
compound can be recrystallized by dissolving the purified compound in a solubilizing
solvent as previously described using techniques known to those of skill in the art. In
a further embodiment, the purified compound is dissolved in a minimal amount of
solubilizing solvent as previously described, the volume of the solution concentrated
by removing some of the solubilizing solvent, and the temperature of the solution
cooled to promote precipitation of the twice-purified compound. One of skill in the
art would readily be able to determine the amount of solubilizing solvent required to
recrystallize the purified compound. The twice-purified precipitated compound can
then be isolated using techniques as previously discussed.
In another embodiment, the purified compound can be dried at atmospheric
pressure or under a vacuum. One of skill in the art would readily be able to select a
suitable vacuum to dry the purified compounds. Higher temperatures can also be
applied to the purified compound during drying to remove entrapped purifying
solvents or solubilizing solvents. Such temperatures can readily be selected by one of
skill in the art.
In one embodiment, the present invention therefore provides a method for
purifying a compound of formula I:

wherein, A and B are independently selected from the group consisting of H,
Ci to C alkenyl, C'2 to Ce alkynyl, substituted C2 to Cg alkynyl, C3 to Cg cycloalkyl, substituted
C3 to Cg cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic,
CORA, and NRBCORA. In another embodiment, A and B are joined to form a ring
comprising (i) a carbon-based 3 to 8 membered saturated spirocyclic ring; (ii) a
carbon-based 3 to 8 membered spirocyclic ring containing in its backbone one or
more carbon-carbon double bonds; or (iii) a 3 to 8 membered heterocyclic ring
containing in its backbone one to three atoms selected from the group
consisting of O, S and N, where the rings of (i), (ii) and (iii) are optionally substituted
by from 1 to 4 groups selected from the group consisting of fluorine, Ci to Cg alkyl,
Ci to C6 alkoxy, d to C6 thioalkyl, CF3, OH, CN, NH2, NH(Ci to C6 alkyl), and N(Ci
to C6 alkyl)2- RA is selected from the group consisting of H, C\ to C3 alkyl, substituted
C\ to C3 alkyl, aryl, substituted aryl, Ci to C3 alkoxy, substituted Ci to C3 alkoxy,
amino, Q to C3 aminoalkyl, and substituted Ci to C3 aminoalkyl. RB is H, Ci to C3
alkyl, or substituted Ci to C3 alkyl. T is O, S, or absent. Q is O, S, or NR3. R3 is
selected from among Q to C& alkyl, substituted Cj to C& alkyl, aryl, substituted aryl,
CN, C(0)R4, S02R4, SCN, OR4, SR4, C(0)OR4, C(S)OR4, C(0)SR4, or C(S)SR4. R1
can be halogen. R1 can also be a substituted benzene ring containing the substituents
X, Y and Z as shown below:
wherein, X is selected from the group consisting of H, halogen, CN, Ci to C3
alkyl, substituted Ci to C3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, Ci to C3 alkoxy, substituted Ci to C3 alkoxy, Ci to C3 thioalkoxy, substituted
Ci to C3 thioalkoxy, amino, Ci to C3 aminoalkyl, substituted C\ to C3 aminoalkyl,
N02, Ci to C3 perfluoroaikyl, 5 or 6 membered heterocyclic ring containing in its
backbone 1 to 3 heteroatoms, S02NH2, CORc, OCORc, and NRDCORc. RC is H, Q
to C3 alkyl, substituted Ci to C3 alkyl, aryl, substituted aryl, Ci to C3 alkoxy,
substituted Ci to C3 alkoxy, Ci to C3 aminoalkyl, or substituted Ci to C3 aminoalkyl.
RD is H, Ci to C3 alkyl, or substituted Ci to C3 alkyl. Y and Z are independently
selected from the group consisting of H, halogen, CN, N02, amino, aminoalkyl, Ci to
C3 alkoxy, C\ to C3 alkyl, and Ci to C3 thioalkoxy'. In another embodiment, R1 is a
five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from
the group consisting of O, S, SO, S02 and NR2 and containing one or two substituents
independently selected from the group consisting of H, halogen, CN, N02, amino, Q
to C3 alkyl, C\ to C3 alkoxy, Ci to C3 aminoalkyl, S02NH2, CORE, and NRFCORE. RE
is H, Ci to C3 alkyl, substituted Ci to C3 alkyl, aryl, substituted aryl, C\ to C3 alkoxy,
substituted Ci to C3 alkoxy, Ci to C3 aminoalkyl, or substituted Ci to C3 aminoalkyl.
RF is H, Ci to C3 alkyl, or substituted Ci to C3 alkyl. R2 is H, absent, O, or Ci to C4
alkyl. The method includes treating the compound of formula I with a base to form a
basic salt; and converting the basic salt to a purified compound of formula I.
la another embodiment, the present invention also provides a method for
purifying a compound of formula I:

wherein, A and B are independently selected from the group consisting of H,
Ci to Ce alkyl, substituted d to C$ alkyl, C2 to Cq alkenyl, substituted C2 to C6
alkenyl, C2 to C& alkynyl, substituted C2 to Cg alkynyl, C3 to Cg cycloalkyl, substituted
C3 tc C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic,
CORA, and NRBCORA. In another embodiment, A and B are joined to form a ring
comprising (i) a carbon-based 3 to 8 membered saturated spirocyclic ring; (ii) a
carbon-based 3 to 8 membered spirocyclic ring containing in its backbone one or
more carbon-carbon double bonds; or (iii) a 3 to 8 membered heterocyclic ring
containing in its backbone one to three heteroatoms selected from the group
consisting of 0, S andN, where the rings of (i), (ii) and (iii) are optionally substituted
by from 1 to 4 groups selected from the group consisting of fluorine, Ci to Ce alkyl,
Ci to C6 alkoxy, Ci to C6 thioalkyl, CF3, OH, CN, NH2, NH(d to C6 alkyl), and N(Ci
to Cg alkyf)2. R is selected from the group consisting of H, Ci to C3 alkyl, substituted
C\ to C3 alkyl, aryl, substituted aryl, Ci to C3 alkoxy, substituted Q to C3 alkoxy,
amino, Ci to C3 aminoalkyl, and substituted Ci to C3 aminoalkyl. RB is H, Ci to C3
alkyl, or substituted d to C3 alkyl. T is 0, S, or absent. Q is O, S, or NR3. R3 is
selected from among Q to C6 alkyl, substituted Q to Ce alkyl, aryl, substituted aryl,
CN, C(0)R4, S02R4, SCN, OR4, SR4, C(0)OR4, C(S)OR4, C(0)SR4, or C(S)SR4. In
another embodiment, R1 is halogen. In still another embodiment, R1 is a substituted
benzene ring containing the substituents X, Y and Z as shown below:

wherein, X is selected from the group consisting of H, halogen, CN, Ci to C3
alkyl, substituted Ci to C3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, Ci to C3 alkoxy, substituted Ci to C3 alkoxy, C\ to C3 thioalkoxy, substituted
Ci to C3 thioalkoxy, amino, Q to C3 aminoall NO2, Ci to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its
backbone 1 to 3 heteroatoms, SQ2NH2, CORc, OCORc, andNRDCORc. Rc is H, Ci
to C3 alkyl, substituted C\ to C3 alkyl, aryl, substituted aryl, Ci to C3 alkoxy,
substituted Ci to C3 alkoxy, Q to C3 aminoalkyl, or substituted Ci to C3 aminoalkyl.
RD is H, Ci to C3 alkyl, or substituted Cj to C3 alkyl. Y and Z are independently
selected from the group consisting of H, halogen, CN, NO2, amino, aminoalkyl, Ci to
C3 alkoxy, Q to C3 alkyl, and Ci to C3 thioalkoxy. In another embodiment, Rl is a
five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from
the group consisting of O, S, SO, SO2 andNR2 and containing one or two substituents
independently selected from the group consisting of H, halogen, CN, NO2, amino, Ci
to C3 alkyl, Ci to C3 alkoxy, Q to C3 aminoalkyl, S02NH2, CORE, and NRFCORE. RE
is H, Ci to C3 alkyl, substituted d to C3 alkyl, aryl, substituted aryl, Ci to C3 alkoxy,
substituted C\ to C3 alkoxy, Ci to C3 aminoalkyl, or substituted Ci to C3 aminoalkyl.
RF is H, Ci to C3 alkyl, or substituted C\ to C3 allcyl. R2 is H, absent, O, or Ci to C4
alkyl. The method includes mixing the compound of formula I and a solvent; adding
a base to the solvent; and precipitating purified, compound of formula I using an agent
selected from the group consisting of an acid, water, or heat.
III. Methods of Using the Purified Compounds of the Invention
The purified compounds of this invention are useful as progesterone receptor
modulators, including antagonists and agonists. In one embodiment, the purified
compounds of this invention can act as competitive inhibitors of progesterone binding
to the PR and therefore act as agonists in functional models, either/or in vitro and in
vivo.
The purified compounds are therefore useful as oral contraceptives in both
males and females. The purified compounds are also useful in hormone replacement
therapy. The purified compounds are further useful in the treatment of endometriosis,
luteal phase defects, hormone-dependent neoplastic disease, the synchronization of
estrus, and benign breast and prostatic diseases. The hormone-dependent neoplastic
disease can include uterine myometrial fibroids, endometriosis, benign prostatic
hypertrophy, carcinomas and adenocarcinomas of the endometrium, ovary, breast,
colon, prostate, pituitary, uterine, and meningioma. The purified compounds are also
useful in treating hirsutism or acne.
In one embodiment, the purified compounds of this invention are used alone
as a sole therapeutic agent. In other embodiments, the purified compounds of this
invention are used in combination with other agents, such as estrogens, progestins,
estrones, or androgens.
The purified compounds of the present invention encompass tautomeric forms
of the structures provided herein characterized by the bioactivity of the drawn
structures. Further, the purified compounds of the present invention can be used in
the form of pharmaceutically acceptable salts derived from pharmaceutically or
physiologically acceptable acids, bases, alkali metals and alkaline earth metals.
Physiologically acceptable acids include those derived from inorganic and
organic acids. A number of inorganic acids are known in the art and include
hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, and phosphoric acids, among
others. Similarly, a variety of organic acids are known in the art and include, without
limitation, lactic, formic, acetic, fumaric, citric, propionic, oxalic, succinic, glycolic,
glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, tartaric, malonic,
mallic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,
panthenoic, benzenesulfonic, toluenesulfonic, stearic, sulfanilic, alginic, and
galacturonic acids, among others.
Physiologically acceptable bases include those derived from inorganic and
organic bases. A number of inorganic bases are known in the art and include
aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc sulfate or
phosphate compounds, among others. A number of organic bases are known in the art
and include, without limitation, N,N,-diben2ylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine, and procaine, among others.
Physiologically acceptable alkali salts and alkaline earth metal salts can
include, without limitation, sodium, potassium, calcium and magnesium salts in the
form of esters, and carbamates. Other conventional "pro-drug" forms can also he
utilized which, when delivered in such form, convert to the active moiety in vivo.
These salts, as well as other purified compounds of the invention can be 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. In a currently
preferred embodiment, the prodrugs are esters. See, e.g., B. Testa and J. Caldwell,
"Prodrugs Revisited: The "Ad Hoc" Approach as a Complement to Ligand Design",
Medicinal Research Reviews, 16(3):233-241, ed., John Wiley & Sons (1996).
The purified compounds discussed herein also encompass "metabolites" which
are unique products formed by processing the compounds of the invention by the cell
or patient. In one embodiment, the metabolites are formed in vivo.
In one embodiment, the purified compounds of this invention are formulated
neat. Ill other embodiments, the purified compounds of the invention are formulated
with a pharmaceutical carrier for administration, tire proportion of which is
determined by the solubility and chemical nature of the compound, chosen route of
administration and standard pharmacological practice. The pharmaceutical carrier
may he solid or liquid.
A solid carrier can include one or more substances which may also act as
flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents; it can also be an
encapsulating material.. In powders, the carrier is a finely divided solid which is in
admixture with the finely divided active ingredient. In tablets, the active ingredient is •
mixed with a carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The powders and tablets
may contain up to 99% of the active ingredient. Suitable solid carriers include, for
example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,
gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions,
syrups, elixirs and pressurized compositions. The active ingredient can be dissolved
or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic
solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid
carrier can contain other suitable pharmaceutical additives such as solubilizers,
emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents,
thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
Suitable examples of liquid carriers for oral and parenteral administration include
water (partially containing additives as above, e.g. cellulose derivatives, such as
sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols
and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g.
fractionated coconut oil and arachis oil). For parenteral administration, the carrier can
also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid
carriers are useful in sterile liquid form compositions for parenteral administration.
The liquid carrier for pressurized compositions can be halogenated hydrocarbon or
other pharmaceutically acceptable propellant
The purified compounds of the invention can be delivered by a route such as
oral, dermal, transdermal, intrabronchial, intranasal, intravenous, intramuscular,
subcutaneous, parenteral, intraperitoneal, intranasal, vaginal, rectal, sublingual,
intracranial, epidural, intratracheal, or by sustained release. In one embodiment,
delivery is oral or transdermal.
In another embodiment, the compositions are delivered orally by tablet,
capsule, microcapsules, dispersible powder, granule, suspension, syrup, elixir, and
aerosol. In one embodiment, when the compositions are delivered orally, delivery is
by tablets and hard- or liquid-filled capsules.
In yet another embodiment, the compositions are delivered intravenously,
intramuscularly, subcutaneously, parenterally and intraperitoneally in the form of
sterile injectable solutions, suspensions, dispersions, and powders which are fluid to
the extent that easy syringe ability exists, Such injectable compositions are sterile,
stable under conditions of manufacture and storage, and free of the contaminating
action of microorganisms such as bacteria and fungi.
Injectable formations can be prepared by combining the compositions with a
liquid. The liquid can be selected from among water, glycerol, ethanol, propylene
glycol and polyethylene glycol, oils, and mixtures thereof. In one embodiment, the
liquid carrier is water. In another embodiment, the oil is vegetable oil. Optionally,
the liquid carrier contains about a suspending agent. In another embodiment, the
liquid carrier is an isotonic medium and. contains about 0.05 to about 5% suspending
agent.
In a further embodiment, the compositions are delivered rectally in the form of
a conventional suppository.
In another embodiment, the compositions are delivered vaginally in the form
of a conventional suppository, cream, gel, ring, or coated intrauterine device (IUD).
In yet another embodiment, the compositions are delivered intranasally or
intrabronchially in the form of an aerosol.
In a further embodiment, the compositions are delivered transdermally or by
sustained release through the use of a transdermal patch containing the composition
and an optional carrier that is inert to the corrrpound(s), is nontoxic to the skin, and
allows for delivery of the purified compound(s)vfor systemic absorption into the blood
stream. Such a carrier can be a cream, ointment, paste, gel, or occlusive device. The
creams and ointments can be viscous liquid or semisolid emulsions. Pastes can
include absorptive powders dispersed in petroleum or hydrophilic petroleum. Further,
a variety of occlusive devices can be utilized to release the active reagents into the
blood stream and include semi-permeable membranes covering a reservoir contain the
active reagents, or a matrix containing the reactive reagents.
In one embodiment, sustained delivery devices are utilized in order to avoid
the necessity for the patient to take medications on a daily basis. The term "sustained
delivery" is used herein to refer to delaying the release of an active agent, i.e.,
compositions of the invention, until after placement in a delivery environment,
followed by a sustained release of the agent at a later time. A number of sustained
delivery devices are known in the art and include hydrogels (US Patent Nos.
5,266,325; 4,959,217; 5,292,515), osmotic pumps (US Patent Nos. 4,295,987 and
5,273,752 and European Patent No. 314,206, among others); hydrophobic membrane
materials, such as ethylenemethacrylate (BMA) and ethylenevinylacetate (EVA);
bioresorbable polymer systems (International Patent Publication No. WO 98/44964
and US Patent Nos. 5,756,127 and 5,854,388); and other bioresorbable implant
devices composed of, for example, polyesters, polyanhydrides, or lactic acid/glycolic
acid copolymers (US Patent No. 5,817,343). For use in such sustained delivery
devices, the compositions of the invention can be formulated as described herein.
See, US Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719.
The dosage requirements vary with the particular compositions employed, the
route of administration, the severity of the symptoms presented and the particular
subject being treated. Based on the results obtained in the standard pharmacological
test procedures, projected daily dosages of active compound would be about 0.1 to
about 500 mg/kg, about 1 to about 100 mg/kg, about 2 to about 80 mg/kg, about 5 to
about 50 mg/kg, or about 5 to about 25 rng/kg. Treatment will generally be initiated
with small dosages less than the optimum dose of the purified compound. Thereafter
the dosage is increased until the optimum effect under the circumstances is reached.
Advantageously, particularly potent PR modulators (e.g., those of formula I)
may be useful at the lower end of the dosage ranges provided herein. The dosage
regimen may however be adjusted to provide the optimal therapeutic response. For
example, several divided doses (e.g., in divided doses 2 to 4 times a day) maybe
administered daily or the dose maybe proportionally reduced as indicated by the
exigencies of the therapeutic situation. Alternatively, a single dose can be delivered.
In certain embodiments, the delivery can be on a daily, weekly, or monthly basis. In
one embodiment, delivery is on a daily basis. Daily dosages can be lowered or raised
based on the periodic delivery.
Precise dosages for oral, parenteral, nasal, or intrabronchial administration can
be determined by the administering physician based on experience with the individual
subject treated. In one embodiment, the pharmaceutical composition is in unit dosage
form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit
dose containing appropriate quantities of the active ingredient; the unit dosage forms
can be packaged compositions, for example, packaged powders, vials, ampoules, pre
filled syringes or sachets containing liquids. The unit dosage form can be, for
IV. Pharmaceutical Kits
The present invention provides kits or packages of pharmaceutical
formulations including the purified compounds of formula I described herein. When
the purified compounds of formula I are to be delivered continuously, a package or kit
can include the purified compound in each tablet. When the purified compound is to
be delivered with periodic discontinuation, a package or kit can include placebos on
those days when the purified compound is not delivered.
In one embodiment, the kits are also organized to indicate a single oral
formulation or combination of oral formulations to be taken on each day of the cycle.
In a further embodiment the kits include oral tablets to be taken on each of the days
specified. In still another embodiment, one oral tablet will contain each of the
combined daily dosages indicated.
Similarly, other kits of the type described above may be prepared in which a
purified compound of formula I is delivered. In one embodiment, the daily dosage of
the purified compound of formula I remains fixed in each particular phase in which it
is delivered. In a further embodiment, the daily dose units described are to be
delivered in the order described, with the first phase followed in order by the second
and third phases. In yet another embodiment, the kits contain the placebo described
for the final days of the cycle to help facilitate compliance with each regimen.
A number of packages or Idts are known in the art for the use in dispensing
pharmaceutical agents for oral use. In one embodiment, the package has indicators
for each day, and may be a labeled blister package, dial dispenser package, or bottle.
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, modific^ons can bemade which are meant to be encompassed by the spirit and scope of tie invention.
EXAMPLES
EXAMPLE 1 - PURIFICATION OF 5~(4,4-DIMETHYL-2-THIOXO-1,4-
DIHYDRO-2H-3,1-BENZOXA2lN-6-YL)-1-METHYL-1H-PYRROLE-2-
CARBONI'TRILE
A slurry of potassium tert-butoxide (126 g) in THF was added to a crude 5-
(4,4-dimethyl-2-tMoxo-l/-dihydro-2H-3,l-benzoxaziii-6-yl)-l-metliyl-lH-pyn:ole-2-
carbonitrile (171 g; purity 75% HPLC area) dissolved in THF (0.50 L) and cooled to
15°C. More THF (0.25 L) was added and the suspension was stirred for 1 hour,
filtered on a Buchner funnel and rinsed with THF (0.50 L). After drying the cake
overnight, it was dissolved in a 1:1 acetone:water mixture (0.70 L) at about 5 °C (pH
of about 13 to about 14). A 10% aqueous HC1 solution (0.35 L) was added dropwise
while maintaining the temperature (pH about 3 to about 4). After stiixing the
suspension for 30 minutes, the stirred suspension was filtered on a Buchner funnel.
The cake from the Buchner funnel was washed with water (0.15 and 0.25 L) and dried
under vacuum to give the purified product (90.0 g) as a yellow solid (purity >99%
HPLC area).
EXAMPLE 2 - PURIFICATION OF 5-(4,4-DIMETHYL-2-THlOXO-1,4-
DIHYDRO-2H-3,1-BENZOXAZIN-6-YL)-1-METHYL-1H-PYRROLE-2-
CARBONITRILE
Crude 5-(4,4-dimethyl-2-thioxo-l,4-dihydro-2H-3,l-benzoxazin-6-yl)-l-
methyl-lH-pyrrole-2-carbonitrile (10.0 g), containing 16% of an impurity, was
suspended in MeOH (25 mL) followed by addition of potassium tert-butoxide (4.48
g). The suspension was stirred at 65°C until a clear solution was obtained. Upon
cooling to about 5°C, a 4M HC1 solution in dioxane (12 mL) was added dropwise.
The yellow precipitate was filtered and washed with a 1:1 acetone:water mixture.
RecrystaEization from an acetonerwater mixture yielded 5.4 g of the product
containing only 0.5% of the impurity.
EXAMPLE 3 - PURIFICATION OF 5-(4,4-DIMETHYL-2-THIOXO-1,4-
DIHYDRO-2H-3,1-BENZOXAZIN-6-YL)-1-METHYL-1H-PYRROLE-2-
CARBONITRILE
Crude 5-(454-dimethyl-2-thioxo-l,4-dih.ydro-2H-3,l-benzoxazm-6-yl)-l-
methyHH~pyrrole-2-cait>onitrile (10.8 g) was stirred in a 1M aqueous NaOH solution
(92 mL) for 1 hour. The insoluble material was removed by filtration and the filtrate
was slowly added to a solution of MeOH (92 mL) containing acetic acid (5.64 g).
The crystalline product was collected via filtration and dried under vacuum at about
50 °C to give 6.95 g (65% yield; purity 96.0% HPLC area).
EXAMPLE 4 - PURIFICATION OF 5-(4,4-DlMETHYL-2-OXO-1,4-DlHYDRO-
2H-3(1-BEN20XAZIN-6-YL)-1-METHYL-1H-PYRROLE-2-CARBONITRILE
SODIUM SALT
A suspension of 5-(4,4-dimethyl»2-oxo-l,4-dihydro-2H-3,l-beiizoxazin-6-yl)-
l-methyl-lH-pyrrole-2-carbonitrile in MeOH or THF, gave solutions upon addition of
potassium tert-butoxide, tetra'methylguanidine or diazabicycloundecene. The solution
in diazabicycloundecene gave the lightest-colored solution. Precipitation of the
purified product occurred Upon acidification with a 5% aqueous HC1 solution.
Substitution of acetic acid for the HC1 solution did not result in precipitation
of the purified compound.
EXAMPLE 5 - PREPARATION OF 6-BROMO-4.4-DIMETHYL-
BENZOXAZINE-2-ONE SODIUM SALT
6-Bromo-4,4-diniethyl-benzoxazine~2--one (2.59 g) was dissolved in THF (50
mL) at ambient temperature followed by addition of sodium tert-butoxide (0.96 g).
The mixture was gently heated until a solution was obtained. The solution was
evaporated to give a white solid (2.86 g; quant, yield) that was soluble in N-
metliylpyrrolidone (NMP) and dimethyl pyrimidone (DMPU) heated to about 40 to
about 50°C. 'H-NMR (DMSO-dg) did not show a peak corresponding to a N-H group.
EXAMPLE 6 - PREPARATION OF 6-BROMO-4.4-DIMETHYL-
BENZOXAZINE-2-ONE LITHIUM SALT
Similarly, 6-bromo-4,4-dimethyl-benzoxazine-2-one (2.55 g) was reacted with
lithium tert-butoxide (10 mL of 1M solution in THF). After evaporation a brownish
solid was obtained (3.35 g; quant yield) that was soluble in dimethyl pyrimidone
(DMPU) without heating. JH NMR (DMSO-dg) did not show a peak corresponding to
a N-H group.
EXAMPLE 7- PREPARATION AND PURIFICATION OF 5-BROMO-
SPlRO[CYCLOHEXANE-1,3'-[3H]-INDOL]-2'(1 H)-ONE
5-Bromo-spiro[cyclohexane-l,3'-[3H]-indolJ-2'(lH)-one was prepared from
5-bromooxihdole (150 g) using 3 eq. of potassium tert-butoxide in THF at about 0 to
about 5°C. Upon completion of the reaction, the reaction mixture containing the
potassium salt was quenched with dilute HC1 (1 L) to a pH of about 1. The organic
layer was washed with brine and distilled to remove some THF. Distillation was
continued while acetonitrile was added. The precipitated product was filtered,
washed with acetonitrile and dried in a vacuum oven to give 5-bromo-
spiro[cyclohexane-l,3'-[3H]-indol]-2'(lH)-one (158 g; 80% yield; purity 98.1%
HPLC area).
EXAMPLE 8 - PREPARATION OF 5'~(5-CYANO-1-METHYL-1H-PYRROL-2-
YL)SPIRO[CYCLOHEXANE-1,3'~[3H3INDOL]-2'-YLIDENECYANAMIDE
CHOLINE SALT
5'-(5-Cyano-l-methyHH-pyrrol-2-yl)spiro[cyclohexane-l,3'-[3H]indol]-2'-
ylidenecyanamide (0.96 g) in ethanol (20 mL) was reacted with choline hydroxide
(0.91 g; 45% solution in methanol) to form, upon cooling, filtering and drying, 5'-(5-
cyano-l-methyl-lH-pyrrol-2-yl)spiro[cyclohexane-l,3'-[3H]indol]-2'-
ylidenecyanamide choline salt (0.88 g) as a solid.
The solubility of 5'-(5-cyano-l-methyl-lH-pyrrol-2-yl)spiro[cyclohexane-
1,3 '-[3H]indol]-2'-ylidenecyanamide choline salt in DMF was 11 mg/mL, while the
solubility of 5'-(5-Cyano-l-methyl-lH-pyrrol-2-yl)spiro[cyclohexane-l,3'-
[3H]indol]-2'-ylidenecyanamide was 3 mg/mL. Similarly, the melting point of 5'-(5-
cyano-l-methyl-lH-pyrrol-2-yl)spiro[cycIohexane-l,3'-[3H]indol]-2'-
ylidenecyanamide choline salt was 205.5°C, while the melting point of 5'-(5-Cyano-
1 -methyl-lH-pynx>l-2-yl)spiro[cyclohexane-l ,3 '-[3H]indol]-2'-ylidenecyanamide
was 270.5-273.5°C.
The choline salt had individual particles of about 5-30 pm. When the choline
salt was combined in water to form a slurry, the precipitated material of the parent
compound had particles of about 20-50 pun.
The ^-NMR data (DMSO-de) for the neutral compound (X=H) and salt
(X=choline) was obtained and is set forth below in Table 1.
Table 1
EXAMPLE 9 - PURIFICATION OF 5-(2'-TH!OXOSPIRO[CYCLOHEXANE-
1,3'-[3H]INDOL]-5'-YL)-1-METHYL-1 H-PYRROLE-2-CARBONITRlLE
5-(2'-Thioxospiro[cyclohexane-l,3'-[3H]indol]-5,-yl)-l-methyl-lH-pyrrole-2-
carbonitrile (12.3 g, 98.7% purity) was dissolved in boiling diethylamine (280 mL).
A portion of the solvent was distilled off and water (230 mL) was added to form a
suspension. The solids were removed via filtration, washed with water and dried at
47°C in vacuo to give 11.25 g (91.5% yield, 99.1% purity, 0.52% residual
diethylamine) of purified product.
EXAMPLE 10 - COMPARISON OF CHEMICAL SHIFTS OF 5'-(5-CYANO-1-
METHYL-1 H-PYRROL-2-YL)SPIRO[CYCLOHEXANE-1,3'-[3H]INDOL]-2'-
YLIDENECYANAMiDE AND SALTS THEREOF
5'-(5-Cyano-l-metlayl-lH-pyrrol-2--yl)spiro[cycloliexane-lJ3'-[3H]indol]-2'-
ylidenecyanamide (0.96 g) in ethanol (20 mL) was reacted with the bases set forth in
Table 2 to form, upon cooling, filtering and. drying, 5'-(5-cyano-l-methyl-lH-pyrrol-
2-yl)spiro[cyclohexane-l,3'-[3H]indol]-2'-ylidenecyanamide salt as a solid. The JH-
NMR spectra (DMSO-de) of the purified compound (X=H) and isolated salts (X=Na,
K, choline, and Et2NH-H) were obtained and the data compiled in Table 2.
This example illustrates that when diethylamine is utilized as the base, the
diethylamine salt produces peaks in the !H-1SIMR spectra that are not consistent with
the peaks for the neutral parent compound or the sodium, potassium, or choline salts.
Specifically, the peaks in the !H-MvlR spectrum for the diethylamine salt are at
chemical shifts between the neutral and sodium, potassium, or choline salts.
EXAMPLE 11 -PREPARATION OF 5~(2'-TH!OXOSP!RO[CYCLOHEXANE-
1,3'-[3H]INDOL]-5'-YL)-1-METHYL-1 H-PYRROLE-2-CARBONITRILE
SODIUM SALT
5-(2 '-Thioxospiro[cyclohexane-l ,3 '-[3H]indol] -5 '-yl)-l -methyl-1 H-pyrrole-2-
carbonitrile (0.72 g) was dissolved in TPIF (10 mL) at ambient temperature. One mL
of this solution was mixed with aqueous IN NaOH (0.22 mL). Evaporation and
trituration with heptane gave 5-(2'-thioxospiro[cyclohexane-l,3'-[3H]indol]-5'-yl)-l-
methyl-lH-pyrrole-2-cafbonitrile sodium salt as a solid (mp 83.4°C).
EXAMPLE 12 - PREPARATION OF 5-(2'-THIOXOSPIRO[CYCLOHEXANE-
1,343H]INDOL]5'-YL)-1-METHYL-1H-PYRROLE-2-CARBONITRILE
CHOLINE SALT
5-(2'-THoxospiro[cyclohexane-l:,3'-[3H]indol]-5'-yl)-l-methyl-lH-pyrrole-2-
carbonitrile (0.72 g) was dissolved in THF (10 mL) at ambient temperature. One mL
of this solution was mixed with aqueous IN choline hydroxide (62.1 mg, 45%
solution in MeOH). Evaporation and trituration with heptane gave 5-(2'-
thioxospiro[cyclohexane-l ,3 '-[3H]indol]-5 '-yl)-l -methyl- lH-pyrrole-2-carbonitrile
sodium salt as a solid (mp 159 °C).
EXAMPLE 13 - PREPARATION OF 5-(2'-THlOXOSPIRO[CYCLOHEXANE-
1,3'-[3H]lNDOL]5'-YL)-1-METHYL-1 H-PYRROLE-2-CARBONITRILE
POTASSIUM SALT-
(i) Procedure A
5-(25-Thioxospiro[cyclohexane-l,3'-[3H]indol]-5'-yl)-l-methyl-lH-
pyrrole-2-earbonitrile (0.72 g) was dissolved in THF (10 mL) at ambient temperature.
One mL of this solution was mixed with potassium tert-butoxide (25.3 mg).
Evaporation and trituration with heptane gave 5-(2'-tliioxospiro[cyclohexane-l ,3 '-
[3H]indol]-5'-yl)-l-methyl-lH-pyrrole-2-carbonitrile sodium salt as a solid (mp 79.2
°C).
(ii) Procedure B
5-(2'-Thioxospiro[cyclohexane-l!3'-[3H]indol]-5'-yl)-l-methyl-lH-
pyrrole-2-carbonitrile (0.163 g) was suspended in acetone (3 mL). Anhydrous 325
mesh potassium carbonate (0.726 g) was added and the mixture was stirred under
nitrogen overnight. The stirred mixture was filtered, washed with acetone (5 mL) and
the filtrate evaporated to give 5-(2'-thioxospiro[cyclohexane-l,3'-[3H]indol]-5'-yl)-l-
methyl-lH-pyrrole-2-carbonirrile potassium salt (0.185 g) as a solid. 'H-NMR
(DMSO-d6, ppm): (absent N-H), 7.64, 7.25, 7.05, 7.0, 6.27, 3.72, 2.1-1.65, and 1.1-
1.0.
EXAMPLE 14 - PURIFICATION OF 5-(2'-THIOXOSPIRO[CYCLOHEXANE-
1,3'-[3H]INDOL3-5'-YL)-1-METHYL-1H-PYRROLE-2-CARBONITRILE VIA ITS
SODIUM SALT
Crude 5-(2'-tlaioxospiro[cyclohexane-l,3'-[3HJindol]-5'-yl)-l-methyl»lH-
pyrrole-2-carbonitrile (1.0 g, purity 97.3% HPLC area) was suspended in acetone (6.6
mL) and water (2 mL). Sodium hydroxide (0.33 g, 50% solution in water) was added
and the mixture was warmed to 32-35 °C for 15 min. The warmed solution was
filtered, diluted with water (2 mL) and cooled to 5-10 °C. The cooled solution was
then neutralized with aqueous HC1 to a pH of 5-7, stirred for 30 minutes, filtered and
washed with a mixture of acetone-water (1:1) to give purified 5-(2 '-
thioxospiro[cyclohexane-l,3'-[3H]indol]-5'-yl)-l-methyl-lH-pyrrole-2-carbonitrile
(0.97 g, purity 98.7% HPLC area). JHNMR (DMSO-d6, ppm): 12.75 (N-H), 7.82,
7.44,7.15, 7.04, 6.35, 3.72, 2.0-1.7, and 1.4-1.3.
EXAMPLE 15 - PURIFICATION OF 5-(2'-THIOXOSPIRO[CYCLOHEXANE-
1,3'-[3H3INDOL]-5'-YL)-1-METHYL-1H-PYRROLE-2-CARBONlTRILE VIA ITS
CESIUM SALT
5-(2'-Thioxospiro[cyclohexane-i,3'-[3H]indol]-5'-yl)-l-methyl-lH-pyrrole-2-
carbonitrile (0.204 g, 96.8% HPLC area) was heated to reflux with cesium carbonate
(0.419 g) in ethanol SDA3 (5 mL) to form a clear solution. Water (5 mL) was added,
followed by concentrated HC1 (0.3 mL) to a pH of 6. The obtained solids were
filtered, washed with water (3 mL) and dried to give purified 5-(2'-
thioxospiro [cyclohexane-1,3' -[3H]indol]-5' -yl) -1 -methyl-1 H-pyrrole-2-carbonitrile
(0.176 g, 99.0% HPLC area).
EXAMPLE 16 - PURIFICATION OF 5'-(5-CYANO-1-METHYL-1 H-PYRROL-
2-YL)SPIRO[CYCLOHEXANE-1,3'-[3H]INDOL]-2'-YLIDENECYANAMIDE
- VIA ITS POTASSIUM SALT
Crude 5'-(5-cyano-l-methyl-lH--pyirol-2-yl)spiro[cyclohexane-ls3'-
[3H]indol]-2'-ylidenecyanamide (2.7 g; purity 90% HPLC area) was dissolved in
. DMSO (11 mL) at 60-70°C, followed by addition of isopropanol (30 mL). After
cooling the suspension to 10°C, the cooled suspension was filtered and washed with
isopropanol. The resultant wet cake containing residual DMSO was suspended in
isopropanol (10 mL) and potassium tert-butoxide (1.9 g) was added. The resultant
clear solution was cooled to 5-15°C and acidified with 10% HC1 to a pH of 3-4 to
form a suspension. The suspension was filtered and washed with water until a sample
of the filtrate was found to be neutral according to pH. The obtaining solids were
dried in vacuo to give purified 5'-(5-cyano-l-methyl-lH-pyrrol-2-
yl)spiro[cyclohexane-l,3'-[3H]indol]-2'-ylidenecyanamide (1.8 g, 67% yield based
on the crude; purity 98.9% HPLC area; DMSO 0.008%).
EXAMPLE 17 - DEPLETION OF RESIDUAL PALLADIUM FROM 5'-(5-
CYANO-1-METHYL-1 H-PYRROL-2-YL)SPIRO[CYCLOHEXANE-1,3'-
[3H]iNDOL]-2'-YLIDENECYANAMIDE VIA ITS POTASSIUM SALT
Crude 5'-(5-cyano-l-methyl-lH-pyrrol-2-yl)spiro[cyclohexane-l,3'-
[3H]indol]-2'-ylidenecyanamide (1.0 g) containing residual Pd (5100 ppm) was
.suspended in THF (5 mL). Upon addition of aqueous 1M KOH (5 mL), a clear
orange solution was obtained. N-Acetylcysteine (1.3 g) was added, the mixture was
stirred for 1 hour, and filtered. Ten percent aqueous HC1 (3 mL) was added dropwise
to the filtrate causing precipitation of a white solid. The solution was filtered, the
solid washed with methanol, and the washed solid dried to give 5'-(5-cyano-l-methyl-
lH-pyrrol-2-yl)spiro[cyclohexane-l,3'-[3H]indol])-2'-ylidenecyanamide (0.6 g; 60%
yield; 96 ppm Pd).
EXAMPLE 18 - PREPARATION OF 5'-(5-CYANO-1-METHYL-1H-PYRROL-
2-YL)SPIRO[CYCLOHEXANE-1,3'-[3H]INDOL]-2'-YLIDENECYANAMIDE
DIETHYLAMINE SALT/COMPLEX
5' ylidenecyanamide (16 g) in THF (100 mL) was treated with, diethylamine (37 g) and
xefluxed until a solution was obtained. Upon cooling to ambient temperature, a white
precipitate was formed. The solution was filtered, the precipitate washed with THF
and dried to give 18.0 g (90% yield) of the diethylamine salt/complex. !H NMR
(DMSO-de, ppm): 7.58, 7.21, 7.05, 7.00, 6.5-6 (br), 6.27, 3.71,2.80 (q), 1.9-1.7,1.5-
1.4, and 1.10 (t).
EXAMPLE 19 - PURIFICATION OF 5'-(5-CYANO-1-METHYL-1H-PYRROL-
2-YL)SPIRO[CYCLOHEXANE-1,3'-[3H]INDOL]-2'-YLIDENECYANAMiDE
VIA ITS DIETHYLAMINE SALT/COMPLEX
Crude 5 '-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)spiro[cyclohexane-1,3'-
[3H]indol]-2'-ylidenecyanamide (95.0 g; purity 78% HPLC area) in THF (250 mL)
was treated with diethylamine (105 g) and refluxed with a concomitant addition of
THF (3.35 L) until dissolved. The solvent was distilled off (2.5 L) during which a
precipitate was formed. The flask was cooled to ambient temperature and the white
precipitate was filtered, washed with ether and dried to give 58.0 g (61% yield) of
purified 5'-(5-cyano-l-methyl-lH-pyrrol-2-yl)spiro[cyclohexane-l,3'-[3H]indol])-2'-
ylidenecyanamide (purity >99% HPLC area).
All publications listed in this specification are incorporated herein by
reference. While the invention has been described with reference to a particularly
preferred embodiment, 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 fbrpurnyiag a compound of formula I:
•wherein:
A sod 3 are joked to ibmi -a rmg coinniisms (i). (H), or
£55):
© a carbon-based 3 to 8 membered saturated spirocycEc
(5) a carbon-based 3 to 8 membered spirocyclic ring con-
tatnfng in its backbone one or more carbon-canxm
double bonds; or
(51) a 3 to 8 membered beterocycSc ring containing in its
backbone erne to tares b^eros&niS selected from, the
STOOD can^stjqg of O. S and N:
fie mss of(I), (5) and 05) being optionally sabsilLuied by
froml io 4 siuubs selected nam fee sroup cansistins: of
finarins, C3 to C5 al&yL Q to C5 alknxy. Q Id C6 frdD-
aliyL CF35 OR CN, NH^ NH(Cx to Cs alkyl). andNCQ
toCgalkyi)^
T is absent;
QisO, ^orNR3;
^isfiv^Cv^orC-vi):
(if) halogen;
(v) a substituted benzene zing containing tie substitosnts
X, YandZ as mownbdovr.
wherem:
X is selected from the group consisting of H, balogen, CN.
C^ to C3 alkyL substituted C^ to C3 aliyi, alksnyl, sub-
stituted aTicenyl, alkynyl, substituted alkyuyl, Q to Q
alkoxy snbstitiited C2 to C, sslkoxy, Q to C3 tMoafk-nxy,
substituted Q to Q thioalkDxy, amino, Cx to C3 21m-
noalkyl, substitutedCx to Q sminoalkyi, NO^ C, to Q
perfioDioalkyl, 5 or 6 membered bsterocyclic rmg con-
tEinms; in its backbone I to 3 beteicatonis, SOjNH^
COR^ OCORc, and NR^COR0;
Rc is H, Cj Id Q alkyi, snbstitafed Cj to C3 alkyL aryl
substituted aryL. Q to C, a!koxys snbstitnted C, to Q
alkoxv; C* to Q gmrnoalkyL or snbstitnted Qto Cj
B? is H, Q to C3 2M or substituted C, to C3 2M;
Y and. Z are independently selected fom the grasp con-
sisting of H, halogen. CN, NOj, amino, aminoalkyl, Cx
to C3 alkoxy, Cx to C3 alkyL, andQ to C, tmoslkoxy: or
(yi) a nre or six memberediingbavnig in its backbone 1,2,
or 3 beteroatoms selected feom fee group consisting of
' O. S, SO, S02 and NR2 and containing one or two sub-
stitnents mdependsatly selected som the group consist-
ing ofH, halogen, CN, NO^ amino, C: to C3 afkyU^ to
C3 alkosy. C^ to C3 aminoalkyl, SC^NB^ COR*, and
NR-'COR^;
R£ is H, CL to C3 alky!, substituted Q to Q alkyi, sryl
substituted aryl, Ca to Q alkaxy, substituted Q to Q
slkoxy, Cj to C^ aminoaliyi, or substituted C^ to Cg
aminoalkyl;
R^is H, Cj to C, alky!, or substituted C, to Cj 2M
R2 is H, absent, O, or C^ to CA alkyl; and
R3 is Cx to C5 alkyl, substituted Cj to Cg aftyl, aryl sub-
stituted aryl, CN, C(0)R4 SCX^R4. SCN. OR4, SR4
CTOPR4 C(S)OR4 C(0)SK*, or C(S>SR4;
R4 is Cj to Cs alkyl, substituted Q to Q alkyL aryL at
substituted aryfc
wherein said method comprises:
(2) treating a sample of 2 compound of fannnl21 which
contains greater than about 1% by weight imparities
with 2 base in the presence of a sorvent to form a basic
salt; and
(b) concerting said basic salt to a purified form of a com-
pound of formula I by treating said basic salt with water,
acid, or neat
2. The method as claimed in claim 1, wherein said com-
pound ofihrninla lis selected irom the group consisting of an
mdol-2-one, Tndpj-2-mJons, indol-2-yHdene cyanarride.
3. The method as claimed in claim 1, wherein said solvent is
selected fem the group consisting of tetrahydrofnran, metha-
nol, diethylamine, acetone, and water.
4. The method as claimed in claim 1„ wherein said base is
selected fexni the group consisting of an alkoxide salt, diethy-
iamine, a hydroxide salt, teiramemylgnanidme, and diazahi-
cycloundeceae,
5. The method as claimed in claim 4, wherein said hydrox-
ide salt is sodium hydroxide, choline hydroxide, orpotassmni
hydroxide.
6. The method as claimed in claim 4. wherein said alkcxide
salt is selected from the group consisting of potasshun tert-
bmoxide, sodium lert-bntoxide, Mmnn tert-iuioxide,
sodium, meihoxide, sadmm epoxide, scdrnin tert-pentoxide,
and potassium leit-pentoxide.
7. The method as claimed in claim 1. wherein said basic salt
is soluble in said servant.
8. The method as claimed in claim 1 y wherein said basic salt
is insolrible in said solvent
9. The method as claimed in claim 8, further comprising
isolating said basic salt
10. The method as claimed in claim 9, wherein said isola-
tion is performed using filtration.
11. The method as claimed in claim 9, "wherein said isolated
basic salt is dissolved in a sohiMIizing solvent
12. The method as claimed in claim 11, wherein said som-
hWrrmcr solvent is acetone or aaneons acetone.
13. The method as claimed in claim 1,. further comprising
jHtfrrng the product of step (a).
14. The method as claimed in claim 1, wherein said purified
compound of ibirrnna I is precipitated
15. The method as claimed in claim 14. wherein said pre-
cipitation is performed using an acid.
16. The method as claimed in claim 15, "wherein said acid is
an organic acid or a mineral acid.
17. The method as claimed in claim 15, wherein said acid is
selected fern the group consisting of hydrochloric acid and
acetic acid.
18. The method as claimed in claim 14, wherein said pre-
cipitation is performed using water
19. The method as claimed in claim 14, wherein said pre-
cipitation is performed rising heat
20. The method as claimed in claim 1, further comprising
isolating said purified compound of formula I.
21. The method as claimed in claim 1, further comprising
jyi-.ry.uiuWTinv said purified compound of formula I.
22. The method as claimed in claim 1, further comprising
ccErperting said purified compound of formula I Id a phanna-
ceulicaBy acceptable salt thereof
23. The method as claimed in claim 1, wherein said com-
pound of formula I is selected from me group consisting of
S^-^no^Dspirofcyclohesane-l 3-{3Hrmcbl]-l -methy±-2-
p^Lrdh-2-osft^mtnlQi 54^Qmo^rro[cycIohexai3e-I3t-
[3HJ-mdol-2(lH}-Qne3 andS-rramo-spu^Fcyciohsxans-lS1-
[3H3-indbl-2ClH>thicme.
24. The method as claimed in claim 1, wherein said basic
salt is selected from the group consisting ^-(S-cyano-l-ine-
myl-lH-pyrrole-2-yI)spiro[cyclohsxaie-13f-[3I^-mdol]-2f-
yBdenecvanamide choline salt and ^-(S-cyanc^l-metrryi-
XH-pyrioI-2-yl)spiix{cydohexane-l J'-iSHj-indol]^-
yHdenecyanamide choline salt
25. The method as claimed in claim 1, wherein said electron
withdrawing group of R3 is CN".
26. A method for purifying a compound of formula I:
wherein:
A and B his independently selected from the grasp con-
sisting of Cj to Ce elkyi substituted C^ to Ce alkyl, C^ to
C6 alkenyi, substituted C, to C6 alkenyi, Q to Cg alky-
nyl substituted C2 to C6 alkynyL C3 to Q cycloalkyl,
sabstimted Q to Cg cycloalkyl, aryi, substituted sry%
heterocyclic, subsiiLuled heterocyclic, COR^, andNS^-
. R^ is selected man fee gronp consisting of H. C, to Q
alky], substituted Cx to Q 2lkyL aiyl, substituted aryl, C,
to C3 alkoxy, sobstitnted Cx to C* alkcxy. amino, Cj to
C3 sminoalkyl, and substituted Cj to C* azninoalkyl;
R* is H, C, to C, sikyL or substituted CL to C3 alkyl;
Tis absent;
QisO?S5orNR3:
Ri is (iv) or (v):
Qv) a substimted benzene ling containing the snhstitneiits
X, Y and Z as shcr*n "below:
wfcsran:
X is selected from the group consisting ofH, halogen, CM,
CL to C3 alkyl, substituted C: to C^ alkyl, alkenyi, sub-
stituted alkenyi, alkynyl, substituted alkynyl, Q to C,
alkoxy, substituted Cx to C3 alkoxy, Cx to C- thioalkoxy.
substituted Cx to C3 thioalkDxy, amino, C2 to Q ami-
noalkyL snbstitnted C^ to C3 aminoalkyl, NO^, Cx to C3
pernuoroalkyl, 5 or 6 membered heterocyclic ling con-
taining in its backbone 1 to 3 heteroatoms, SO^NH^.
COR*5, OCORc, andNR^COR0:
Rc is EL C± to C- alkyl, substituted Cj to C3 alkyl aryi
substituted aryi, Cx to Q alkoxy. snbstitnted C. to C3
afkoxy, Cx to C3 ammoalkyl, or subs&uied C2 to CL
aminoalkyl;
X?is E, C, to Q alkyl or substituted C, to Q alkyl:
Y and Z are independently selected from the group con-
sisting of H, halogen, CN, NOj, amino, aminoalkyl. Cx
to C3 alkoxy, Cx to C$ aJkyi, aadQ to C3 thioalkaxy: or
(v) a five ox six membered ring having in its backbone 1,2,
or 3 heteroatoms selected from the group consisting of
O, S, SO, S02 and NR2 and containing one or two snb~
stitnents independently selected from the group consist-
ing 01H, halogen, CN, NO^ amino, Ci to C* alkyl^Cj to
C3 alkoxy. Cj to €3 ammoalkyl, SOJ^H^ COR^ and
NirCOR^
R^ is H. Q to Q alkyl, substituted Q to C3 alky^ aryi,
snhstimted aryi, Cj to Q alkoxy. substituted C^ to C3
alkoxy, Cx to C^ aminoalkyl, or snbstimted Q to C3
ammoalfcyi;
Rr is H, Cx to C3 alkyl, or snbstitnted Cx to Q alkyl:
R2 isH, absent, O, orCj to CA alkyl; and Rs is C, to C£alkyl,
snbstitnted C2 to C5 alkyl, aryi. substituted aryi, CN,
C(0)R4' SO^4, SCN, OR4, SR4 QPPR4, CCSpR4,
C(0)SR4,orC(S)SR4;
R4 is Cj to C6 alkyl, substituted C^ to C6 alkyl aryi, or
substituted aryi;
RB is H. CL to Cs alkyl, or substituted C: to C3 alkyl;
T is absent;
Q is Sox MR*
'Rr is {ty),(y), or (yi):
Qy) halogen;
(v) a snbstitnted benzene ring containing the snbsiitrients
X, Y and Z as shown below:
wherein:
X is selected from fee group consisting of H, halogen. CN,
Cj to Cj alkyl, substituted C^ to C3 alkvL alkenyl sub-
stituted alkeTTyl, alkynyl, substitnted alkynyL Cx to C^
alkoxy, substituted Cx to C3 alkoxy, d to C3 thioalkosy,
substituted Cx to C3 thioalkDxy, amino, C, to C^ aim-
noalkyl, substituted Q to C3 annnaaZkyi NQ^ Q to C3
perfluoroalkyl, 5 or 6 rnemhered heterocyclic ring con-
tainine in its backbone 1 to 3 heteroatoms, S02NH2,
COR Rc is H, Cj to C3 alkyl, substituted C; to Q alkyl, aiyi,
substituted aryl, C, to Q alkoxy, substituted C2 to C3
alkoxy, Cj to Q aminoalkyl, or snbstitnted C^to C^
andnoalkyl;
R13 is H, Q to C3 alkyl, or substituted d to Q alkyl;
Y and Z are independently selected from the group con-
sisting of H, halogen, CN, NO,, amino, armnoalkyl, C2
to C3 alkoxy, Cx to C3 alkyl, and Cx to C3 thioalkoxy; or
wherein said method comprises:
(a) treating a sample of £ compound of formula I which
contains greats' than about 1% by -weight impurities
with 2 base in the presence of a solvent to form a bade
salt; and
(b) csnverimg said basic salt to a purified zbzm of a com-
ponndof fornmla I by treating saidbasic saltwith wak£.
27. A method for bnrifvins: a coznpoimd of tbrnrnla I:
A and B are innependesny selected from the gross con-
sisting of Cx to Ce alkyi snbstitnted C, to Q alkyi. Gj to
C6 aTkssyL substituted O, to Cg alfercyi, Q to Cg aiky-
nyl, substituted C^ to C6 aJkynyl, Q to Cg cydcalkyl,
snbsiiluied C- to Cg cycloalkyL aryl, snbstitnted aiyl,
heterocyclic, snbsnnifed heterocyclic, CQRA. and NR2-
corV
S^ is selected fiam. the group consisting of H. Cx to C3
alkyL snbstitotsd C, to C3 alkyl, aryi, substitntedaryL Cj
to C, a&oxy, substituted Q to C3 alkoxy, amino, Cx to
Cs annnoalkyL and snbstitnted CL to C3 aminoalkyl:
(vi) a ibs or six nisnibered ring having mits baddsone 1,2,
or 3 ueteroatoins selected fem the group consisting of
O. S3 SO. SQj and NR2 and containing one or two sub-
stitnents mdependestry selected man the group consist-
ing ofR halogen, CN, NO^ amino, Q to Q alkyL Cx to
C* alkoxy. Cj to Q annnoalksl SO^NH^ CDR% and
R-2 is H, C to C3 alkyi, substituted Cx to Q alkyl aryL
substituted aryi, Q to CL alkoxy, substituted Cx to C3
alkoxYt Cj to €3 aminoalkyl, or substitiitsd QtoC,
sminoalkyi;
R^is H, Cj to C2 alkyi, or substituted C2 to C3 alkyi;
R2 is H, absent, b3 or Cj to Q alkyi; and
R3 is Cx to C6 alkyi, substituted Q to C5 alkyL aryl, sub-
stituted aryL CN, Qp)R*' SO^. SCN, OR*3 SR* C(0)
OR*, q£)OR4, C(0)SR43 or C(S)SR^
5^ is C, to Cg alkyi, substituted C^ to C6 alkyi, aryl, or
, substituted aryl;
wherein said method comprise:
(a) treating a sample of a compound of formula I which
contains greater than about 1% by weight impurities
with a base in fee presence of a solvent to form a basic
salt; and
(b) concerting said basic salt to a ptmSed form of a com-
rx>t2nd of formula Iby treating said basic salt with, water,
add, or heat
28. A method for purifying a compound of formats I:
wherein;
A and B are independently selected, from the group con-
sisting of Cj to C6 slkyl, Q Id C5 alkenyl, Cj to C6
alkynyL C, to Cg cycloalkyL aryL lieterocydic, snbsti-
tnted heterocycEc, COR*, and mfCOB^i
R~ is selected fenn the groop consisting of H, C^ to Cs
alkyl, ssbsfentadCjto C^ alkyl, aryi, snbstitiitedarylsC1
to Q alkoxy. substituted Q to C3 alkaxy. amino, Q to
C3 smncalkyL and substituted C^ to Q anrinoalkyl;
RskB, Q to C3 alkyL or si&stitnied Q to Gj alkyi;
Tis absent;
QisO:
Rj is Civ), (v) or (vi):
(iv) halogen:
(v) a substituted benzene ring containiiig fas snbstitiients
X, Y and Z as shown below:
wherein:
X is selected from the group consisting ofH, halogen, CN,
Cj to C3 alkyi, substituted Cx to Cs alkyl. alksnyL sub-
stituted alkenyL, alkynyl, substituted alkynyl, C2 to C3
alkoxy, substituted C^ to C- alkoxy, Cr to Q thicalkosy.
substituted Ct to C~ tinoalkaxy, amino, Q to C- arm-
DoalkyL substituted C2 tc C, aimnoalkyL NO^ Cj to Q
psnooroalkyL 5 or 6 meinbei^iieteiocyclic ring con-
taining in its backbone I to 3 igfesromoms, SOjNH^
CORe5 OCORc, and N^COR^:
Rc is H, C, to Cj alkyL suhsdintBd Cj. to C^ alkyi aryL
substituted aryl, Cx to C* alkoxy, substituted Cj. to Q
alkoxy, C, to C~ armrroalkyi, ox substituted €, to C-
arrnncalkyl;
R15 is H, Q to Q alkyi, or substituted Q to C^ alkyi;
Y and Z are ilKiependenily selected irom the group con-
sisting of H. halogen. CN, NCX, amino, arrririoalkyi, Q
toQalkoxy,Cj to CL alkyi.andCxtoC,thioalkDxy;or
(vf) a nve or six rnanberedring having in its backbone 1.2,
or 3 heteroatoms selected fom the gronp consisting of
O, S, SO. SOj and NR2 and containing one or two snb-
stitaents independently selected Irani the group consist-
ing ofH,ialogsn,CN,NO2,amino,C. to C3alkyi,Qto
C= alkoxy^Q to G* aniinoalkyi, SCNH^ COR^. and -
_NRf COR-,
R^ is H, Q to Qs alkyL substituted Cx to C- alkyi, aryL
sabstitnted aryl, Ct to C. slknxy, snbstitmed C, to C3
alkoxy, Cx to C, aminoalkyl. or substituted Cj to C,
amincslkyi;
R-~is H, C2 to Q alky!, orsnbstitcSedQ to C, alkyi;
R3 is H, absent, O, orQ to C4 alkyi: and
Rs is C2 to C6 alkyi, substituted C, to C6 alkyi, aryl, snb-
stitnted aryl, CN, C(0)R4' S02R4 SCK, OR4, SK4, C(0)
OR4 C(S)OR45 C(0)SR4 or C(S)SR4;
R* is Cx to C6 alkyL, substituted Cx to C6 alkyi, aryl, or
substituted aryl;
wherein said method comprises:
(a) treating a sample of a compound of formula I which
contains greater man about 1% by weight impurities
with a base in the presence of a solvent to form a basic
salt; and
(b) converting said basic salt to a purified form of a com-
pound of fcrmnla I by freatmg saidbasic salt with wafer,
acid, or heat
29. A method far purifying a compound of formula I:
wherein:
A and B 2re independently selected from the'group con-
sistingof CitoCgalkyiand substituted Q to Chalky!: or
A and B are joined to form a carbon-based 3 to S msmbered
saturated spirocyclic rirrg. which is optionally substi-
tuted by from 1 to 4 groups selected man the group
consisting of nuarine, C2 to C6 alkyl, C to Ce alkoxy, Cx
to C6 thioaikyi CF3, OH, CNT, Nf4 NH(Q to C6 alkyl),
andNCCitoQalkyl)^
lis absent
QisOjSjGrNRg.
R, is Civ), (\% or (vi):
(W) halogen;
(v) a substituted benzene ring containing the snbsntosnts
X. Y and Z as shown below:
wherein:
X is selected fesin the group consisting ofH. halogen. CN,
**-o to C3 as»ryi; sntstrnited C^ to Q? SsKyi., slksoyl, stii/-
snmted alksayi, slkywL stibsntnted alkynyL Q to C3
alknxy. snbstitnred Q to C, alkoxy, Cx to C3 thioalkQxy,
snbstitnled C^ to C3 tmoaJkorfj amino, Q to Q and-
noalkvl sdbsfitnfed. C, to Q ananoalkyi, NO^, C, to Q
perfmoTDalkyl, 5 or 6 inembered heterocyclic ring con-
taining in its backbone 1 to 3 heteroatems, SOjNH^,
COR0, OCORc; and m?COR.c:
Rc is H, Q to C3 alfcyi, snbstitnisd C, to C, alkyl, aryL
substituted aryl Ci to C3 alknxy, substitntsd Cj to C~
alkoxy, C2 to C3 aminoalkyL. or snh&Txtnted Cx to Q
aniinoalkyi;
R^ is H, Q to Cs alky!, or robstituted C2 to C3 alkyl:
Y and Z are independently selected &om the group con-
sg
sisting of H, halogen, CN, NO^ amino, aminoalkyl, Ca
to C3 alkoxy, CL to C3 alkyl, and C^ to C3 thioalkoxy; or
(vi) a five or sis membered ring having in its backbone 1,2,
or 3 heteroaiams selected fenn the gronp consisting of
O, S, SO, S02 and NR2 and containing one or two sub-
stituents independently selected from.the gronp consist-
ing ofH, halogen, CN, NO^ amino, Q to C3 alkyl, Cx to
Gj alkoxy, Q to Q aminoalkyl, SO J4H2, CORF, and
NR'COR^;
R2 is H, Q to C3 alkyl, snbstitnted C, to Q alkyl, aryi,
snbstitnted aryi, C, to Q alkoxy, substituted Cx to C3
alkoxy, Q to C~ aminoalkyl, or scbsntntsd C^ to C,
aminoalkyl;
Zf is R Cj to C- alky!, or safastimtsd C^ to Q alkyl;
R2 Is H, absent. O. orQ to C4 alkyl; and
R3 is Cx to C6 alkyl, snbstitnted Cj to C6 alkyl, aryl, sub-
stitntedaryl, CN, 0(0)^ SO^, SCN, OR4, SR4, C(0)
OR4, CCSPR4,C(0)SK*9 or C(S)SR4;
R4 is Cj to Cg alkyl, substituted Cx to C6 alkyL aryl, or
substituted aryl;
wherein said method comprises:
(a) treating a sample of a compound of fatnmla I which
contains greater "man about 1% by weight iirgrarities
"wifh. a base is the presence of a solvent to form, a basic
salt; and
(b) converting said basic salt to a pnfned form of a com-
ponnd of formula Iby treating said basic salt with water,
acid, or heat


Methods for purifying a compound of formula I are provided, wherein A, B, X, Q, and R are defined herein. The
methods include mixing the compound of formula I and a. solvent; adding a base to the solvent; and precipitating purified compound
of formula, I.

Documents:

02984-kolnp-2006 abstract.pdf

02984-kolnp-2006 assignment.pdf

02984-kolnp-2006 claims.pdf

02984-kolnp-2006 correspondenc others.pdf

02984-kolnp-2006 description(complete).pdf

02984-kolnp-2006 form1.pdf

02984-kolnp-2006 form3.pdf

02984-kolnp-2006 form5.pdf

02984-kolnp-2006 international publication.pdf

02984-kolnp-2006 pctform.pdf

02984-kolnp-2006 priority document.pdf

2984-KOLNP-2006-ABSTRACT 1.1.pdf

2984-kolnp-2006-assignment.pdf

2984-KOLNP-2006-CLAIMS.pdf

2984-kolnp-2006-correspondence.pdf

2984-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

2984-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2984-kolnp-2006-examination report.pdf

2984-KOLNP-2006-FORM 1 1.1.pdf

2984-KOLNP-2006-FORM 13.pdf

2984-kolnp-2006-form 18.1.pdf

2984-kolnp-2006-form 18.pdf

2984-KOLNP-2006-FORM 2.pdf

2984-KOLNP-2006-FORM 3 1.1.pdf

2984-kolnp-2006-form 3.pdf

2984-kolnp-2006-form 5.pdf

2984-KOLNP-2006-FORM-27.pdf

2984-kolnp-2006-gpa.pdf

2984-kolnp-2006-granted-abstract.pdf

2984-kolnp-2006-granted-claims.pdf

2984-kolnp-2006-granted-description (complete).pdf

2984-kolnp-2006-granted-form 1.pdf

2984-kolnp-2006-granted-form 2.pdf

2984-kolnp-2006-granted-specification.pdf

2984-KOLNP-2006-OTHERS.pdf

2984-kolnp-2006-others1.1.pdf

2984-KOLNP-2006-PETITION UNDER RULE 137.pdf

2984-kolnp-2006-reply to examination report.pdf

abstract-02984-kolnp-2006.jpg


Patent Number 249754
Indian Patent Application Number 2984/KOLNP/2006
PG Journal Number 45/2011
Publication Date 11-Nov-2011
Grant Date 08-Nov-2011
Date of Filing 16-Oct-2006
Name of Patentee WYETH
Applicant Address FIVE GIRALDA FARMS, MADISON, NJ 07940, U.S.A.
Inventors:
# Inventor's Name Inventor's Address
1 WILK BOGDAN, KAZIMIERZ 6 CONRAD LANE, NEW CITY, NY 10956, UNITED STATES OF AMERICA
2 HADFIELD, ANTHONY, FRANCIS 1799, BLAIR CASTLE CIRCLE, RUSKIN, FL 33570, UNITED STATES OF AMERICA
3 HELOM, JEAN, LOUISE 316, LIBERTY AVENUE, HILLSDALE, NJ 07642, UNITED STATES OF AMERICA
4 RUBEZHOV, ARKADIY, ZINOVIY 3 FAWN COURT, WEST NYACK, NY 10994, UNITED STATES OF AMERICA
PCT International Classification Number C07D 265/18
PCT International Application Number PCT/US2005/013997
PCT International Filing date 2005-04-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/565,659 2004-04-27 U.S.A.