CA2371758A1 - 2,1-benzisothiazoline 2,2-dioxides - Google Patents
2,1-benzisothiazoline 2,2-dioxides Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
A progesterone receptor antagonist of formula (1) wherein R1, and R2 are eac h, independently, hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, heteroarylalkyl, and alkynyl; or R1 and R2 are taken together to form a ring and together contain -CH2(CH2)nCH2-, -CH2CH2CMe2CH2C H2- , -O(CH2)pCH2-, O(CH2)qO-, -CH2CH2OCH2CH2-, -CH2CH2NR7CH2CH2-; or R1 and R2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having a n oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end; R5 is a trisubstituted phenyl ring having structure (z), or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO2 and NR6 or pharmaceutically acceptable salt thereof.
Description
2,1-BENZISOTHIAZOLINE 2,2-DIOXIDES
Background of the Invention Intracellular receptors (IR) form a class of structurally related gene regulators known as "ligand dependent transcription factors" (R. M. Evans, Science 240, 889, 1988). 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).
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.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
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 an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates 2~ that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann et al, Ann. N. Y. Acad Sci. 261, 248, 1995), in combination with a PR agonist (Kekkonen et al, Fertility and Sterility 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 95-9619997 Al 960704).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz et al, Horm Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy et al, J. Clin. Endo. Metab. 76, 513, 1993) and endometriosis (Kettel et al, Fertility and Sterility 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (US 5719136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna et al, Ann. N. Y.
Acad. Sci.
761, 224, 1995).
Jones et al (US 5,688,810) is the PR antagonist dihydroquinoline A.
Me a A
Jones et al described the enol ether B (US 5,693,646) as a PR ligand.
F
Me H Me B
Background of the Invention Intracellular receptors (IR) form a class of structurally related gene regulators known as "ligand dependent transcription factors" (R. M. Evans, Science 240, 889, 1988). 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).
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.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
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 an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates 2~ that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann et al, Ann. N. Y. Acad Sci. 261, 248, 1995), in combination with a PR agonist (Kekkonen et al, Fertility and Sterility 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 95-9619997 Al 960704).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz et al, Horm Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy et al, J. Clin. Endo. Metab. 76, 513, 1993) and endometriosis (Kettel et al, Fertility and Sterility 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (US 5719136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna et al, Ann. N. Y.
Acad. Sci.
761, 224, 1995).
Jones et al (US 5,688,810) is the PR antagonist dihydroquinoline A.
Me a A
Jones et al described the enol ether B (US 5,693,646) as a PR ligand.
F
Me H Me B
Jones et al described compound C (US 5,696,127) as a PR ligand.
F
Me a C
Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem. 41, 291, 1998).
~ O O Me I ~ O Me I ~ Me i ~ ~ / ~ ~ i Me ~ ~ Me ~ ~ Me H Me H Me O O H Me D E F
Zhi et al described the ether G as a PR antagonist (J. Med Chem. 41, 291, 1998).
~O Me i Me Me G
Combs et al disclosed the amide H as a ligand for the PR (J. Med. Chem. 38, 4880, 1995).
F
Me a C
Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem. 41, 291, 1998).
~ O O Me I ~ O Me I ~ Me i ~ ~ / ~ ~ i Me ~ ~ Me ~ ~ Me H Me H Me O O H Me D E F
Zhi et al described the ether G as a PR antagonist (J. Med Chem. 41, 291, 1998).
~O Me i Me Me G
Combs et al disclosed the amide H as a ligand for the PR (J. Med. Chem. 38, 4880, 1995).
/ F
I
~N.N ~ gr O
H
Penman et al described the vitamin D analog I as a PR ligand (Tetrahedron.
Lett. 35, 2295, 1994).
I
Hamann et al described the PR antagonist J (Ann. N. Y. Acad. Sci. 761, 383, 1995).
OMe Br I ~HZC ~ Me OAc Me Me J
Chen et al described the PR antagonist K (Chen et al, POI-37, 16'~ Int. Cong.
Het. Chem., Montana, 1997).
I
~N.N ~ gr O
H
Penman et al described the vitamin D analog I as a PR ligand (Tetrahedron.
Lett. 35, 2295, 1994).
I
Hamann et al described the PR antagonist J (Ann. N. Y. Acad. Sci. 761, 383, 1995).
OMe Br I ~HZC ~ Me OAc Me Me J
Chen et al described the PR antagonist K (Chen et al, POI-37, 16'~ Int. Cong.
Het. Chem., Montana, 1997).
CI
N
H
K
Kurihari et al described the PR ligand L (J. Antibiotics 50, 360, 1997).
OAc O
O ~ \ OH
L
There are several examples of 2,1-benzisothiazoline 2,2-dioxides ('sultams') in the chemical and patent literature which contain no reference to progesterone activity, and do not carry the correct substitution pattern for PR modulator activity.
Chiarino et al described the preparation of the parent 2,1-benzisothiazoline 2,2-dioxide, i.e., M (and derivatives, e.g., N), that was used in the present invention (J.
Heterocycl. Chem. 23(6), 1645-9, 1986).
SO ~N
N 2 ~ S02 H ~ N
H
M N
Skorcz et al described a series of 5-(2-morpholinyl)-2,1-benzisothiazolines, e.g., O, which are useful as central nervous depressants (U.S. 3,635,964).
N
H
K
Kurihari et al described the PR ligand L (J. Antibiotics 50, 360, 1997).
OAc O
O ~ \ OH
L
There are several examples of 2,1-benzisothiazoline 2,2-dioxides ('sultams') in the chemical and patent literature which contain no reference to progesterone activity, and do not carry the correct substitution pattern for PR modulator activity.
Chiarino et al described the preparation of the parent 2,1-benzisothiazoline 2,2-dioxide, i.e., M (and derivatives, e.g., N), that was used in the present invention (J.
Heterocycl. Chem. 23(6), 1645-9, 1986).
SO ~N
N 2 ~ S02 H ~ N
H
M N
Skorcz et al described a series of 5-(2-morpholinyl)-2,1-benzisothiazolines, e.g., O, which are useful as central nervous depressants (U.S. 3,635,964).
CN
O /
SOZ
N
O
Kasnireddy et al disclosed a series of cyclic sulfonamides, e.g., P and Q, useful for controlling undesired vegetation (WO 9533746).
_ /
N
O ~
N O O N- 'O
F / I F
N S02 ~ ~ N S02 H H
CI CI
P Q
Detailed Description of the Invention This invention provides progesterone receptor antagonists of Formula 1 having the structure R~ R2 R5 \
~~ ~S 02 ~~N
R4 v wherein R,, and Rzare each, independently, hydrogen, alley, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or R, and Rz are taken together form a ring and together contain -CHz(CHz)nCHz- , -CHZCHZCMezCHzCHz-, -O(CHz)pCHz-, O(CHz)q0-, -CHZCHZOCHZCHz-, -CHZCHZNR~CHZCHz-; or R, and Rz are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R~ is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NHz, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR";
RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoallcyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NHz, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoallcyl;
RS is a trisubstituted phenyl ring having the structure, Y~'~~ Z
I
X
X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)zalkyl, aminoalkyl, substituted aminoalkyl, _g_ -NOz, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -CORB, -OCORB, or -NR~CORB;
RB is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R~ is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NOz, alkoxy, alkyl, or thioallcyl; or RS is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SOz and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NOz alkyl, alkoxy, aminoalkyl, CORD, and NRECORD;
RD is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoallcyl;
RE is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, which are usefiil for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy Preferred compounds of this invention are those having the structure:
R~ R2 R5 \
~S 02 wherein R, and Rz are taken together form a ring and together contain -CHz(CHz)"CHz- ;
n = 2-3;
R3 is hydrogen;
R4 is hydrogen;
RS is a trisubstituted phenyl ring having the structure, Y\=~~ z s x X is halogen, OH, -CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NOz, perffuoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, or thioalkoxy;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioallcyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NOZ , alkyl, or alkoxy;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
More preferred compounds of this invention are those having the structure R~ R2 R5 \
~~ N S02 Ra v wherein R, and RZ are taken together form a ring and together contain -CHZ(CHZ)nCH2- ;
n = 2-3;
R3 is hydrogen;
R4 is hydrogen;
R5 is a disubstituted phenyl ring having the structure, X
Y
X is halogen, -CN, or -NOz ;
Y is hydrogen, halogen, -CN, -NOz, alkoxy, alkyl, or thioalkyl; or RS is a five or six membered heteroaryl ring containing a heteroatom selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, or NOz ;
R6 is hydrogen, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereoisomers. While shown without respect to stereochemistry in Formula 1, the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S
stereoisomers and pharmaceutically acceptable salts thereof.
The term "alkyl" is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms; "alkenyl"
includes both straight- and branched-chain alkyl group of 2-6 carbon atoms containing at least one carbon-carbon double bond; "alkynyl" group includes both straight- and branched-chain alkyl group of 2-6 carbon atoms with at least one carbon-carbon triple bond.
The terms "substituted alkyl", "substituted alkenyl", and "substituted alkynyl"
refer to alkyl, alkenyl, and alkynyl as containing one or more substituents from the group including halogen, CN, OH, NOz, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, allcylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term "aryl" is used herein to refer to an aromatic system of 6-14 carbon atoms, which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl groups.
The term "substituted aryl" refers to aryl substituted by one or more substituents from the group including halogen, CN, OH, NOz, amino, alkyl, cycloallcyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term "heterocyclic" is used herein to describe a stable 4-14 membered monocyclic or multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized, as an N-oxide, sulfoxide, or sulfone. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
T'he term "substituted heterocyclic" is used herein to describe a heterocyclic having one or more substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term "thioallcyl" is used herein to refer to the SR group, where R is alkyl or substituted alkyl.
The term "alkoxy" is used herein to refer to the OR group, where R is alkyl or substituted alkyl.
The term "aryloxy" is used herein to refer to the OR group, where R is aryl or substituted aryl.
The term "alkylcarbonyl" is used herein to refer to the RCO group, where R is alkyl or substituted alkyl.
The term "alkylcarboxy" is used herein to refer to the COOR group, where R is alkyl or substituted alkyl. This term is also referred to as alkoxycarbonyl.
The term "aminoallcyl" refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups may be either same or different and the point of attachment is on the nitrogen atom The term "halogen"is defined as Cl, Br, F, and I.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids. for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, malefic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. Salts may also be formed from inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, and organic bases, such as ammonium, mono-, di-, and trimethylammonium, mono-, di- and triethylammonium, mono-, di- and tripropyl-ammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpho-linium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-iso-propylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butyl piperidinium, 2-methyl-piperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methyl-ammonium, phenylmonoethanolammonium, and the like.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
SO2CI SO2NH2 / / I ,SO2 / I / I ~ W I N W N
CI ~ CI H PG
,) ~~) I -.~, _-.
R f '' R~ R2 Br ~ R2 R~ R~
/ / Ar / R2 Ar / R2 I N SO2 ~ \ I N SO2 \ I N SO2 I ,SO2 H
PG PG PG
1 ~ B 9 10 11 Scheme 1 According to Scheme 1, commercially available sulfonyl chloride 4 is converted via the sulfonamide 5 to the 2,1-benzisothiazoline 2,2-dioxide 6 as described in the literature (Chiarino et al, J. Heterocycl. Chem. 23(6), 1645-9, 1986). The nitrogen atom of sultam 6 is then protected by a suitable protecting group, e.g., trimethyl silyl ethyl.
The protected sultam 7 next is treated with a strong organo-metallic base (e.g., butyl lithium, lithium diisopropylamide, potassium hexamethyldisilylazide) in an inert solvent (e.g., THF, diethyl ether) under nitrogen at reduced temperature (ca. -20 °C) (Kende et al, Synth. Commun. 12, 1, 1982). The resulting di-anion then is treated with excess electrophile such as an alkyl halide, preferably the iodide. If R, and Rz are to be joined such as the product contains a spirocycle at position 3, then the electrophile should be bifunctional, i.e., a diiodide. Subsequent bromination of the sultam proceeds regioselectively at room temperature with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium acetate, to give the aryl bromide 9. Judicious choice of reaction conditions may facilitate simultaneous removal of the protecting group at this step.
The bromide 9 then is reacted with a palladium salt (e.g., tetrakis(triphenylphoshine)palladium(0)), in a suitable solvent (e.g., THF, dimethoxyethane, ethanol, toluene) under an inert atmosphere (argon, nitrogen). The mixture then is treated with an arylboronic acid or arylboronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions at elevated temperature to give the biphenyl sultam 10. Finally, the protecting group is removed under appropriate conditions and the final product 11 is isolated and purified by standard means.
If R, and Rz are different then the intermediate is prepared by reacting the dianion of 7 with one equivalent of the electrophile R,-X (X = leaving group, e.g., iodide). The resultant mono-alkylated compound may be then isolated and re-subjected to the reaction conditions using Rz-X, or alternatively used in situ for the second allcylation with RZ-X. Alternatively, if the desired product is to contain RZ
= H, then the isolated mono-alkylated intermediate is taken though the subsequent steps.
Br ~ R~,. 'Rz Ar ~ R~,. 'Rz N SOz ~ N SOz i PG PG
Scheme 2 Other methodologies also are available for coupling the aryl group, Ar, to the sultam platform: for example, reaction of the bromide 9 with an aryl stannane, aryl zinc, or aryl magnesium halide in the presence of a palladium or nickel catalyst (Scheme 2). The required aryl-metallic species are formed via standard techniques.
Furthermore, the bromide 9 may be converted to an aryl boronic acid via standard procedures (treatment with n-butyllithium followed by addition of trimethyl borate and subsequent boronic ester hydrolysis) that will then undergo the range of previously described coupling procedures with a suitable aryl bromide.
The antiprogestational activity of the compounds of this invention was demonstrated in an in vitro standard pharmacological test procedure which evaluated the antiprogestational potency of a representative compound of this invention by measuring its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. The procedure used and results obtained are described in Example 2 below.
The results obtained in this standard pharmacological test procedure demonstrate that the compounds of this invention are progestational antagonists, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endometriosis, luteal phase defects, benign breast and prostatic diseases and prostatic, breast, ovarian, uterine and endometrial cancers.
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 other estrogens, progestins, or androgens.
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 preferably 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, preferably 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.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of this invention can also be administered orally either in liquid or solid composition form.
The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. T'he compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
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 0.02 ~g/kg -750 ~g/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; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated. Preferably, 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 The following provides the preparation of a representative compound of this invention.
Example 1 5-(3-chlorophenyl~piro[2.1-benzisothiazole-3(1H).1'-cyclohexane] 2,2-dioxide To 1,3-dihydro-2,1-benzisothiazoline 2,2-dioxide (Chiarino et al, J.
Heterocycl. Chem. 23(6), 1645-9, 1986) (0.74 g, 4.4 mmol) in anhydrous dichloromethane (minimum amount) at room temperature was added sequentially N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.77 mL, 4.4 mmol). After 30 min, the reaction was poured into water (50 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give 1, 3-dihydro-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (1.3 g, 99%) as an off white solid. 'H NMR (CDC13, 300MHz) 8 0.02 (s, 9 H), 0.97 (dd, 2 H, J= 8.3, 8.2 Hz), 3. 73 (dd, 2 H, J = 8.2, 8.3 Hz), 4.40 (s, 2 H), 5.08 (s, 2 H), 7.05 (d, 1 H, J = 7.4 Hz), 7.07 (dd, 1 H), 7.26 (d, 1 H, J = 7.4 Hz), 7.35 ('t', 1 H, J = 7.6, 7.6 Hz). MS
((+) ApCI m/z 317 [M+NH4]+.
To 1,3-dihydro-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide ~(1.3 g, 4.3 mmol) in anhydrous tetrahydrofuran (13 mL) at room temperature was added 1,5-diiodopentane (1.29 mL, 8.6 mmol). The mixture was cooled to -78 °C
and lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofiu-an, 17.3 mL, 17 mmol) was added. After 15 min, the reaction mixture was poured into water (50 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (5% ethyl acetate/hexane) on silica gel gave 1,3-dihydro-3-spirocyclohexyl-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (0.8 g, 51%) as an off white solid. 'H NMR (CDCl3, 300 MHz) S 0.00 (s, 9 H), 0.95 (dd, H, J = 8.3, 8.2 Hz), 1.18-2.36 (m, 10 H), 3.72 (dd, 2 H, J = 8.2, 8. 3 Hz), 5.
06 (s, 2 H), 7.03 ('t', 1 H, J= 7.8 Hz), 7.06 (dd, 1 H, J= 1, 7.6 Hz), 7.18 (dd, 1 H, J= l.l, 7.6 Hz), 7.28 (dt, 1 H, J= 1.3, 7.7 Hz). MS (EI) mlz 367 [M]+.
To a stirred solution of 1,3-dihydro-3-spirocyclohexyl-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (0.8 g, 2.2 mmol) in glacial acetic acid (5 mL) at room temperature was added dropwise a solution of bromine (0.11 mL, 2.2 mmol) in glacial acetic acid (2.2 mL) After stirring for 10 min, anhydrous sodium acetate (0.18 g, 2.2 mmol) was added and the solution was concentrated in vacuo.
The residue was dissolved in ethyl ether (50 mL) and washed sequentially with water (50 mL), aqueous saturated sodium bicarbonate solution (50 mL), water (50 mL) and brine (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (20% ethyl acetate/hexane) on silica gel gave a complex mixture of products (0.56 g) with identical TLC characteristics as a white foam. The mixture was used without further purification.
A solution of the mixture containing 5-bromo-1,3-dihydro-3-spirocyclohexyl-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (0.56 g, 1.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg) in toluene (25 mL) was stirred under a flow of nitrogen for 25 min. To the solution was added sequentially solutions of 3-chlorophenylboronic acid (0.4 g, 2.5 mmol) in absolute ethanol (5 mL) and potassium carbonate (0.35 g, 2.5 mmol) in water (5 mL). The mixture was heated to 80 °C for 16 h and allowed to cool. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution (50 mL) and the layers were separated.
The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with water (50 mL) and brine (30 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (2% ethyl acetate/toluene) and then by HPLC to give the title compound (65 mg) as a low melting yellow foam. HPLC
conditions: Zorbax PRO, C18, 10u, 15A, 50 x 250 mm; mobile phase composition and gradient program, 70% water/ 30% AcCN; flow rate, 100 mL/min; injection volume, 120 mg/3 mL MeOH; detection wavelength, 280 nm, 500 PSI; temperature, amb. 'H NMR (DMSO-db, 300 MHz), 8 1.47-2.19 (m, 10 H), 6.87 (d, 1 H , J = 8.2 Hz), 7.38 ('d', 1 H, J = 8.1 Hz), 7.46 ('t', 1 H, J = 7.9, 7.7 Hz), 7.56 (dd, 1 H, J =
1.7, 8.2 Hz), 7.62 ('d', 1 H, J = 7.7 Hz), 7.71, ('d', 1 H, J = 1.7 Hz), 7.75 (bs, 1H), 10.55 (bs, 1 H). MS (EI) m/z 347 [M]+. Anal. Calcd for CISH,sCINOaS: C, 62.15;
H, 5.22: N, 4.03. Found: C, 59.84; H, 5.30; N, 3.57.
Example 2 - Biological Activity The antiprogestational activity of the compound of Example 1 was demonstrated in a conventional pharmacological test.
Rea~ants Growth medium: DMEM (BioWhittaker) containing 10% (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acids, 100U/ml penicillin, 100mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
Experimental medium: DMEM (BioWhittaker), phenol red-free, containing 10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM
MEM non-essential amino acids, 100U/ml penicillin, 100mg/ml streptomycin, and mM GlutaMax (GIBCO, BRL).
Test Procedure Stock CV-1 cells were maintained in growth medium. Co-transfection was done using 1.2x10' cells, 5 mg pLEM plasmid with hPR-B inserted at Sphl and BamHl sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg sonicated calf thymus DNA as Garner DNA in 250 ml.
Electroporation was carned out at 260 V and 1,000 mF in a Biorad Gene Pulser II.
After electroporation, cells were resuspended in growth medium and plated in 96-well plate at 40,000 cells/well in 200 ml. Following overnight incubation, the medium was changed to experimental medium Cells were then treated with reference or test compounds in experimental medium Compounds were tested for antiprogestational activity in the presence of 3 nM progesterone. Twenty-four hours after treatment, the medium were discarded, cells were washed three times with D-PBS (GIBCO, BRL).
Fifty ml of cell lysis buffer (Promega, Madison, WI) was added to each well and the plates were shaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.).
Luciferase activity was measured using luciferase reagents from Promega.
When evaluated in the above-described test procedure, the compound of Example 1 had an ICSO of 900 nM. The ICSO is the concentration of test compound that gives half maximal decrease in 3 nM progesterone induced PRE-luciferase activity.
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.
O /
SOZ
N
O
Kasnireddy et al disclosed a series of cyclic sulfonamides, e.g., P and Q, useful for controlling undesired vegetation (WO 9533746).
_ /
N
O ~
N O O N- 'O
F / I F
N S02 ~ ~ N S02 H H
CI CI
P Q
Detailed Description of the Invention This invention provides progesterone receptor antagonists of Formula 1 having the structure R~ R2 R5 \
~~ ~S 02 ~~N
R4 v wherein R,, and Rzare each, independently, hydrogen, alley, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or R, and Rz are taken together form a ring and together contain -CHz(CHz)nCHz- , -CHZCHZCMezCHzCHz-, -O(CHz)pCHz-, O(CHz)q0-, -CHZCHZOCHZCHz-, -CHZCHZNR~CHZCHz-; or R, and Rz are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R~ is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NHz, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR";
RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoallcyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NHz, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoallcyl;
RS is a trisubstituted phenyl ring having the structure, Y~'~~ Z
I
X
X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)zalkyl, aminoalkyl, substituted aminoalkyl, _g_ -NOz, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -CORB, -OCORB, or -NR~CORB;
RB is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R~ is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NOz, alkoxy, alkyl, or thioallcyl; or RS is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SOz and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NOz alkyl, alkoxy, aminoalkyl, CORD, and NRECORD;
RD is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoallcyl;
RE is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, which are usefiil for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy Preferred compounds of this invention are those having the structure:
R~ R2 R5 \
~S 02 wherein R, and Rz are taken together form a ring and together contain -CHz(CHz)"CHz- ;
n = 2-3;
R3 is hydrogen;
R4 is hydrogen;
RS is a trisubstituted phenyl ring having the structure, Y\=~~ z s x X is halogen, OH, -CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NOz, perffuoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, or thioalkoxy;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioallcyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NOZ , alkyl, or alkoxy;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
More preferred compounds of this invention are those having the structure R~ R2 R5 \
~~ N S02 Ra v wherein R, and RZ are taken together form a ring and together contain -CHZ(CHZ)nCH2- ;
n = 2-3;
R3 is hydrogen;
R4 is hydrogen;
R5 is a disubstituted phenyl ring having the structure, X
Y
X is halogen, -CN, or -NOz ;
Y is hydrogen, halogen, -CN, -NOz, alkoxy, alkyl, or thioalkyl; or RS is a five or six membered heteroaryl ring containing a heteroatom selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, or NOz ;
R6 is hydrogen, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereoisomers. While shown without respect to stereochemistry in Formula 1, the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S
stereoisomers and pharmaceutically acceptable salts thereof.
The term "alkyl" is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms; "alkenyl"
includes both straight- and branched-chain alkyl group of 2-6 carbon atoms containing at least one carbon-carbon double bond; "alkynyl" group includes both straight- and branched-chain alkyl group of 2-6 carbon atoms with at least one carbon-carbon triple bond.
The terms "substituted alkyl", "substituted alkenyl", and "substituted alkynyl"
refer to alkyl, alkenyl, and alkynyl as containing one or more substituents from the group including halogen, CN, OH, NOz, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, allcylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term "aryl" is used herein to refer to an aromatic system of 6-14 carbon atoms, which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl groups.
The term "substituted aryl" refers to aryl substituted by one or more substituents from the group including halogen, CN, OH, NOz, amino, alkyl, cycloallcyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term "heterocyclic" is used herein to describe a stable 4-14 membered monocyclic or multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized, as an N-oxide, sulfoxide, or sulfone. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
T'he term "substituted heterocyclic" is used herein to describe a heterocyclic having one or more substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term "thioallcyl" is used herein to refer to the SR group, where R is alkyl or substituted alkyl.
The term "alkoxy" is used herein to refer to the OR group, where R is alkyl or substituted alkyl.
The term "aryloxy" is used herein to refer to the OR group, where R is aryl or substituted aryl.
The term "alkylcarbonyl" is used herein to refer to the RCO group, where R is alkyl or substituted alkyl.
The term "alkylcarboxy" is used herein to refer to the COOR group, where R is alkyl or substituted alkyl. This term is also referred to as alkoxycarbonyl.
The term "aminoallcyl" refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups may be either same or different and the point of attachment is on the nitrogen atom The term "halogen"is defined as Cl, Br, F, and I.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids. for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, malefic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. Salts may also be formed from inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, and organic bases, such as ammonium, mono-, di-, and trimethylammonium, mono-, di- and triethylammonium, mono-, di- and tripropyl-ammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpho-linium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-iso-propylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butyl piperidinium, 2-methyl-piperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methyl-ammonium, phenylmonoethanolammonium, and the like.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
SO2CI SO2NH2 / / I ,SO2 / I / I ~ W I N W N
CI ~ CI H PG
,) ~~) I -.~, _-.
R f '' R~ R2 Br ~ R2 R~ R~
/ / Ar / R2 Ar / R2 I N SO2 ~ \ I N SO2 \ I N SO2 I ,SO2 H
PG PG PG
1 ~ B 9 10 11 Scheme 1 According to Scheme 1, commercially available sulfonyl chloride 4 is converted via the sulfonamide 5 to the 2,1-benzisothiazoline 2,2-dioxide 6 as described in the literature (Chiarino et al, J. Heterocycl. Chem. 23(6), 1645-9, 1986). The nitrogen atom of sultam 6 is then protected by a suitable protecting group, e.g., trimethyl silyl ethyl.
The protected sultam 7 next is treated with a strong organo-metallic base (e.g., butyl lithium, lithium diisopropylamide, potassium hexamethyldisilylazide) in an inert solvent (e.g., THF, diethyl ether) under nitrogen at reduced temperature (ca. -20 °C) (Kende et al, Synth. Commun. 12, 1, 1982). The resulting di-anion then is treated with excess electrophile such as an alkyl halide, preferably the iodide. If R, and Rz are to be joined such as the product contains a spirocycle at position 3, then the electrophile should be bifunctional, i.e., a diiodide. Subsequent bromination of the sultam proceeds regioselectively at room temperature with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium acetate, to give the aryl bromide 9. Judicious choice of reaction conditions may facilitate simultaneous removal of the protecting group at this step.
The bromide 9 then is reacted with a palladium salt (e.g., tetrakis(triphenylphoshine)palladium(0)), in a suitable solvent (e.g., THF, dimethoxyethane, ethanol, toluene) under an inert atmosphere (argon, nitrogen). The mixture then is treated with an arylboronic acid or arylboronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions at elevated temperature to give the biphenyl sultam 10. Finally, the protecting group is removed under appropriate conditions and the final product 11 is isolated and purified by standard means.
If R, and Rz are different then the intermediate is prepared by reacting the dianion of 7 with one equivalent of the electrophile R,-X (X = leaving group, e.g., iodide). The resultant mono-alkylated compound may be then isolated and re-subjected to the reaction conditions using Rz-X, or alternatively used in situ for the second allcylation with RZ-X. Alternatively, if the desired product is to contain RZ
= H, then the isolated mono-alkylated intermediate is taken though the subsequent steps.
Br ~ R~,. 'Rz Ar ~ R~,. 'Rz N SOz ~ N SOz i PG PG
Scheme 2 Other methodologies also are available for coupling the aryl group, Ar, to the sultam platform: for example, reaction of the bromide 9 with an aryl stannane, aryl zinc, or aryl magnesium halide in the presence of a palladium or nickel catalyst (Scheme 2). The required aryl-metallic species are formed via standard techniques.
Furthermore, the bromide 9 may be converted to an aryl boronic acid via standard procedures (treatment with n-butyllithium followed by addition of trimethyl borate and subsequent boronic ester hydrolysis) that will then undergo the range of previously described coupling procedures with a suitable aryl bromide.
The antiprogestational activity of the compounds of this invention was demonstrated in an in vitro standard pharmacological test procedure which evaluated the antiprogestational potency of a representative compound of this invention by measuring its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. The procedure used and results obtained are described in Example 2 below.
The results obtained in this standard pharmacological test procedure demonstrate that the compounds of this invention are progestational antagonists, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endometriosis, luteal phase defects, benign breast and prostatic diseases and prostatic, breast, ovarian, uterine and endometrial cancers.
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 other estrogens, progestins, or androgens.
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 preferably 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, preferably 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.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of this invention can also be administered orally either in liquid or solid composition form.
The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. T'he compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
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 0.02 ~g/kg -750 ~g/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; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated. Preferably, 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 The following provides the preparation of a representative compound of this invention.
Example 1 5-(3-chlorophenyl~piro[2.1-benzisothiazole-3(1H).1'-cyclohexane] 2,2-dioxide To 1,3-dihydro-2,1-benzisothiazoline 2,2-dioxide (Chiarino et al, J.
Heterocycl. Chem. 23(6), 1645-9, 1986) (0.74 g, 4.4 mmol) in anhydrous dichloromethane (minimum amount) at room temperature was added sequentially N,N-diisopropylethylamine (0.76 mL, 4.4 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.77 mL, 4.4 mmol). After 30 min, the reaction was poured into water (50 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give 1, 3-dihydro-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (1.3 g, 99%) as an off white solid. 'H NMR (CDC13, 300MHz) 8 0.02 (s, 9 H), 0.97 (dd, 2 H, J= 8.3, 8.2 Hz), 3. 73 (dd, 2 H, J = 8.2, 8.3 Hz), 4.40 (s, 2 H), 5.08 (s, 2 H), 7.05 (d, 1 H, J = 7.4 Hz), 7.07 (dd, 1 H), 7.26 (d, 1 H, J = 7.4 Hz), 7.35 ('t', 1 H, J = 7.6, 7.6 Hz). MS
((+) ApCI m/z 317 [M+NH4]+.
To 1,3-dihydro-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide ~(1.3 g, 4.3 mmol) in anhydrous tetrahydrofuran (13 mL) at room temperature was added 1,5-diiodopentane (1.29 mL, 8.6 mmol). The mixture was cooled to -78 °C
and lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofiu-an, 17.3 mL, 17 mmol) was added. After 15 min, the reaction mixture was poured into water (50 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (5% ethyl acetate/hexane) on silica gel gave 1,3-dihydro-3-spirocyclohexyl-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (0.8 g, 51%) as an off white solid. 'H NMR (CDCl3, 300 MHz) S 0.00 (s, 9 H), 0.95 (dd, H, J = 8.3, 8.2 Hz), 1.18-2.36 (m, 10 H), 3.72 (dd, 2 H, J = 8.2, 8. 3 Hz), 5.
06 (s, 2 H), 7.03 ('t', 1 H, J= 7.8 Hz), 7.06 (dd, 1 H, J= 1, 7.6 Hz), 7.18 (dd, 1 H, J= l.l, 7.6 Hz), 7.28 (dt, 1 H, J= 1.3, 7.7 Hz). MS (EI) mlz 367 [M]+.
To a stirred solution of 1,3-dihydro-3-spirocyclohexyl-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (0.8 g, 2.2 mmol) in glacial acetic acid (5 mL) at room temperature was added dropwise a solution of bromine (0.11 mL, 2.2 mmol) in glacial acetic acid (2.2 mL) After stirring for 10 min, anhydrous sodium acetate (0.18 g, 2.2 mmol) was added and the solution was concentrated in vacuo.
The residue was dissolved in ethyl ether (50 mL) and washed sequentially with water (50 mL), aqueous saturated sodium bicarbonate solution (50 mL), water (50 mL) and brine (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (20% ethyl acetate/hexane) on silica gel gave a complex mixture of products (0.56 g) with identical TLC characteristics as a white foam. The mixture was used without further purification.
A solution of the mixture containing 5-bromo-1,3-dihydro-3-spirocyclohexyl-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (0.56 g, 1.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg) in toluene (25 mL) was stirred under a flow of nitrogen for 25 min. To the solution was added sequentially solutions of 3-chlorophenylboronic acid (0.4 g, 2.5 mmol) in absolute ethanol (5 mL) and potassium carbonate (0.35 g, 2.5 mmol) in water (5 mL). The mixture was heated to 80 °C for 16 h and allowed to cool. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution (50 mL) and the layers were separated.
The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with water (50 mL) and brine (30 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (2% ethyl acetate/toluene) and then by HPLC to give the title compound (65 mg) as a low melting yellow foam. HPLC
conditions: Zorbax PRO, C18, 10u, 15A, 50 x 250 mm; mobile phase composition and gradient program, 70% water/ 30% AcCN; flow rate, 100 mL/min; injection volume, 120 mg/3 mL MeOH; detection wavelength, 280 nm, 500 PSI; temperature, amb. 'H NMR (DMSO-db, 300 MHz), 8 1.47-2.19 (m, 10 H), 6.87 (d, 1 H , J = 8.2 Hz), 7.38 ('d', 1 H, J = 8.1 Hz), 7.46 ('t', 1 H, J = 7.9, 7.7 Hz), 7.56 (dd, 1 H, J =
1.7, 8.2 Hz), 7.62 ('d', 1 H, J = 7.7 Hz), 7.71, ('d', 1 H, J = 1.7 Hz), 7.75 (bs, 1H), 10.55 (bs, 1 H). MS (EI) m/z 347 [M]+. Anal. Calcd for CISH,sCINOaS: C, 62.15;
H, 5.22: N, 4.03. Found: C, 59.84; H, 5.30; N, 3.57.
Example 2 - Biological Activity The antiprogestational activity of the compound of Example 1 was demonstrated in a conventional pharmacological test.
Rea~ants Growth medium: DMEM (BioWhittaker) containing 10% (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acids, 100U/ml penicillin, 100mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
Experimental medium: DMEM (BioWhittaker), phenol red-free, containing 10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM
MEM non-essential amino acids, 100U/ml penicillin, 100mg/ml streptomycin, and mM GlutaMax (GIBCO, BRL).
Test Procedure Stock CV-1 cells were maintained in growth medium. Co-transfection was done using 1.2x10' cells, 5 mg pLEM plasmid with hPR-B inserted at Sphl and BamHl sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg sonicated calf thymus DNA as Garner DNA in 250 ml.
Electroporation was carned out at 260 V and 1,000 mF in a Biorad Gene Pulser II.
After electroporation, cells were resuspended in growth medium and plated in 96-well plate at 40,000 cells/well in 200 ml. Following overnight incubation, the medium was changed to experimental medium Cells were then treated with reference or test compounds in experimental medium Compounds were tested for antiprogestational activity in the presence of 3 nM progesterone. Twenty-four hours after treatment, the medium were discarded, cells were washed three times with D-PBS (GIBCO, BRL).
Fifty ml of cell lysis buffer (Promega, Madison, WI) was added to each well and the plates were shaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.).
Luciferase activity was measured using luciferase reagents from Promega.
When evaluated in the above-described test procedure, the compound of Example 1 had an ICSO of 900 nM. The ICSO is the concentration of test compound that gives half maximal decrease in 3 nM progesterone induced PRE-luciferase activity.
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.
Claims (9)
1. A compound formula I having the structure wherein R1, and R2 are each, independently, hydrogen, alky, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-, -CH2CH2CMe2CH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-, -CH2CH2NR7CH2CH2-; or R1 and R2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2; alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perffuoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl, alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2; alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perffuoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl, alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein wherein R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-;
n = 2-3;
R3 is hydrogen;
R4 is hydrogen;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, or thioalkoxy;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl, or alkoxy;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
n = 2-3;
R3 is hydrogen;
R4 is hydrogen;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, or thioalkoxy;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl, or alkoxy;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein R5 is a disubstituted phenyl ring having the structure, X is halogen, -CN, or -NO2;
Y is hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing a heteroatom selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, or NO2;
R6 is hydrogen, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
Y is hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing a heteroatom selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, or NO2;
R6 is hydrogen, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
4. A compound of Claim 3 wherein R5 is selected from the group of
5. The compound of claim 1, which is 5-(3-chlorophenyl)-spiro[2,1-benzisothiazole-3(1H),1'-cyclohexane] 2,2-dioxide or a pharmaceutically acceptable salt thereof.
6. A method of providing progestational therapy to a mammal in need thereof which comprises administering a progestationally effective amount of compound formula 1 having the structure wherein R1, and R2 are each, independently, hydrogen, alley, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-, -CH2CH2CMeCH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-, -CH2CH2NR7CH2CH2-; or R1 and R2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl, alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof to said mammal.
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl, alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof to said mammal.
7. A method of treating or inhibiting breast, uterine, ovarian, endometrial, or prostate cancer which comprises administering a compound formula 1 having the structure wherein R1, and R2 are each, independently, hydrogen, alky, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-, -CH2CH2CMe2CH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-, -CH2CH2NR7CH2CH2-; or R1 and R2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2, alkyl, alkoxy, aminoalkyl, CORD, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, to said mammal.
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2, alkyl, alkoxy, aminoalkyl, CORD, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, to said mammal.
8. A method of providing contraception in a mammal in need thereof, which comprises administering an effective amount compound formula 1 having the structure wherein R1, and R2 are each, independently, hydrogen, alky, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-, -CH2CH2CMe2CH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-, -CH2CH2NR,CH2CH2-; or R1 and R2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2 alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR7COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2, alkyl, alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, to said mammal.
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2 alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR7COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2, alkyl, alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, to said mammal.
9. A pharmaceutical composition, which comprises a compound formula 1 having the structure wherein R1, and R2 are each, independently, hydrogen, alky, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-, -CH2CH2CMe2CH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-, -CH2CH2NR7CH2CH2-; or R1 and R2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl, alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B, -OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl, alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18303999P | 1999-05-04 | 1999-05-04 | |
| US60/183,039 | 1999-05-04 | ||
| US09/552,630 | 2000-04-19 | ||
| US09/552,630 US6339098B1 (en) | 1999-05-04 | 2000-04-19 | 2,1-benzisothiazoline 2,2-dioxides |
| PCT/US2000/011823 WO2000066574A1 (en) | 1999-05-04 | 2000-05-01 | 2,1-benzisothiazoline 2,2-dioxides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2371758A1 true CA2371758A1 (en) | 2000-11-09 |
Family
ID=26878685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002371758A Abandoned CA2371758A1 (en) | 1999-05-04 | 2000-05-01 | 2,1-benzisothiazoline 2,2-dioxides |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1175413A1 (en) |
| JP (1) | JP2002543195A (en) |
| CN (1) | CN1349518A (en) |
| AU (1) | AU4813800A (en) |
| CA (1) | CA2371758A1 (en) |
| MX (1) | MXPA01011292A (en) |
-
2000
- 2000-05-01 MX MXPA01011292A patent/MXPA01011292A/en not_active Application Discontinuation
- 2000-05-01 EP EP00930286A patent/EP1175413A1/en not_active Withdrawn
- 2000-05-01 CA CA002371758A patent/CA2371758A1/en not_active Abandoned
- 2000-05-01 CN CN 00807091 patent/CN1349518A/en active Pending
- 2000-05-01 AU AU48138/00A patent/AU4813800A/en not_active Abandoned
- 2000-05-01 JP JP2000615604A patent/JP2002543195A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP1175413A1 (en) | 2002-01-30 |
| AU4813800A (en) | 2000-11-17 |
| CN1349518A (en) | 2002-05-15 |
| JP2002543195A (en) | 2002-12-17 |
| MXPA01011292A (en) | 2003-07-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |