Title of Invention

THIOAMIDE DERIVATIVES AS PROGESTERONE RECEPTOR MODULATORS

Abstract Thioamide compounds, and specifically, thioamide pyrrole compounds, and preparation thereof are provided. These thioamide compounds can be used as progesterone receptor modulators, in contraception, and in the treatment of progesterone-related maladies (formula I).
Full Text BACKGROUND OF THE INVENTION
The present invention relates to progesterone receptor modulators.
Intracellular receptors (IR) form a class of structurally related gene regulators
known as "ligand dependent transcription factors". The steroid receptor family is a
subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER),
androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor
(MR). A compound that binds to an IR and mimics the action of the natural hormone
is termed an agonist, whilst a compound that inhibits the effect of the hormone is an
antagonist.
The natural hormone, or ligand, for the PR is the steroid progesterone, but
synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have
been made which also serve as ligands. Once a ligand is present in the fluid
surrounding a cell, it passes through the membrane via passive diffusion, and binds to
the IR to create a receptor/ligand complex. This complex binds to specific gene
promoters present in the cell's DNA. Once bound to the DNA the complex modulates
the production of mRNA and protein encoded by that gene.
PR agonists (natural and synthetic) are known to play an important role in the
health of women. PR agonists are used in birth control formulations, typically in the
presence of ER agonists, alternatively they may be used in conjunction with PR
antagonists. ER agonists are used to treat the symptoms of menopause, but have been
associated with a proliferative effect on the uterus that can lead to an increased risk of
uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
US Patent No. 6,407,101, which is hereby incorporated by reference, describes
the preparation of cyclocarbamate derivatives, which are useful as progesterone
receptor modulators. These cyclocarbamate derivatives, including, e.g.,

5-(4,4-dimethy]-2-thioxo-1,4-dihydro-2H-benzoxazin-6-yl)-1-methyl-1H-2-cyano-
pyrrole, are prepared by thionation of the corresponding benzoxazin-2-one (Scheme
1).

What is needed in the art are alternate compounds that are effective as
progesterone receptor modulators.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of formula I of the
structure:

In another aspect, the present invention provides the compounds 5-(4,4-
dimethyl-2-thioxo-1,4-dihydro-2H-3,1 -benzoxazin-6-yl)-1 -methyl-1H-pyrrole-2-
carbothioamide, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1 -benzoxazin-6-yl)-1-
methyl-1H-pyrrole-2-carbothioarnide, 5-(2'-thioxospiro[cyclobexane-1,3'-[3H]-
indol]-5'-yl)-1-methyl-1H-pyrrole-2-carbothioamide, or a pharmaceutically
acceptable salt thereof.
In a further aspect, the present invention provides pharmaceutical
compositions containing compounds of the invention, or a pharmaceutically
acceptable salt thereof, for use in contraception; hormone replacement therapy,
treating or preventing hormone-dependent neoplastic disease; treating dysfunctional

bleeding, uterine leiomyomata, endometriosis, or polycystic ovary syndrome;
synchronizing estrus; treating acne; or treating hirsutism.
In yet another aspect, the present invention provides use of compounds of the
invention in preparing a medicament useful in contraception; hormone replacement
therapy; treating or preventing hormone-dependent neoplastic disease; treating
dysfunctional bleeding, uterine leiomyomata, endometriosis, or polycystic ovary
syndrome; synchronizing estrus; treating acne; or treating hirsutism; in a mammal in
need thereof.
In still another aspect, the present invention provides pharmaceutical kits or
packs containing a course of treatment for contraception; hormone replacement
therapy; treating or preventing hormone-dependent neoplastic disease; treating
dysfunctional bleeding, uterine leiomyomata, endometriosis, or polycystic ovary
syndrome; synchronizing estrus; treating acne; or treating hirsutism, comprising a
container having a compound or composition of the invention in unit dosage form.
In yet another aspect, the present invention provides methods for preparing
compounds of the invention.
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 novel progesterone receptor modulators,
including thioamide compounds, and methods for preparing the same. The thioamide
compounds of the invention are useful for a variety of purposes including use as
progesterone receptor modulators, and specifically for contraception; hormone
replacement therapy; treating or preventing hormone-dependent neoplastic disease;
treating dysfunctional bleeding, uterine leiomyomata, endometriosis, or polycystic
ovary syndrome; synchronizing estrus; treating acne; or treating hirsutism by
administering the compounds of the invention to a mammal in need thereof.
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 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" 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 4 to about 10 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 including, without limitation, halogen,
CN, OH, NO2, ammo, aryl, heterocyclic, alkoxy, aryloxy, alkylcaTbonyl,
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 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. The aryl
groups can include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl, fluorenyl, 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 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. 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, 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, oxathiazinyl, morpholinyl,
thiamorpholiny], 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, benzothienyl, pyridopyridinyl, benzoxazinyl,
xanthenyl, acridinyl, and purinyl rings.
The term "substituted heterocyclic" as used herein refers to a heterocyclic
group having one or more subsrituents 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 heterocyclic group is substituted with 1 to about 4
subsrituents.


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(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 "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
The term "thioalkoxy" or "thioalkyl" as used herein refers to the S(alkyl),
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 Cl, Br, F, or I groups.
The term "acne" is meant to include any skin disorder where a skin pore
becomes blocked and/or thereby becomes inflamed. The term acne includes without
limitation superficial acne, including comedones, inflamed papules, superficial cysts,
and pustules; and deep acne, including deep inflamed modules and pus-filled cysts.
Specific acne conditions can include, but are not limited to, acne vulgaris, acne
comedo, papular acne, premenstrual acne, preadolescent acne, acne venenata, acne
cosmetica, pomade acne, acne detergicans, acne excoriee, gram negative acne, acne


rosacea, pseudofolliculitis barbae, folliculitis, perioral dermatitis, and hiddradenitis
suppurativa.
The term "hirsutism" is meant to describe a skin disorder where an overgrowth
of hair growth is observed in areas of the body which are not normally subject to
excessive hair growth.
The term "selective estrogen receptor modulator" or "SERM" is meant to
describe a compound that exhibits activity as an agonist or antagonist of an estrogen
receptor in a tissue-dependent manner. SERMs can act as estrogen receptor agonists
in some tissues and as antagonists in other tissue types. The term SERMs can also be
interchanged with the term "anti-estrogen".
II. Compounds of the Invention
The present invention therefore provides for compounds of formula I of the
structure:

wherein, R1 and R2 can be, independently, H, C1 to C6 alkyl, or substituted C1
to C6 alkyl. R1 and R2 can also be fused to form a ring including -CH2(CH2)nCH2-,
-CH2CH2C(CH3)2CH2CH2-, -O(CH2)pCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or
-CH2CH2NR6CH2CH2-, where n is 1 to 5; p is 1 to 4; and q is 1 to 4. R3 can be 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, or CORA.
RA can be 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. R4 can be 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. R5 can be C1 to C6 alkyl,

substituted C1 to C6 alkyl, or CORA, R6 can be H or C1 to C6 alkyl. X can be O, S, or
absent Q can be O or S.
The present invention also provides for compounds of formula I, where R and
R2 are C1 to C6 allcyl, R3 is H, R4 is H, and R5 is C1 to C6 alkyl.
In one embodiment, the present invention provides for compounds of the
following formulae, where R1-R3 and R5 are defined as described above.

In another embodiment, the present invention provides the following
compounds:

Examples of R1 and R2 are CH3, or R1 and R2 are fused to form a ring
comprising -CH2(CH2)nCH2-. An example of n is 3.
An example of R3 is H. R4 may be for example H.
An example of R5 is CH3.
Q may be O in some embodiments or Q is S in other embodiments.
An example of X is O. In other embodiments X is absent.
The pyrrole ring may be for example 2,5-disubstituted.
III. Methods for Preparing Thioamides
The thioamides of the present invention can be prepared by reacting a
compound containing a CN moiety with a sulfur-containing agent in the presence of a
base. The compounds containing the CN moieties can have substituents other than
CN moieties. Examples of compounds containing CN moieties and other optional
substituents include compounds of formula n, wherein R1-R5, Q, and X are defined as
described above. In one embodiment, the compound containing the CN moiety
contains a pyrrole group containing one or more CN substituents attached to the

pyrrole ring. In another embodiment, the CN moiety is attached at the 2-position, 3-
position, or 4-position of the pyrrole ring. In yet another embodiment, the CN moiety
is attached at the 2-position of the ring. However, the location and number of CN
moieties is not a limitation of the present invention.
The thioamides of the present invention can be prepared by reacting the
cyanopyrrole compound with a sulfur-containing agent, in the presence of a solvent
and a base, optionally in the presence of heat, (based on procedure by R. Shabana, H.
J. Meyer, S.-O. Lawesson Phosphorus and Sulfur 1985, 25, 297).

The solvent can include any reagent that does not react with the components
of the reaction mixture and includes ethers. In one embodiment, the solvent is 1,2-
dimethoxyethane (DME), tetrahydrofuran (THF) or diethylether. In another
embodiment, the solvent is DME. The solvent can also include other agents that do
not interfere with the reaction and includes, without limitation, water or alcohols.
The sulfur-containing agent must be capable of reacting with the nitrile moiety
of the pyrrole group and includes, without limitation, a dialkyldithiophosphate, a
diaryldithiophosphate, hydrogen sulfide (H2S), 2,4-bis(4-methoxyphenyl)-l,3-dithia-
2,4-diphosphetane-2,4-disulfide (Lawesson's reagent), or phosphorus pentasulfide. In
one embodiment, the sulfur-containing agent is a dialkyldithiophosphate or
diaryldithiophosphate. In another embodiment, the sulfur-containing agent is
diethyldithiophosphate.
In one embodiment, a 1:1 ratio of sulfur-containing agent to the compound of
formula II in the range of 1:1 to 3:1 is utilized. One of skill in the art would readily
be able to determine the amount of sulfur-containing agent to utilize depending on the •
reaction conditions, reagents, and purification required. For example a ratio of about
1:1, about 1.5:1, about 2:1 ratio, about 2.5:1, or about 3:1 can be used.

The base utilized according to the present invention can be an amine. In one
embodiment, the amine is an alkylated amine including N,N-diisopropylethylamine
(Hünig's base), triethylamine, and pyridine, among others. Only catalytic amounts of
the base are required, but greater amounts of the same can be utilized and can be
readily determined by one of skill in the art.
The thioamides of the present invention can be formed by the addition of
hydrogen sulfide (H2S) or Lawesson's reagent derivatives to the nitrile moiety of the
cyanopyrrole group. The H2S can result from the hydrolysis of Lawesson's reagent or
phosphorus pentasulfide by water. The H2S can also be formed by reaction of any
alcohol, including methanol (MeOH) or isopropanol (iPrOH) that is present in the
solvent, with Lawesson's reagent to give O-esters of phosphonodithioic acid and H2S.
The compounds of formula I can be purified using techniques known to those
of skill in the art and include, without limitation, extraction, recrystallization,
chromatography, precipitation, and distillation. In one embodiment, the compound of
formula I is purified by dissolving the compound of formula I in a dissolving solvent
to form a solution. The dissolving solvent can include any solvent that dissolves the
compound of formula I with or without heating the same. The selection of the
dissolving solvent can be readily determined by one of skill in the art In another
embodiment, the dissolving solvent is acetone, 2-butanone, tetrahydrofuran, or DME.
In yet another embodiment, the solvent is acetone, or acetone heated to its boiling
point. The dissolving solvent containing the compound of formula I can then be
concentrated by distillation or vacuum. In still another embodiment, the dissolving
solvent containing the compound of formula I is concentrated by distillation.
Thereafter, purified compound of formula I is isolated by precipitation, optionally by
cooling the concentrated dissolving solvent
In one embodiment the present invention provides a method for preparing a
compound of formula I of the structure:


wherein, R1 and R2 can be, independently, H, C1 to C6 alkyl, or substituted C1
to C6 alkyl. R1 and R2 can also be fused to form a ring including -CH2(CH2)nCH2-,
-CH2CH2C(CH3)2CH2CH2-, -O(CH2)pCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or
-CH2CH2NR6CH2CH2-, where n is 1 to 5; p is 1 to 4; and q is 1 to 4. R3 can be H,
OH, NH2, CN, halogen, C1 to C6 alkyl, substituted d to C6 alkyl, C2 to C6 alkenyl,
substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, or CORA.
RA can be 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. R4 can be 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. R5 can be C1 to C6 alkyl,
substituted C1 to C6 alkyl, or CORA. R6 can be H or C1 to C6 alkyl. X can be O, S, or
absent Q can be O or S, or a pharmaceutically acceptable salt thereof, by combining
a base, a dialkyldithiophosphate, and a compound of formula II of the structure, or a
pharmaceutically acceptable salt thereof, where R1-R3, Q, and X are defined above.
See, Scheme 2.



The method can further include purifying the compound of formula I
including dissolving the compound of formula I in acetone to form a solution; heating
the acetone solution to the boiling point of acetone; concentrating the acetone solution
by distillation; and isolating the purified compound of formula I.
In a further embodiment, the present invention provides a method for
preparing 6-(2-carbothioamide-pyrroIe)-benzoxazine compounds, or pharmaceutically
acceptable salts thereof, including reacting a 6-(2-cyanopyrrole)-benzoxazine
compound, a base, and a sulfur-containing agent
In another embodiment, the present invention provides a method for preparing
6-(2-carbothioamide-pyrrole)-benzoxazine compounds, or pharmaceutically
acceptable salts thereof, including reacting a 6-(2-cyanopyrroIe)-benzoxazine
compound, a base, and a dialkyldithiophosphate.
In yet a further embodiment, the present invention provides a method for
preparing 6-(2-carbothioamide-pyrrole)-benzoxazine compounds, or pharmaceutically
acceptable salts thereof, including reacting a 6-(2-cyanopyrrole)-benzoxazine
compound, a base, and hydrogen sulfide.
In still another embodiment, the present invention provides a method for
preparing 6-(2-carbothioamide-pyrrole)-benzoxazine compounds, or pharmaceutically
acceptable salts thereof, including reacting a 6-(2-cyanopyrrole)-benzoxazine
compound, a base, and diethyldithiophosphate.
In yet another embodiment, the present invention provides a method for
preparing 6-(2-carbothioamide-pyrrole)-benzoxazine compounds, or pharmaceutically
acceptable salts thereof, including reacting a 6-(2-cyanopyrrole)-benzoxazine
compound, Hünig's base, and diethyldithiophosphate.

In still a further embodiment, the present invention provides a method for
preparing 6-(2-carbothioamide-pyrrole)-benzoxazin-2-one compounds, or
pharmaceutically acceptable salts thereof, including reacting a 6-(2-cyanopyrrole)-
benzoxazin-2-one compound, a base, and a dialkyldithiophosphate.
In yet another embodiment, the present invention provides a method for
preparing 6-(2-carbothioamide-pyrrole)-benzoxazin-2-thione compounds, or
pharmaceutically acceptable salts thereof, including reacting a 6-(2-cyanopyrrole)-
benzoxazin-2-thione compound, a base, and a dialkyldithiophosphate.
In a further embodiment, the present invention provides a method for
preparing 6-(2-carbotbioamide-pyrrole)-benzoxazine compounds, or pharmaceutically
acceptable salts thereof, including reacting a 6-(2-cyanopyrrole)-benzoxazine
compound and hydrogen sulfide.
In still another embodiment, the present invention provides a method for
preparing 6-(2-carbothioamide-pyrrole)-benzoxazine compound, or pharmaceutically
acceptable salts thereof, including reacting a 6-(2-cyanopyrro]e)-benzoxazine
compound and diethyldithiophosphate.
IV. Methods of Using the Compounds of the Invention
The thioamide compounds of this invention are useful as progesterone
receptor modulators, including antagonists and agonists. Specifically, the 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 compounds utilized according to the present invention can contain one or
more asymmetric centers and can thus give rise to optical isomers and diastereomers.
While shown without respect to stereochemistry, the compounds can include optical
isomers and diastereomers; racemic and resolved enantiomerically pure R and S
stereoisomers; other mixtures of the R and S stereoisomers; and pharmaceutically
acceptable salts thereof.
The compounds are therefore useful as oral contraceptives in both males and
female. The compounds are also useful in hormone replacement therapy, and in
preparing medicaments useful therefor. The compounds are further useful in the
treatment of endometriosis, luteal phase defects, hormone-dependent neoplastic

disease, and benign breast and prostatic diseases, and in preparing medicaments
useful therefor. 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 compounds are also useful in treating hirsutism or acne, and in
preparing medicaments useful therefor. The compounds are further useful in the
synchronization of estrus, and in preparing medicaments useful therefor.
The compounds of this invention can be used alone as a sole therapeutic agent
or can be used in combination with other agents, such as estrogens such as those
described in US Patent Publication Nos. US-2004-0006122-A1 and US-2004-
0014798-A1, which are hereby incorporated by reference, progestins, estrones,
androgens, estrogen receptor agonist, or selective estrogen receptor modulators such
as those described in US Patent Publication Nos. US-2004-0002535-A1 and US-
2O04-0006O60-A1, which are hereby incorporated by reference.
The compounds of the present invention encompass tautomeric forms of the
structures provided herein characterized by the bioactivity of the drawn structures.
Further, the 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, einbonic, methanesulfonic, ethanesulfom'c,
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
aluminum, 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,-dibenzylethylenediamine, 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 be
utilized which, when delivered in such form, convert to the active moiety in vivo.
These salts, as well as other 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 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, metabolites are formed in vivo.
The compounds of this invention can be formulated neat or with a
pharmaceutical carrier for administration, the 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 be 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 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 one embodiment, the compositions are delivered orally by tablet, capsule,
microcapsules, dispersible powder, granule, suspension, syrup, elixir, and aerosol. In
another embodiment, when the compositions are delivered orally, delivery is by
tablets and hard- or liquid-filled capsules.
In 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 compound(s), is nontoxic to the skin, and
allows for delivery of the compound(s) for 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.
The use of sustained delivery devices can be desirable, 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 (EMA) 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 mg/kg. Treatment will generally be initiated
with small dosages less than the optimum dose of the 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 may be proportionally reduced as indicated by the
exigencies of the therapeutic situation. Alternatively, a single dose can be delivered.
In one embodiment, the delivery can be on a daily, weekly, or monthly basis. In
another embodiment, delivery is daily. 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
example, a capsule or tablet itself, or it can be the appropriate number of any such
compositions in package form.

V. Pharmaceutical Kits
The present invention provides kits or packages of pharmaceutical
formulations including the compounds of formula I described herein. When the
compounds of formula I are to be delivered continuously, a package or kit can include
the compound in each tablet When the compound is to be delivered with periodic
discontinuation, a package or kit can include placebos on those days when the
compound is not delivered.
The kits can also be organized to indicate a single oral formulation or
combination of oral formulations to be taken on each day of the cycle, in one
embodiment including oral tablets to be taken on each of the days specified, and in
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
compound of formula I is delivered. In one embodiment, the daily dosage of the
compound of formula I remains fixed in each particular phase in which it is delivered.
It is further preferable that 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.
To help facilitate compliance with each regimen, it is also preferred that the kits
contain the placebo described for the final days of the cycle.
The kits can also include an agent such as one or more of an agent selected
from among estrogen, progestin, estrone, androgen, estrogen receptor agonist, or
selective estrogen receptor modulator. One of skill in the art would readily be able to
formulate a suitable amount of the above-noted agent for use in the kits of the
invention.
A number of packages or kits 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. In a further embodiment, the package is a labeled blister package, dial
dispenser package, or bottle.
The following examples are provided to illustrate the invention and do not
limit the scope mereof. 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 5-(4,4-DIMETHYL-2-THIOXO-1,4-
DIHYDRO-2H-3,1-BENZOXAZIN-6-YL)-1-METHYL-1H-PYRROLE-2-
CARBOTHIOAMIDE
In a 500-mL round-bottomed flask equipped with a magnetic stirrer,
thermometer, addition funnel, and a reflux condenser, 5-(4,4-dimethyl-2-thioxo-1,4-
dihydro-2H-3,1-benzoxazm-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile(29.3 g, 98.6
mmol) was suspended in 1,2-dimethoxyethane (DME; 200 mL). Hunig's base (1 mL,
0.747 g, 5.75 mmol) was added followed by water (1 mL, 1.00 g, 55.6 mmol) and the
mixture was heated to reflux. Diethyl dithiophosphate (49.0 g, 263 mmol, Aldrich,
tech.) was added dropwise. The mixture turned homogenous after 15 minutes of
heating and reaching 84 °C. Eight minutes later, the temperature had reached 90 °C
and solids started to precipitate. The high performance liquid chromatograph (HPLC)
graph of the liquid phase sampled after 5 hours showed a 20/80 ratio of
substrate/product. More diethyl dithiophosphate (11.0 g, 59 mmol) was added and the
mixture was heated for an additional 30 minutes. The heating was thereby turned off
and the mixture was stirred at room temperature for 20 hours, cooled, and filtered. A
yellow solid was obtained (16.6 g; 51% crude yield; HPLC area%; 12/81
substrate/product).
A 5-L round-bottomed flask equipped with a mechanical stirrer and a reflux
condenser was charged with the isolated solid (16.5 g) and acetone (2700 mL) was
added in portions via the condenser while the suspension was heated to reflux. The
reflux condenser was replaced with a regular one and acetone was distilled off. After
distilling 2130 mL of acetone, the formed slurry was cooled to room temperature,
stirred overnight, and filtered on a sintered-glass funnel to give a dark-yellow,
crystalline, sandy solid. The filtered solid was dried at 40 °C in vacuo to give 12.5 g
(76% recrystallization yield; 38% total yield) of 5-(4,4-dimethyl-2-thioxo-1,4-
dmydro-2H-3,1-benzoxazm-6-yl)-1-methyl-1H-pyrrole-2-carbothioamide. LC purity:

95.94%; 1.65% NSP-989; rrt 0.88. LC-MS: 331 (M+); impurity 297 (NSP-989). Mp:
particles of various shapes; small particles melted 210-215 °C; next 218-220 °C; final
melt 223-226 °C. IR (KBr, cm-1): 3375, 3269, 3165, 2211, 1624,1610, 1540, 1526,
1466, 1370,1294, 1261, 1186,1114, 1086, 959, 880, 822, 779. 1H NMR(DMSO-d6,
ppm): 12.28 (s, 1H), 9.22 (s, 1H, S=CNH2), 8.97 (s, 1H, S=CNH2), 7.41 (d, 1H, J=
7.05 Hz), 7.40 (s, 1H), 7.12 (d, 1H, J= 8.85 Hz), 6.72 (d, 1H, J= 3.9 Hz), 6.23 (d, 1H,
J= 3.9 Hz), 3.83 (s, 3H), 1.68 (s, 6H). The solids were sparingly soluble in
dimethylsulfoxide (DMSO). 13C NMR(DMSO-d6,PPm): 189.3 ((NH2)C=S), 183.1
(HN(O)C=S), 140.6, 138.5, 135.2, 131.5, 129.8, 128.6, 127.2, 124.4, 114.8, 112.7,
108.4,83.7,35.8,27.6.
EXAMPLE 2 - PREPARATION OF 5-(4,4-DIMETHYL-2-OXO-1,4-DIHYDRO-
2H-3,1-BENZOXAZIN-6-YLM-METHYL-1H-PYRROLE-2-
CARBOTHIOAMIDE
This compound was prepared by following the procedure of Example 1 using
5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-
carbonitrile (1.45 g) to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-
yl)-1-methyl-1H-pyrrole-2-carbothioamide (0.79 g, 49% yield). 1H NMR (DMSO-d6,
ppm): 9.17 (s, 1H, S=CNH2), 8.93 (s, 1H, S=CNH2).
EXAMPLE 3 - PREPARATION OF 5-(2'-THIOXOSPIRO[CYCLOHEXANE-
1,3'-[3H]-INDOL]-5'-YL)-1 -METHYL-1H-PYRROLE-2-CARBOTHIOAMIDE
This compound was prepared by following the procedure of Example 1 using
5-(2'-thioxospiro[cyclohexane-1,3,-[3H]-indol]-5'-yl)-1-methyl-1H-pyrrole-2-
carbonitrile (1.45 g) to give 5-(2'-thioxospiro[cyclohexane-1,3'-[3H]-indol]-5'-yl)-1-
methyl-1H-pyrrole-2-carbothioamide (0.20 g, 55% yield). 1H NMR (DMSO-d6, ppm):
9.24 (s, 1H, S=CNH2), 8.96 (s, 1H, S=CNH2).
EXAMPLE 4 - PHARMACOLOGY
5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-
pyrrole-2-carbothioamide (1) and 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-
benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbothioamide (2) were tested in a T47D

cytosol alkaline phosphatase assay (Table 1). The purpose of this functional assay
was to identify progestins or antiprogestins by determining the compound's effect on
alkaline phosphatase activity in T47D cells.

(i) Culture medium:
DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 5% (v/v) charcoal
stripped fetal bovine serum (not heat-inactivated), 100U/mL penicillin, 100 µg/mL
streptomycin, and 2 mM the GlutaMax™ reagent (GIBCO, BRL).
(ii) Alkaline phosphatase assay buffer:
I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% the Triton™ reagent X-100
II. 0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenyl phosphate
(Sigma).
(iii) Cell Culture and Treatment:
Frozen T47D cells were thawed in a 37°C water bath and diluted to
280,000 cells/mL in culture medium. To each well in a 96-well plate (Falcon, Becton
Dickinson Labware), 180 µL of diluted cell suspension was added. Twenty µL of
reference or test compounds diluted in the culture medium was then added to each well.
When testing for progestin antagonist activity, reference antiprogestins or test
compounds were added in the presence of 1 nM progesterone. The cells were incubated
at 37°C in a 5% CO2/humidified atmosphere for 24 hours.
(iv) Alkaline Phosphatase Enzyme Assay:
At the end of treatment, the medium was removed from the plate and 50
uL of assay buffer I was added to each well. The plates were shaken in a titer plate
shaker for 15 minutes. Then 150 µL of assay buffer II was added to each well. Optical
density measurements were taken at 5 minute intervals for 30 minutes at a test
wavelength of 405 nM.

(v) Analysis of Results:
Analysis of dose-response data: For reference and test compounds, a
dose response curve is generated for dose (X-axis) vs. the rate of enzyme reaction
(slope) (Y-axis). Square root-transformed data are used for analysis of variance and
nonlinear dose response curve fitting for both agonist and antagonist modes. Huber
weighting is used to downweight the effects of outliers. EC50 or IC50 values are
calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used
for both one-way analysis of variance and non-linear dose response analyses in both
single dose and dose response studies.
(vi) Reference Compounds:
Progesterone and trimegestone are reference progestins and RTJ486
was the reference antiprogestin. All reference compounds are run in full dose
response curves and the EC50 or IC50 values calculated.


All publications cited in this specification are incorporated herein by reference
herein. 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 compound of formula I of the structure:

wherein:
R1 and R2 are, independently, H, C1 to C6 alkyl, or substituted C1 to C6 alkyl;
or R1 and R2 are fused to form a ring comprising -CH2(CH2)nCH2-,
-CH2CH2C(CH3)2CH2CH2-, -O(CH2)PCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or
-CH2CH2NR6CH2CH2-;
n is 1 to 5;
p is 1 to 4;
q is 1 to 4;
R3 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, 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;
R4 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;
R5 is C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;
R6 is H or C1 to C6 alkyl;
X is O, S, or absent;
Q is O or S;
wherein the substituents for said substituted groups are selected from the group consisting
of halogen, CN, OH, NO2, amino, C1 to C10 alkoxy, (C1 to C10 alkyl)carbonyl, and (C1 to C10
alkyl)carboxy and are attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that
the attachment constitutes a stable chemical moiety.

2. The compound of formula I as claimed in claim 1 wherein R1 and R2 are CH2.
3. The compound of formula I as claimed in claim 1 wherein R1 and R2 are fused to
form a ring comprising -CH2(CH2)nCH2-.
4. The compound of formula I as claimed in claim 3 wherein n is 3.
5. The compound of formula I as claimed in any one of claims 1 to 4 wherein R3 is H.
6. The compound of formula I as claimed in any one of claims 1 to 5 wherein R4 is H.
7. The compound of formula I as claimed in any one of claims 1 to 6 wherein R5 is
CH3.
8. The compound of formula I as claimed in any one of claims 1 to 7 wherein Q is O.
9. The compound of formula I as claimed in any one of claims 1 to 7 wherein Q is S.
10. The compound of formula I as claimed in any one of claims 1 to 9 wherein X is O.
11. The compound of formula I as claimed in any one of claims 1 to 9 wherein X is
absent.
12. The compound of formula 1 as claimed in any one of claims 1 to 11 wherein the
pyrrole ring is a 2,5-substituted pyrrole.
13. The compound of formula I as claimed in claim 1 selected from the group
consisting of:

(a) 5-(4,4-dimethy 1-2-thioxo-1,4-dihydro-2H-3,1 -benzoxazin-6-yl)-1 -methyl-1H-
pyrrole-2-carbothioamide;
(b) 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1 -benzoxazin-6-yl)- 1-methyl-1H-
pyrrole-2-carbothioamide; and
(c) 5-(2'-thioxospiro[cyclohexane-1,3'-[3H]-indol]-5'-yl)-1-methyl-1H-pyrrole-2-
carbothioamide.

14. A pharmaceutical composition comprising a compound of formula I as claimed in any one of
claims 1 to 13 and a pharmaceutically acceptable carrier or excipient
15. A method for preparing a compound of formula I as claimed in any one of claims
1 to 13, said method comprising reacting a sulfur-containing agent, and a compound of formula
II of the structure:

in the presence of a base.
16. The method as claimed in claim 15, wherein said sulfur-containing agent is a
dialkyldithiophosphate.
17. The method as claimed in claim 16, wherein the ratio of said
dialkyldithiophosphate to said compound of formula II is about 1:1 to about 3:1.
18. The method as claimed in claim 16 or 17, wherein said dialkyldithiophosphate is
diethyl dithiophosphate.
19. The method as claimed in claim 15, wherein said sulfur-containing agent is H2S.

20. The method as claimed in any one of claims 15 to 19, wherein said base is an
amine.
21. The method as claimed in claim 20, "Wherein said amine is Hünig's base.
22. The method as claimed in any one of claims 15 to 21, wherein said compound of
formula I is purified comprising:
(a) dissolving said compound of formula I in acetone to form a solution;
(b) heating said acetone solution to the boiling point of acetone;
(c) concentrating said acetone solution by distillation; and
(d) isolating said purified compound of formula I.
23. The method as claimed in any one of claims 15 to 22, comprising a solvent.
24. The method as claimed in claim 23, wherein said solvent is dimethoxyethane.
25. The method as claimed in claim 23 or 24, wherein said solvent is heated to the
boiling point of said solvent.
26. A compound of formula I prepared as claimed in any of the methods of claims 15
to 25.
27. A pharmaceutical kit useful for contraception; hormone replacement therapy;
treating or preventing hormone-dependent neoplastic disease; treating dysfunctional bleeding,
uterine leiomyomata, endometriosis, or polycystic ovary syndrome; synchronizing estrus;
treating acne; or treating hirsutism, said kit comprising a compound of formula I as claimed in
any one of claims 1 to 13.
28. The kit as claimed in claim 27, comprising an estrogen, progestin, estrone,
androgen, estrogen receptor agonist, or selective estrogen receptor modulator.


Thioamide compounds, and specifically, thioamide pyrrole compounds, and preparation thereof are provided. These
thioamide compounds can be used as progesterone receptor modulators, in contraception, and in the treatment of progesterone-related
maladies (formula I).

Documents:

02932-kolnp-2006 abstract.pdf

02932-kolnp-2006 assignment.pdf

02932-kolnp-2006 claims.pdf

02932-kolnp-2006 correspondence others.pdf

02932-kolnp-2006 description(complete).pdf

02932-kolnp-2006 form-1.pdf

02932-kolnp-2006 form-3.pdf

02932-kolnp-2006 form-5.pdf

02932-kolnp-2006 international publication.pdf

02932-kolnp-2006 international search authority report.pdf

02932-kolnp-2006 pct form.pdf

02932-kolnp-2006 priority document.pdf

02932-kolnp-2006-correspondence others-1.1.pdf

02932-kolnp-2006-form-3-1.1.pdf

2932-KOLNP-2006-ABSTRACT 1.1.pdf

2932-KOLNP-2006-AMANDED CLAIMS.pdf

2932-KOLNP-2006-AMANDED PAGES OF SPECIFICATION.pdf

2932-KOLNP-2006-ASSIGNMENT.pdf

2932-KOLNP-2006-CORRESPONDENCE.pdf

2932-kolnp-2006-description (complete) 1.1.pdf

2932-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2932-KOLNP-2006-EXAMINATION REPORT.pdf

2932-KOLNP-2006-FORM 1-1.1.pdf

2932-KOLNP-2006-FORM 13.1.pdf

2932-KOLNP-2006-FORM 13.pdf

2932-KOLNP-2006-FORM 18.1.pdf

2932-kolnp-2006-form 18.pdf

2932-KOLNP-2006-FORM 2.pdf

2932-KOLNP-2006-FORM 3-1.1.pdf

2932-KOLNP-2006-FORM 3.pdf

2932-KOLNP-2006-FORM 5.pdf

2932-KOLNP-2006-FORM-27.pdf

2932-KOLNP-2006-GPA.pdf

2932-KOLNP-2006-GRANTED-ABSTRACT.pdf

2932-KOLNP-2006-GRANTED-CLAIMS.pdf

2932-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

2932-KOLNP-2006-GRANTED-FORM 1.pdf

2932-KOLNP-2006-GRANTED-FORM 2.pdf

2932-KOLNP-2006-GRANTED-SPECIFICATION.pdf

2932-KOLNP-2006-OTHERS.pdf

2932-KOLNP-2006-OTHERS1.1.pdf

2932-KOLNP-2006-PETITION UNDER RULE 137.pdf

2932-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf


Patent Number 249679
Indian Patent Application Number 2932/KOLNP/2006
PG Journal Number 44/2011
Publication Date 04-Nov-2011
Grant Date 02-Nov-2011
Date of Filing 11-Oct-2006
Name of Patentee WYETH
Applicant Address FIVE GIRALDA FARMS MADISON, NJ 07940
Inventors:
# Inventor's Name Inventor's Address
1 WILK, BOGDAN, KAZIMIERZ 6 CONRAD LANE, NEW CITY, NY 10956
PCT International Classification Number A61K31/404; A61K31/5
PCT International Application Number PCT/US2005/011757
PCT International Filing date 2005-04-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/560,569 2004-04-08 U.S.A.