WO2004000225A2 - Use of thio-oxindole derivatives in treatment of hormone-related conditions - Google Patents
Use of thio-oxindole derivatives in treatment of hormone-related conditions Download PDFInfo
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- WO2004000225A2 WO2004000225A2 PCT/US2003/019710 US0319710W WO2004000225A2 WO 2004000225 A2 WO2004000225 A2 WO 2004000225A2 US 0319710 W US0319710 W US 0319710W WO 2004000225 A2 WO2004000225 A2 WO 2004000225A2
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- indol
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- cyclohexane
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- 0 *c(cc1)cc(C23CCCCC2)c1NC3=C[N+]([O-])=O Chemical compound *c(cc1)cc(C23CCCCC2)c1NC3=C[N+]([O-])=O 0.000 description 2
- NYHLTQQLXYEXSJ-UHFFFAOYSA-N CCCS=C(C(OC(C)(C)O1)=O)C1=O Chemical compound CCCS=C(C(OC(C)(C)O1)=O)C1=O NYHLTQQLXYEXSJ-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Definitions
- This invention relates generally to the treatment of hormone-related conditions using compositions containing small molecules.
- estrogen has been utilized for its positive effects including the maintenance of bone density, central nervous system (CNS) function, and the protection of organ systems from the effects of aging.
- CNS central nervous system
- the delivery of estrogen also has important disadvantages including an increase in the risk of cancers.
- a method of inducing contraception which includes delivering a compound of formula I and a selective estrogen receptor modulator, wherein formula I is:
- a method of providing hormone replacement therapy which includes delivering a compound of formula I and a selective estrogen receptor modulator.
- methods of treating carcinomas, dysfunctional bleeding, uterine leiomyomata, endometriosis, and polycystic ovary syndrome is provided which includes delivering a compound of formula I and a selective estrogen receptor modulator.
- the present invention provides methods of treating hormone related conditions including delivering to a mammal a composition comprising a compound of formula I in a regimen which includes delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to the mammal.
- the mammalian patient treated according to the present invention is a human, and more preferably a female.
- the mammalian patient is a female of child-bearing age.
- the mammalian patient is preferably a pre-menopausal, menopausal, or post-menopausal female.
- SERM selective estrogen receptor modulator
- SERMs can act as estrogen receptor agonists in some tissues and as antagonists in other tissue types.
- SERMs can also be interchanged with the term "anti-estrogen”.
- estrogen is mean to describe any estrogenic agent.
- the estrogenic agent is a conjugated equine estrogen.
- estrogen-related conditions are treated using the compositions of the present invention.
- Such estrogen related conditions can include, without limitation, the induction of contraception, providing hormone replacement therapy, the treatment of obesity, carcinomas, osteoporosis, endometriosis, menopausal syndromes (including perimenopausal, menopausal, or postmenopausal syndromes), hair loss (alopecia), diabetes, Alzheimer's Disease, urinary incontinence, arthritis, gastrointestinal (GI) tract conditions, acne, cataracts, hirsutism, polycystic ovary syndrome, uterine leiomyomata, multiple myeloma, dysfunctional bleeding, lymphoma, dysmennorhea, and the stimulation of food intake.
- carcinomas examples include breast, prostate, colon, lung, ovarian, melanoma, central nervous system (CNS), cervical, uterine, endometrial, and renal carcinomas.
- the present invention provides methods of inducing contraception including the step of delivering to a female of child-bearing age a composition comprising a compound of formula I in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to the female.
- methods for providing hormone replacement therapy including the step of delivering to a female a composition comprising a compound of formula I in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to the female.
- the present invention further provides methods for treating carcinomas including the step of delivering to a mammal in need thereof a composition comprising a compound of formula I in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to the mammal. Additionally provided are methods for treating dysfunctional bleeding, uterine leiomyomata, endometriosis, or polycystic ovary syndrome, including the step of delivering to a female in need thereof a composition comprising a compound of formula I in a regimen which involves delivering a pharmaceutically effective amount of one or more of a selective estrogen receptor modulator to the female.
- the methods of the present invention include the delivery of compounds of formula I, the preparation of which is described in US Patent No. 6,355,648 and International Patent Publication No. WO 00/66555, and hereby incorporated by reference.
- these compounds are progesterone-receptor (PR) modulators, which, when used in the methods of the invention, are delivered as a PR agonist.
- PR progesterone-receptor
- R and R are selected from the group consisting of H, alkyl, substituted alkyl,
- OH O(alkyl), O(substituted alkyl), O(Acetyl), aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, alkylaryl, substituted alkylaryl, alkylheteroaryl, substituted alkylheteroaryl, 1-propynyl, substituted 1-propynyl, 3-propynyl, and substituted 3-propynyl; or R and R are joined to form a ring selected from the group consisting of
- R 3 is selected from the group consisting of H, OH, NH 2 , Cj to C alkyl, substituted Ci to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, and COR A ;
- R A is selected from the group consisting of H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, Ci to C 3 alkoxy, substituted Ci to C alkoxy, Ci to C 3 aminoalkyl, and substituted C ⁇ to C 3 aminoalkyl;
- R 4 is selected from the group consisting of H, halogen, CN, NH 2 , C
- R 5 is selected from the group consisting of a), b) and c): a) a substituted benzene ring having the structure:
- X is selected from the group consisting of halogen, OH, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, Ci to C 3 alkoxy, substituted Cj to C 3 alkoxy, d to C thioalkyl, substituted Ci to C 3 thioalkyl, S(O)alkyl, S(O) 2 alkyl, Ci to C 3 aminoalkyl, substituted Ci to C aminoalkyl, NO2, Ci to C 3 perfluoroalkyl, substituted Ci to C perfluoroalkyl, 5 or 6 membered heterocyclic ring comprising 1 to 3 heteroatoms, CONH 2 , CSNH 2, CNHNHOH, CNH 2 NOH, CNHNOH, COR B , CSR B , OCOR B , and NR c COR B ; R B is selected from the group consisting of H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl
- R D is H, NH 2 , Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 aminoalkyl, or substituted Ci to C 3 aminoalkyl;
- R E is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl
- R 6 is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, or Ci to C 4 CO 2 alkyl
- Q 1 is S, NR 7 , or CR 8 R 9 ;
- R 7 is selected from the group consisting of CN, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO 2 CF 3 , OR 1 ', and NR 1 *R 12 ; R and R are independent substituents selected from the group consisting of
- alkyl substituted alkyl, acyl, substituted acyl, aroyl, substituted aroyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO2, CN, and CO2R 10 ;
- R 10 is Ci to C 3 alkyl or substituted Ci to C 3 alkyl; or CR R comprise a six membered ring having the structure:
- R 11 and R 12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl; or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
- R and R are selected from among substituted or unsubstituted C ⁇ -C 6 alkyls.
- R 1 and R 2 are alkyl or substituted alkyl;
- R 3 is H;
- R 11 and R 12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl; the other substituents are as defined above, and a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
- R and R are joined to form a ring selected from the group consisting of -CH2(CH 2 ) complicatCH 2 -, -CH 2 CH 2 C(CH 3 )2CH2CH2-, -O(CH 2 ) m CH 2 -, -O(CH 2 ) p O-,
- the ring has the structure
- R when R 1 and R 2 are joined to form a ring, R is H; R and R are independent substituents selected from the group consisting of H, Ci to C alkyl, substituted Ci to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, NO 2 , CN, and CO 2 R 1 ; and the other substituents are as defined above; or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
- R 3 is H; Q 1 is S or
- R 7 is selected from the group consisting of CN, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, SO 2 CF 3 , OR ⁇ and NR 1 ⁇ 12 ; R u and R 12 are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic ring, substituted heterocyclic ring, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl; or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
- R 11 is selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl;
- R 5 is (i), (ii), or (iii):
- X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2j CNHNHOH, CNH 2 NOH, Ci to C 3 alkoxy, Ci to C 3 alkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocyclic ring comprising 1 to 3 heteroatoms, and Cj to C 3 thioalkyl;
- Y is selected from the group consisting of H, halogen, CN, NO 2 , d to C 3 alkoxy, Ci to C 4 alkyl, and to C thioalkyl;
- U is O, S, or NR 6 ;
- R 6 is H, Ci to C 3 alkyl, or Ci to C 4 CO 2 alkyl;
- X' is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CNHNHOH, CNH 2 NOH, CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2( Ci to C 3 alkyl, and Ci to C 3 alkoxy;
- Y' is selected from the group consisting of H, F, and Ci to C 4 alkyl; or (iii) a six membered ring having the structure:
- X 1 is N or CX 2 ;
- X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 ; or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
- R 5 is the five membered ring (ii) and U is O or S.
- the compound is of formula III:
- R 5 is (i), (ii), or (iii):
- X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2> CNHNOH, C, to C 3 alkoxy, Ci to C alkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocyclic ring comprising 1 to 3 heteroatoms, and Ci to C 3 thioalkyl;
- Y is selected from the group consisting of H, halogen, CN, NO 2 , Ci to C alkoxy, Ci to C 4 alkyl, and C ⁇ to C 3 thioalkyl;
- U is O, S, or NR 6 ;
- R 6 is H, C, to C 3 alkyl, or C, to C 4 CO 2 alkyl;
- X' is selected from the group consisting of halogen, CN, NO 2 , CONH , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2, C, to C 3 alkyl, and d to C 3 alkoxy;
- Y' is selected from the group consisting of H, F and Ci to C 4 alkyl; or (iii) a six membered ring having the structure:
- X 1 is N or CX 2 ;
- X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 ; or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
- R 5 is the five membered ring (ii) and U is O or S.
- the compound is of formula IV:
- R 8 is selected from the group consisting of H, CO 2 R 10 , acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, and CN; R 10 is C, to C 3 alkyl; R 5 is (i), (ii), or (iii):
- X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2, CNHNOH, Q to C 3 alkoxy, Ci to C 3 alkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocyclic ring comprising 1 to 3 heteroatoms, and Ci to C 3 thioalkyl;
- Y is selected from the group consisting of H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C 4 alkyl, and d to C 3 thioalkyl;
- U is O, S, or NR 6 ;
- R 6 is H, Ci to C 3 alkyl, or C, to C 4 CO 2 alkyl;
- X' is selected from the group consisting of halogen, CN, NO 2 , CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2, Ci to C 3 alkyl, and C, to C 3 alkoxy;
- Y' is selected from the group consisting of H, F and Ci to C 4 alkyl; (iii) a six membered ring having the structure:
- X 1 is N or CX 2 ;
- X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 or NO 2 ; or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
- R 5 is the five-membered ring (ii) and U is O or S.
- the compound is of formula V:
- R 5 is (i), (ii), or (iii):
- X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2, CNHNOH, C, to C 3 alkoxy, Ci to C 3 alkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocyclic ring comprising 1 to 3 heteroatoms, and Ci to C 3 thioalkyl; Y is selected from the group consisting of H, halogen, CN, NO 2 , Ci to
- U is O, S, or NR 6 ;
- R 6 is H, Ci to C 3 alkyl, or Ci to C 4 CO 2 alkyl;
- X' is selected from the group consisting of halogen, CN, NO 2 , CONH , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 ⁇ C, to C 3 alkyl, and C, to C 3 alkoxy;
- Y' is selected from the group consisting of H, F, and Ci to C 4 alkyl;
- X' is N or CX 2 ;
- X 2 is halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl,
- R 5 is the five membered ring (ii) and U is O or S.
- the compound is selected from the group consisting of 5'-(3-Chlorophenyl)spiro[cyclohexane-l,3'-[3H]indol]-2'(rH)-thione, 3- ( 1 ',2'-Dihydro-2'-thioxospiro [cyclohexane- 1 ,3 "-[3 H] indol] -5 '-yl)benzonitrile, 4-( 1 ' ,2 ' - Dihydro-2 ' -thioxospiro [cyclohexane- 1 ,3 ' - [3 H] indol] -5 ' -yl)-2-thiophenecarbonitrile, 3 -( 1 ,2-Dihydro-2-thioxospiro [cyclohexane- 1 ,3 - [3 H] indol] -5 -yl)-5 -fluorobenzonitrile,
- the compound is 5'-(5-Cyano-l-methyl-lH-pyrrol-2-yl)spiro [cyclohexane- 1,3'- [3 H] indol] -2 ' -ylidenecyanamide, or a pharmaceutically acceptable salt, tautomer, metabolite, or prodrug thereof.
- the compounds utilized according to the present invention can contain one or more asymmetric centers and can thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the compounds can include optical isomers and diastereomers; racemic and resolved enantiomerically pure R and S stereoisomers; other mixtures of the R and S stereoisomers; and pharmaceutically acceptable salts thereof.
- alkyl is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having about 1 to about 8 carbon atoms, and preferably about 1 to about 6 carbon atoms.
- alkenyl is used herein to refer to both straight- and branched-chain alkyl groups having one or more carbon- carbon double bonds and containing about 2 to about 8 carbon atoms.
- alkenyl refers to an alkyl group having 1 or 2 carbon-carbon double bonds and having 2 to about 6 carbon atoms.
- alkynyl group is used herein to refer to both straight- and branched-chain alkyl groups having one or more carbon-carbon triple bond and having 2 to about 8 carbon atoms.
- alkynyl refers to an alkyl group having 1 or 2 carbon-carbon triple bonds and having 2 to about 6 carbon atoms.
- substituted alkyl refers to alkyl, alkenyl, and alkynyl groups, respectively, having one or more substituents including, without limitation, halogen, CN, OH, NO 2 , amino, aryl, heterocyclic groups, aryl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl, alkylcarboxy, amino, and arylthio which groups can be optionally substituted.
- acyl refers to a carbonyl substituent, i.e., a C(O)(R) group where R is a straight- or branched-chain saturated aliphatic hydrocarbon group including, without limitation, alkyl, alkenyl, and alkynyl groups.
- R groups Preferably, the R groups have 1 to about 8 carbon atoms, and more preferably 1 to about 6 carbon atoms.
- substituted acyl refers to an acyl group which is substituted with 1 or more groups including halogen, CN, OH, and NO 2 .
- aryl refers to an aromatic system which can include a single ring or multiple aromatic rings fused or linked together where at least one part of the fused or linked rings forms the conjugated aromatic system.
- the aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl, fluorenyl, and carbazolyl.
- substituted aryl refers to an aryl group which is substituted with one or more substituents including halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio, which groups can be optionally substituted.
- a substituted aryl group is substituted with 1 to about 4 substituents.
- heterocyclic refers to a stable 4- to 7-membered monocyclic or multicyclic heterocyclic ring which is saturated, partially unsaturated, or wholly unsaturated.
- the heterocyclic ring has in its backbone carbon atoms and one or more heteroatoms including nitrogen, oxygen, and sulfur atoms.
- the heterocyclic ring has about 1 to about 4 heteroatoms in the backbone of the ring.
- the nitrogen or sulfur atoms can be oxidized.
- heterocyclic also refers to multicyclic rings in which a heterocyclic ring is fused to an aryl ring.
- the heterocyclic ring can be attached to the aryl ring through a heteroatom or carbon atom provided the resultant heterocyclic ring structure is chemically stable.
- heterocyclic groups include, without limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and combinations thereof.
- Oxygen-containing rings include, but are not limited to, furyl, tetrahydrofuranyl, pyranyl, pyronyl, and dioxinyl rings.
- Nitrogen-containing rings include, without limitation, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, azepinyl, triazinyl, pyrrolidinyl, and azepinyl rings.
- Sulfur-containing rings include, without limitation, thienyl and dithiolyl rings.
- Mixed heteroatom containing rings include, but are not limited to, oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, and diazepinyl rings.
- Fused heteroatom-containing rings include, but are not limited to, benzofuranyl, thionapthene, indolyl, benazazolyl, purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl, benzodiazonyl, napthylridinyl, benzothienyl, pyridopyridinyl, benzoxazinyl, xanthenyl, acridinyl, and purinyl rings.
- substituted heterocyclic refers to a heterocyclic group having one or more substituents including halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio, which groups can be optionally substituted.
- a substituted heterocyclic group has 1 to 4 substituents.
- aroyl refers to a carbonyl substituent bound to a phenyl or heterocyclic group.
- the aroyl heterocyclic groups include 2- pyridinyl, 3-pyridinyl, 2-furanyl, 3-furanyl, 3-thiophenyl, 2-pyrimidinyl, and 4- pyrimidinyl groups.
- substituted aroyl refers to an aroyl group which is substituted with one or more groups including, without limitation, halogen, CN, OH, and NO 2 .
- thioalkyl as used herein is used interchangeably with the term
- thioalkoxy with both referring to an S(alkyl) group, where the point of attachment is through the sulfur-atom and the alkyl group can be optionally substituted.
- arylthio refers to the S(aryl) group, where the point of attachment is through the sulfur-atom and the aryl group can be optionally substituted.
- alkoxy refers to the O(alkyl) group, where the point of attachment is through the oxygen-atom and the alkyl group is optionally substituted.
- aryloxy refers to the O(aryl) group, where the point of attachment is through the oxygen-atom and the aryl group is optionally substituted.
- alkylcarbonyl refers to the C(O)(alkyl) group, where the point of attachment is through the carbon-atom of the carbonyl moiety and the alkyl group is optionally substituted.
- alkylcarboxy refers to the C(O)O(alkyl) group, where the point of attachment is through the carbon-atom of the carboxy moiety and the alkyl group is optionally substituted.
- aminoalkyl refers to both secondary and tertiary amines where the point of attachment is through the nitrogen-atom and the alkyl groups are optionally substituted.
- the alkyl groups can be the same or different.
- halogen refers to CI, Br, F, or I groups.
- the compounds of the present invention encompass tautomeric forms of the structures provided herein characterized by the bioactivity of the drawn structures. Further, the compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids, bases, alkali metals and alkaline earth metals.
- Physiologically acceptable acids include those derived from inorganic and organic acids. A number of inorganic acids are known in the art and include hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, and phosphoric acids, among others.
- organic acids include, without limitation, lactic, formic, acetic, fumaric, citric, propionic, oxalic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, tartaric, maionic, mallic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, panthenoic, benzenesulfonic, toluenesulfonic, stearic, sulfanilic, alginic, and galacturonic acids, among others.
- Physiologically acceptable bases include those derived from inorganic and organic bases.
- inorganic bases include aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc sulfate or phosphate compounds, among others.
- organic bases include, without limitation, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine, among others.
- Physiologically acceptable alkali salts and alkaline earth metal salts can include, without limitation, sodium, potassium, calcium and magnesium salts in the form of esters, and carbamates.
- prodrug forms can also be utilized which, when delivered in such form, convert to the active moiety in vivo.
- These salts, as well as other compounds of the invention can be in the form of esters, carbamates and other conventional "pro-drug” forms, which, when administered in such form, convert to the active moiety in vivo.
- the prodrugs are esters. See, e.g., B. Testa and J. Caldwell, "Prodrugs Revisited: The "Ad Hoc” Approach as a Complement to Ligand Design", Medicinal Research Reviews, 16(3):233-241, ed., John Wiley & Sons (1996).
- the compounds of formula I and/or salts, prodrugs or tautomers thereof are delivered in regimens which further involve delivery of SERMS.
- the compounds discussed herein also encompass "metabolites" which are unique products formed by processing the compounds of the invention by the cell or patient. Preferably, metabolites are formed in vivo.
- the SERMs used in the compositions and methods of the present invention can be chemically synthesized according to known methods, and include the salt forms of the compounds including tamoxifene (Nolvadex - AstraZeneca); 4-hydroxy- tamoxifene (AstraZeneca); raloxifene (Evista - Eli Lilly); droloxifene (Pfizer); toremifene (Fareston - Schering); iodotamoxifen (AstraZeneca); idoxifene (GSK); ICI182780 (Faslodex - AstraZeneca); EM-800 (Schering); EM-652 (Schering); arzoxifene (Eli Lilly); lasofoxifene (Pfizer
- SERMS include cycladiene (Dienestrol); nafoxidine; nitromifene citrate; 13 -ethyl- 17 ⁇ -ethynyl-17 ⁇ -hydroxygona- 4-9-1 l-trien-3-one; diphenol hydrochryscne; erythro-MEA; allenolic acid; cyclofenyl; chlorotrianisene (TACE); ethamoxytriphetol (MER-25); triparanol; CI-626; CI-680; U-11.555A; U-11.100A; ICI-46,669; ICI-46,474; and CN-55,945 as described in US Patent No. 6,258,802.
- the SERM is raloxifene hydrochloride, arzoxifene, lasofoxifene, droloxifene, tamoxifen citrate, 4-hydroxytamoxifen citrate, clomiphene citrate, toremifene citrate, pipendoxifene, or avadoxifene.
- oxindole 3 can be treated with a strong organometallic base (e.g. butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide) 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) in the presence of lithium chloride or N,N,N',N'-tetramethylethylenediamine.
- a strong organometallic base e.g. butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide
- an inert solvent e.g. THF, diethyl ether
- the electrophile should be bifunctional, i.e. a diiodide.
- Subsequent bromination of 4 proceeds smoothly with bromine in acetic acid (an organic co-solvent such as dichloromethane can be added as required) in the presence of sodium acetate, to afford the aryl bromide 5.
- the bromide 5 can be reacted with a palladium salt (e.g. tetrakis(triphenylphosphine)palladium(0) or palladium acetate), in a suitable solvent (e.g.
- the resultant mono-alkylated compound can then be isolated and re- subjected to the reaction conditions using R 2 -X, or alternatively used in-situ for the second alkylation with R 2 -X.
- R 2 -X or alternatively used in-situ for the second alkylation with R 2 -X.
- An alternative mode of preparation is to react compound 5 with either Lawessen's reagent or phosphorous pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent, under an inert atmosphere (nitrogen or argon) providing access to the thiocarbonyl derivative 13.
- a suitable organic solvent pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene
- an inert atmosphere nitrogen or argon
- Compound 14 can then be reacted under palladium catalyzed conditions tetrakis(triphenylphosphine)palladium(0) or palladium acetate, base (NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , triethylamine, CsF) solvent (toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane) with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired compounds 7.
- base NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , triethylamine, CsF
- solvent toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxy
- Compound 15 can then be reacted under palladium catalyzed conditions tetrakis(triphenylphosphine)palladium(0), base (NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , triethylamine, CsF) solvent (toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane) with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired compounds 6.
- base NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , triethylamine, CsF
- solvent toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane
- An alternative strategy can be to prepare an organozinc or magnesium reagent from compound 5 and react it in-situ with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate of aryl or heteroaryl fluorosulfonate, under palladium catalyzed conditions to afford compound 6.
- an organozinc or magnesium species could be prepared by treatment of the bromide 7 in an anhydrous solvent (e.g.
- thioamide derivative 7 can be converted into enamine derivative 16 (Wrobel, et al, J. Med. Chem., 1989, 2493).
- a carbon nucleophile such as a malonate derivative (e.g., malononitrile, a cyano acetate ester, a nitro acetate ester or a malonate) in the presence of a suitable base (e.g. an amine base such as pyridine, triethylamine or di-iso-propylethylamine or lithium, sodium, potassium or cesium carbonate) or a Lewis acid (e.g. boron trifluoride etherate, a lead II salt, titanium tetrachloride, a magnesium II salt, or a silver salt) in a solvent compatible with the chosen base or Lewis acid (e.g.
- a suitable base e.g. an amine base such as pyridine, triethylamine or di-iso-propylethylamine or lithium, sodium, potassium or cesium carbonate
- a Lewis acid e.g. boron trifluoride etherate, a lead II salt, titanium
- R 3 group in adduct 19 is an ester of a carboxylic acid
- it can be decarboxylated directly to give the enamine derivative 20 by treatment with, e.g. sodium iodide in DMSO at a temperature between room temperature and thee boiling point of the solvent.
- the ester can be first hydro lyzed to the carboxylic acid by treatment with an aqueous base (e.g. lithium, sodium, or potassium hydroxide) in a suitable solvent (e.g.
- the xanthate ester of the carboxylic acid can be prepared by reaction with a base such as sodium or potassium hydride in THF, followed by treatment with carbon disulfide.
- the bromide 13 (the corresponding chloride, iodide or inflate ester can also be employed) can be treated with an alkylating agent, e.g., methyl iodide, ethyl iodide, 2,4-dinitrofluoro benzene, or 4-nitro fluorobenzene, in the presence of a suitable base (e.g. an amine base such as pyridine, triethylamine or di-iso- propylethylamine or lithium, sodium, potassium or cesium carbonate) in a suitable organic solvent (e.g.
- a suitable base e.g. an amine base such as pyridine, triethylamine or di-iso- propylethylamine or lithium, sodium, potassium or cesium carbonate
- a suitable organic solvent e.g.
- Intermediate 22 could then be protected with a compatible group (e.g. benzyl ether, acyl derivative, tetrahydropyranyl ether, methoxy methyl ether, silyl ether) to give the derivative 23.
- a compatible group e.g. benzyl ether, acyl derivative, tetrahydropyranyl ether, methoxy methyl ether, silyl ether
- compound 21 can be reacted directly with a protected hydroxylamine derivative (chosen, but not limited to, from the protecting groups described above) to directly afford derivative 23.
- Compound 23 can then be reacted with a palladium salt (e.g. tetrakis(triphenylphosphine)palladium(0) or palladium acetate), in a suitable solvent (e.g.
- Compound 24 can then be deprotected under the conditions prescribed by the nature of the protecting group.
- the protecting group is a benzyl ether
- treatment with boron tribromide or trimefhylsilyl iodide in a suitable solvent (dichloromethane for example) can afford the compound 18.
- Other methods to remove the benzyl ether can involve hydrogenation (hydrogen gas or other hydrogen source such as cyclohexadiene or ammonium formate) in the presence of a palladium catalyst.
- Solvents suitable for such a process include methanol, ethanol, THF, ethyl acetate and dioxane, at a temperature between room temperature and the boiling point of the solvent.
- the protecting group was an acetal derivative (tetrahydropyranyl or methoxymethyl ethers) then hydrolysis could be effected under acidic conditions (hydrochloric acid, sulfuric acid, p-toluene sulfonic acid or acidic ion exchange resin) in a solvent such as methanol, ethanol, THF dioxane or acetonitrile.
- acidic conditions hydrolysis
- a solvent such as methanol, ethanol, THF dioxane or acetonitrile.
- the protecting group was an acyl derivative (acetate, or benzoate for example) then hydrolysis can be effected under acidic conditions as described above or under basic conditions (lithium, sodium or potassium hydroxide) in a solvent such as an alcohol, THF dioxane or acetonitrile at a temperature between room temperature and the boiling point of the solvent
- compound 18 can be prepared by hydrolyzing intermediate 24 under the acidic conditions described above or alternately by exposing compound 24 to a fluoride source (e.g., potassium fluoride, cesium fluoride or tetrabutylammonium fluoride) in a solvent such as an alcohol, THF dioxane or acetonitrile at a temperature between room temperature and the boiling point of the solvent. An inert atmosphere of nitrogen or argon can be necessary. Another method of synthesizing compound 18 can be to convert the protected fluoride source (e.g., potassium fluoride, cesium fluoride or tetrabutylammonium fluoride) in a solvent such as an alcohol, THF dioxane or acetonitrile at a temperature between room temperature and the boiling point of the solvent. An inert atmosphere of nitrogen or argon can be necessary. Another method of synthesizing compound 18 can be to convert the protected fluoride source (e.g., potassium fluoride, cesium fluor
- N-hydroxy amidine 23 into a boronic acid or boronic acid ester (by lithium halogen exchange followed by quench with tri-isopropyl borate, or palladium catalyzed coupling with diboron pinacolate) and then couple this boronic acid or ester derivative with an aryl chloride, bromide, iodide or triflate under a suitable palladium catalysis system as described previously. Subsequent deprotection as described for Scheme 8 can afford the desired compounds 18.
- cyanogen bromide, N-cyanobenzotriazole or cyanogen bromide/ 4-dimethylaminopyridine complex in a suitable solvent (THF acetonitrile or DMF, optionally in the presence of a base such as pyridine or sodium hydride or potassium tert-butoxide) can then afford the desired compound 27.
- a suitable solvent THF acetonitrile or DMF, optionally in the presence of a base such as pyridine or sodium hydride or potassium tert-butoxide
- a base such as pyridine or sodium hydride or potassium tert-butoxide
- compositions of the invention can be delivered by a route such as oral, dermal, transdermal, intrabronchial, intranasal, intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, intranasal, vaginal, rectal, sublingual, intracranial, epidural, intratracheal, or by sustained release.
- delivery is oral or transdermal.
- the compounds of formula I are delivered in a regimen with one or more SERMS, but with each active component delivered by different routes.
- a pharmaceutically effective amount of the compositions used according to the present invention can vary depending on the specific compositions, mode of delivery, severity of the hormone related condition being treated, and any other active ingredients used in the formulation or the selected regimen, among others.
- the dosing regimen can be adjusted to provide the optimal therapeutic response. Several divided doses can be delivered daily, e.g., in divided doses 2 to 4 times a day, or a single daily dose can be delivered. The dose can however be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
- the dosing schedule for each can be the same, or can differ.
- the delivery can be on a daily, weekly, or monthly basis, and more preferably on a daily delivery. Daily dosages can be lowered or raised based on the periodic delivery.
- the compound(s) of formula I are delivered at a daily dosage of from about 0.1 to about 500 mg body weight, more preferably at a total daily dosage is from about 0.1 to about 100 mg, and most preferably from about 0.1 to about 50 mg.
- the amount of SERM utilized according to the present invention is preferably at least 0.2 mg per day, more preferably from about 0.2 mg to about 200 mg per day, and most preferably from about 0.2 mg to about 100 mg per day.
- the compounds of formula I and/or the SERMs can be combined with one or more pharmaceutically acceptable carriers or excipients including, without limitation, solid and liquid carriers. Where formulated together, the components are selected to be compatible with the PR modulators used in the invention.
- Such carriers can include adjuvants, syrups, elixirs, diluents, binders, lubricants, surfactants, granulating agents, disintegrating agents, emollients, and combinations thereof.
- Adjuvants can include, without limitation, flavoring agents, coloring agents, preservatives, and supplemental antioxidants, which can include vitamin E, ascorbic acid, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).
- Elixers and/syrups can be prepared from acceptable sweeteners such as sugar, saccharine or a biological sweetener, a flavoring agent, and/or solvent.
- a syrup can contain about 10 to about 50% of a sugar carrier.
- the elixir can contain about 20 to about 50% of an ethanol carrier.
- Diluents can include materials in which the compositions can be dispersed, dissolved, or inco ⁇ orated.
- the diluents include water, lower monovalent alcohols, and low molecular weight glycols and polyols, including propylene glycol, diethylene glycol, polyethylene glycol, polypropylene glycol, glycerol, butylene glycol, 1,2,4-butanetriol, sorbitol esters, 1 ,2,6-hexanetriol, ethanol, isopropanol, sorbitol esters, butanediol, ether propanol, ethoxylated ethers, propoxylated ethers, oils such as corn, peanut and sesame oils, dimethylsulfoxide (DMSO), dimethylformamide (DMF), and combinations thereof.
- DMSO dimethylsulfoxide
- DMF dimethylformamide
- the diluent is water.
- Binders can include, without limitation, cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, starch, sugars such as sucrose, kaolin, and lactose, among others.
- Lubricants can include magnesium stearate, light anhydrous silicic acid, talc and sodium lauryl sulfate, among others.
- Granulating agents can include, without limitation, silicon dioxide, microcrystalline cellulose, starch, calcium carbonate, pectin, and crospovidone, polyplasdone, among others.
- Disintegrating agents can include starch, carboxymethylcellulose, hydroxypropyl starch, substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, and calcium citrate, among others
- Emollients can include, without limitation, stearyl alcohol, mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol, olive oil, petroleum jelly, palmitic acid, oleic acid, and myristyl myristate.
- the present invention provides dosing regimens utilizing the compounds of formula I in combination with one or more selective estrogen receptor modulators.
- the compositions can be delivered by a route such as oral, dermal, transdermal, intrabronchial, intranasal, intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, intranasal, vaginal, rectal, sublingual, intracranial, epidural, intratracheal, or by sustained release.
- delivery is oral or transdermal.
- compositions are delivered orally by tablet, capsule, microcapsules, dispersible powder, granule, suspension, syrup, elixir, and aerosol.
- compositions when the compositions are delivered orally, delivery is by tablets and hard- or liquid-filled capsules.
- compositions are delivered intravenously, intramuscularly, subcutaneously, parenterally and intraperitoneally in the form of sterile injectable solutions, suspensions, dispersions, and powders which are fluid to the extent that easy syringe ability exists.
- injectable compositions are sterile, stable under conditions of manufacture and storage, and free of the contaminating action of microorganisms such as bacteria and fungi.
- Injectable formations can be prepared by combining the compositions with a liquid.
- the liquid can be selected from among water, glycerol, ethanol, propylene glycol and polyethylene glycol, oils, and mixtures thereof, and more preferably the liquid carrier is water.
- the oil is vegetable oil.
- the liquid carrier contains about a suspending agent.
- the liquid carrier is an isotonic medium and contains about 0.05 to about 5% suspending agent.
- compositions are delivered rectally in the form of a conventional suppository.
- compositions are delivered vaginally in the form of a conventional suppository, cream, gel, ring, or coated intrauterine device (IUD).
- IUD intrauterine device
- compositions are delivered intranasally or intrabronchially in the form of an aerosol.
- compositions are delivered transdermally or by sustained release through the use of a transdermal patch containing the composition and an optional carrier that is inert to the compound(s), is nontoxic to the skin, and allows for delivery of the compound(s) for systemic absorption into the blood stream.
- a carrier can be a cream, ointment, paste, gel, or occlusive device.
- the creams and ointments can be viscous liquid or semisolid emulsions.
- Pastes can include absorptive powders dispersed in petroleum or hydrophilic petroleum.
- sustained delivery devices can be utilized to release the active reagents into the blood stream and include semi-permeable membranes covering a reservoir contain the active reagents, or a matrix containing the reactive reagents.
- the use of sustained delivery devices can be desirable, in order to avoid the necessity for the patient to take medications on a daily basis.
- sustained delivery is used herein to refer to delaying the release of an active agent, i.e., compositions of the invention, until after placement in a delivery environment, followed by a sustained release of the agent at a later time.
- a number of sustained delivery devices are known in the art and include hydrogels (US Patent Nos.
- compositions of the invention can be formulated as described herein.
- compositions of the invention including compounds of formula I, and SERMS can be delivered (separately or together) using the same delivery route.
- the compounds of formula I and SERMS are delivered orally or transdermally.
- the compounds of formula I and SERMS can be delivered using different delivery routes.
- the SERM is delivered orally and the compound of formula I is delivery transdermally through the use of a patch.
- the methods of the invention can include the continuous delivery of the compounds of formula I and/or SERMS.
- the methods include the periodic discontinuation of the delivery of the compositions of the invention and/or SERMS.
- Such periodic discontinuation can include delivery of a placebo during the period of time where the compositions of the invention or SERMS are not delivered to the patient.
- no placebo or active agent is delivered to the patient when the compositions and SERMS are not being delivered to the patient.
- placebo or "inactive agent” is meant a reagent having pharmacological properties that are not relevant to the condition being treated, i.e., does not contain an active agent.
- Typical placebos include sugar as the primary constituent.
- active agent any reagent which assists in treating a hormone-related condition.
- the method of the present invention can be carried out over a cycle of 21 or more days, preferably 21 or more consecutive days, more preferably 21, 28, 30, or 31 days, and most preferably 21 or 28 days.
- One of skill in the art would readily be able to select and adjust the appropriate period of delivery.
- the terminal portion of a cycle can be the last 1 to about 10 days of the cycle, and preferably the last 7 days of the cycle.
- the terminal portion of the 28-day cycle can include the last 7 days of the cycle, i.e., days 22 to 28 of the 28-day cycle.
- the terminal portion of a cycle can include the delivery of an agent other than the compositions of the invention or SERMS and is preferably a placebo. Alternatively, no agent or placebo is delivered during the terminal portion of the cycle.
- the regimen can include delivering a daily dosage of the compound of formula I and SERM, which are incorporated into a combined, single daily dosage unit.
- the regimen can also include delivering a single daily dosage unit of the compound of formula I and a single daily dosage unit of the SERM. Delivery of the compounds of formula I can be prior to, simultaneous with, or subsequent to the delivery of the SERM.
- the regimen can further include alternating delivery of the compounds of formula I alone, the SERM alone, and a combination of the compound of formula I and the SERM.
- the regimen can also include the delivery of another reagent prior to, in conjunction with, or subsequent to the compound of formula I and the SERM.
- the regimen can further include alternating delivery of the compounds of formula I alone, a SERM alone, and a combination of the compound of formula I and the SERM.
- the regimen can also include the delivery of another reagent prior to, in conjunction with, or subsequent to the compound of formula I and the SERM.
- a single combined daily dosage of the compound of formula I and a SERM can be delivered for the entire 21 -day, 28-day, 30-day, or 31 - day cycle.
- a single combined daily dosage of the compound of formula I and an SERM can be delivered for the first 21 days of a 28-day, 30-day, or 31-day cycle.
- a single combined daily dosage of the compound of formula I and an SERM can also be delivered for the first 24 days of a 28-day, 30-day, or 31 -day cycle.
- a daily dosage of the compound of formula I can be delivered by one route of delivery and a daily dosage of a SERM can be delivered by a second route of delivery for the entire 21 -day, 28-day, 30-day, or 31 -day cycle.
- a daily dosage of the compound of formula I can be delivered by one route of delivery and a daily dosage of a SERM can be delivered by a second route of delivery for the first 21 days of a 28-day, 30-day, or 31-day cycle. Further, a daily dosage of the compound of formula I can be delivered by one route of delivery and a daily dosage of a SERM can be delivered by a second route of delivery for the first 24 days of a 28-day, 30-day, or 31 -day cycle.
- a daily dose of the compound of formula I can be delivered, followed by a daily dose of the SERM for the entire 21 -day, 28-day, 30- day, or 31-day cycle.
- a daily dose of the compound of formula I can be delivered, followed by a daily dose of the SERM for the first 21 days of a 28-day, 30- day, or 31-day cycle.
- a daily dosage of the compound of formula I can be delivered, followed by a daily dosage of the SERM for the first 24 days of a 28- day, 30-day, or 31 -day cycle.
- the compounds of formula I are delivered with the
- SERM for the first 14 to 24 days of a 28-day cycle, followed by delivery of the SERM alone for a period of 1 to 11 days beginning on any cycle day between day 14 and 24.
- the compounds of formula I can be delivered for the initial 18 to 21 days of a 28-day cycle, followed by delivery of the SERM alone for from 1 to 7 days.
- the compounds of formula I can be delivered alone over a 28 day cycle for the first 21 days, followed by delivery of a SERM alone from day 22 to day 24.
- the compounds of formula I and an estrogen can be delivered for the initial 21 days of a 28 day cycle, followed by a SERM alone from days 22 to 24.
- the dosage regimens can be adjusted to provide the optimal therapeutic response. For example, several divided doses of each component can be delivered daily or the dose can be proportionally increased or reduced as indicated by the exigencies of the therapeutic situation.
- reference to a daily dosage unit can also include divided units which are delivered over the course of each day of the cycle contemplated.
- This invention further provides methods of treatment and dosing regimens further utilizing in combination with these progestins, estrogens such as ethinyl estradiol.
- An isoflavone can alone be delivered or co-delivered with the compositions of the present invention in an amount sufficient to assist in the treatment of carcinomas.
- a number of isoflavones can be utilized and include, without limitation, genistein, daidzein, biochanin A, formononetin, and naturally occuring glucosides and glucoside conjugates.
- the amount of isoflavone sufficient to treat the carcinoma is dependent on the particular isoflavone utilized, the amount and activity of the co-delivered active agent, the size of the patient, the route of delivery, and the severity of the carcinoma.
- the amount of isoflavone sufficient to treat the hormone related condition is preferably at least 1 mg per day, more preferably from about 1 mg to about 1000 mg per day, and most preferably from about 50 mg to about 500 mg per day.
- Estrogens can also be included in the compositions of the present invention.
- the estrogen can include natural estrogens, synthetic estrogens, catechol estrogens, conjugated estrogens, and non-steroidal estrogens, among others, or pharmaceutically acceptable salts or esters thereof.
- the estrogen is a natural estrogen including estrone, including the acetate, propionate, sulfate, and sulfate piperazine ester salts; estradiol, including the 3-benzoate, 17b-cypionate, 17- proprionate, d-propionate, hemisuccinate, 17-heptanotate, 17-undecanoate, and 17- valerate ester salts; or estriol.
- the estrogen is a synthetic estrogen including ethinyl estradiol.
- the estrogen is a conjugated estrogen including conjugated equine estrogens and sodium estrone sulfate and is available in formulations for intravenous, intramuscular, and topical administration (Wyeth).
- the estrogen is a catechol estrogen including 2- or 4-hydroxyestrogens.
- the nonsteroidal estrogen is diethylstilbestrol. See, Chapter 50 entitled "Hormones" in Remington's Pharmaceutical Sciences, 18 th Ed., Mack Publishing Company, Easton, Pennsylvania, 1990.
- the desired estrogen may however be selected from a variety of products commercially available.
- the estrogen is present in the formulation at about 0.01 mg to about 1.0 mg.
- reagents can also be delivered in combination with the compositions of the present invention.
- Such reagents can include, chemotherapeutic agents, cytokines, androgens, and antiprogestins, among others.
- the chemotherapeutic agents are taxol or cisplatin.
- such reagents can be alone administered prior or subsequent to the composition of the invention.
- the compositions of the invention can be delivered in conjunction with other cancer treatments, including radiation therapy and/or surgery.
- anti-progestational agents As used herein, the terms “anti-progestational agents”, “anti-progestins” and “progesterone receptor antagonists” are understood to be synonymous. Similarly, “progestins”, “progestational agents” and “progesterone receptor agonists” are understood to refer to compounds of the same activity. Optionally, progestins, other than those of formula I, can be delivered in combination with the compositions of the present invention.
- progestins include, without limitation, progesterone, micronized progesterone, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, and (17- deacetyl)norgestimate, among others.
- the progestins are levonorgestrel, gestodene or trimegestone.
- kits or packages of pharmaceutical formulations designed for use in the regimens described herein. These kits are preferably designed for daily oral delivery over 21-day, 28-day, 30-day, or 31-day cycles, among others, and more preferably for one oral delivery per day.
- a package or kit can include the composition and/or SERM in each tablet.
- a package or kit can include placebos on those days when the composition and SERM are not delivered.
- kits are also preferably organized to indicate a single oral formulation or combination of oral formulations to be taken on each day of the cycle, preferably including oral tablets to be taken on each of the days specified, and more preferably one oral tablet will contain each of the combined daily dosages indicated.
- a kit can include a single phase of a daily dosage of the compound of formula I over a 21-day, 28-day, 30-day, or 31-day cycle.
- kits can include a single phase of a daily dosage of the compound of formula I over the first 21 days of a 28-day, 30-day, or 31 -day cycle.
- a kit can also include a single phase of a daily dosage of the compound of formula I over the first 28 days of a 30-day or 31 -day cycle.
- a kit can include a single combined phase of a daily dosage of the compound of formula I and a SERM over a 21 -day, 28-day, 30-day, or 31 -day cycle.
- a kit can include a single combined phase of a daily dosage of the compound of formula I and a SERM over the first 21 days of a 28-day,
- kits can also include a single combined phase of a daily dosage of the compound of formula I and a SERM over the first 28 days of a 30-day or 31 -day cycle.
- a 28-day kit can include a first phase of from 14 to 28 daily dosage units of the compound of formula I; a second phase of from 1 to 11 daily dosage units of a SERM; and, optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle.
- a 28-day kit can include a first phase of from 14 to 21 daily dosage units of the compound of formula I; a second phase of from 1 to 11 daily dosage units of a SERM; and, optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle.
- a 28-day kit can include a first phase of from 18 to 21 daily dosage units of a compound of formula I; a second phase of from 1 to 7 daily dose units of a SERM; and, optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0 to 9 days in the 28-day cycle.
- a 28-day kit can include a first phase of 21 daily dosage units of a compound of formula I; a second phase of 3 daily dosage units for days 22 to 24 of a SERM; and, optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
- the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is delivered. It is further preferable that the daily dose units described are to be delivered in the order described, with the first phase followed in order by the second and third phases. To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle.
- the package has indicators for each day of the 28-day cycle, and more preferably is a labeled blister package, dial dispenser packages, or a bottle.
- the following examples are provided to illustrate the invention and do not limit the scope thereof.
- One skilled in the art will appreciate that although specific reagents and conditions are outlined in the following examples, modifications can be made which are meant to be encompassed by the spirit and scope of the invention.
- MCF-7 breast carcinoma cells are plated in 24-well dishes in phenol-red free DMEM:F-12 (1 : 1) medium containing antibiotics, ⁇ -mercaptoethanol, ethanolamine, sodium selenite and 5% charcoal-stripped FCS.
- the compositions of the invention and vehicle are added the following day and refreshed with media change every 48 hours. Cultures are stopped 9 days later and proliferation assayed using the Cyquant kit (Molecular Probes, Eugene, Oregon).
- the women are selected for the study.
- the women are randomly divided into two groups, one of which receives a regimen of the invention, and the other of which receives a placebo.
- the patients are evaluated as to the character of their dysfunctional uterine bleeding (blood loss, timing, etc.) prior to the study's initiation. Women in the test group receive between 50-200 mg of the drug per day by the oral route. This therapy continues for 6 months.
- Utility of the compositions of the invention is illustrated by the therapeutic effect they have on the patients' dysfunctional uterine bleeding.
- compositions of the invention in the L929 cells which express the AR but not the PR was evaluated as described in Zhang et al., Steroids, 65(10-11): 637-643 (October- November 2000).
- DHT dihydrotestosterone
- 2-hydroxyflutamide (2-OH-fluta) reference or 5 ' -(5-Cyano- 1 -methyl- 1 H-pyrrol-2-yl)spiro [cyclohexane- 1 ,3 ' - [3H] indol] -2 ' - ylidenecyanamide diluted in the same medium.
- DHT dihydrotestosterone
- 2-OH-fluta 2-hydroxyflutamide
- 5 ' -(5-Cyano- 1 -methyl- 1 H-pyrrol-2-yl)spiro [cyclohexane- 1 ,3 ' - [3H] indol] -2 ' - ylidenecyanamide diluted in the same medium To test the anti-androgenic activity, cells were co-treated with 3 nM DHT. Luciferase activity was measured 24 hours following the treatment. The following data were obtained:
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Abstract
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003245637A AU2003245637A1 (en) | 2002-06-25 | 2003-06-23 | Use of thio-oxindole derivatives in treatment of hormone-related conditions |
MXPA04012419A MXPA04012419A (en) | 2002-06-25 | 2003-06-23 | Use of thio-oxindole derivatives in treatment of hormone-related conditions. |
IL16539503A IL165395A0 (en) | 2002-06-25 | 2003-06-23 | Use of thio-oxubdile derivatives in treatment of hormone-related conditions |
EP03739264A EP1531806A4 (en) | 2002-06-25 | 2003-06-23 | Use of thio-oxindole derivatives in treatment of hormone-related conditions |
CA002489813A CA2489813A1 (en) | 2002-06-25 | 2003-06-23 | Use of thio-oxindole derivatives in treatment of hormone-related conditions |
JP2004516125A JP2005535623A (en) | 2002-06-25 | 2003-06-23 | Use of thio-oxindole derivatives in the treatment of hormone-related symptoms |
BR0312054-6A BR0312054A (en) | 2002-06-25 | 2003-06-23 | Use of thiooxyindole derivatives in the preparation of medicaments useful in the treatment of hormone related conditions, and pharmaceutical kit |
NO20045217A NO20045217L (en) | 2002-06-25 | 2004-11-29 | Use of thio-oxindole derivatives for the treatment of hormone-related conditions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US39182602P | 2002-06-25 | 2002-06-25 | |
US60/391,826 | 2002-06-25 |
Publications (2)
Publication Number | Publication Date |
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WO2004000225A2 true WO2004000225A2 (en) | 2003-12-31 |
WO2004000225A3 WO2004000225A3 (en) | 2004-06-10 |
Family
ID=30000758
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2003/019710 WO2004000225A2 (en) | 2002-06-25 | 2003-06-23 | Use of thio-oxindole derivatives in treatment of hormone-related conditions |
Country Status (17)
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US (3) | US7488734B2 (en) |
EP (1) | EP1531806A4 (en) |
JP (1) | JP2005535623A (en) |
CN (1) | CN1662234A (en) |
AR (1) | AR040339A1 (en) |
AU (1) | AU2003245637A1 (en) |
BR (1) | BR0312054A (en) |
CA (1) | CA2489813A1 (en) |
CR (1) | CR7610A (en) |
EC (1) | ECSP055574A (en) |
IL (1) | IL165395A0 (en) |
MX (1) | MXPA04012419A (en) |
NO (1) | NO20045217L (en) |
RU (1) | RU2005101635A (en) |
TW (1) | TW200407124A (en) |
WO (1) | WO2004000225A2 (en) |
ZA (1) | ZA200410409B (en) |
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US7700641B2 (en) | 2005-04-11 | 2010-04-20 | Xenon Pharmaceuticals Inc. | Spiro-oxindole compounds and their uses as therapeutic agents |
US7799798B2 (en) | 2005-04-11 | 2010-09-21 | Xenon Pharmaceuticals Inc. | Spiroheterocyclic compounds and their uses as therapeutic agents |
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US8101647B2 (en) | 2008-10-17 | 2012-01-24 | Xenon Pharmaceuticals Inc. | Spiro-oxindole compounds and their use as therapeutic agents |
US8263606B2 (en) | 2008-10-17 | 2012-09-11 | Xenon Pharmaceuticals Inc. | Spiro-oxindole compounds and their use as therapeutic agents |
US8445696B2 (en) | 2009-10-14 | 2013-05-21 | Xenon Pharmaceuticals Inc. | Synthetic methods for spiro-oxindole compounds |
US8450358B2 (en) | 2009-06-29 | 2013-05-28 | Xenon Pharmaceuticals Inc. | Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents |
US8466188B2 (en) | 2006-10-12 | 2013-06-18 | Xenon Pharmaceuticals Inc. | Use of spiro-oxindole compounds as therapeutic agents |
US8703810B2 (en) | 2010-06-10 | 2014-04-22 | Seragon Pharmaceuticals, Inc. | Estrogen receptor modulators and uses thereof |
US9187460B2 (en) | 2011-12-14 | 2015-11-17 | Seragon Pharmaceuticals, Inc. | Estrogen receptor modulators and uses thereof |
US9504671B2 (en) | 2010-02-26 | 2016-11-29 | Xenon Pharmaceuticals Inc. | Pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents |
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US6355648B1 (en) | 1999-05-04 | 2002-03-12 | American Home Products Corporation | Thio-oxindole derivatives |
US6407101B1 (en) * | 1999-05-04 | 2002-06-18 | American Home Products Corporation | Cyanopyrroles |
US6391907B1 (en) | 1999-05-04 | 2002-05-21 | American Home Products Corporation | Indoline derivatives |
US6509334B1 (en) | 1999-05-04 | 2003-01-21 | American Home Products Corporation | Cyclocarbamate derivatives as progesterone receptor modulators |
UA73119C2 (en) * | 2000-04-19 | 2005-06-15 | American Home Products Corpoir | Derivatives of cyclic thiocarbamates, pharmaceutical composition including noted derivatives of cyclic thiocarbamates and active ingredients of medicines as modulators of progesterone receptors |
TW200407124A (en) * | 2002-06-25 | 2004-05-16 | Wyeth Corp | Use of thio-oxindole derivatives in treatment of hormone-related conditions |
US7683052B2 (en) * | 2004-04-07 | 2010-03-23 | Wyeth | Crystalline polymorph of bazedoxifene acetate |
WO2005100316A1 (en) * | 2004-04-07 | 2005-10-27 | Wyeth | Crystalline polymorph of a bazedoxifene acetate |
CA2569738A1 (en) * | 2004-06-07 | 2005-12-22 | Duramed Pharmaceuticals, Inc. | Dispenser for progestin used for acute and maintenance treatment of dub |
GT200500185A (en) * | 2004-08-09 | 2006-04-10 | PROGESTERONE RECEIVER MODULATORS UNDERSTANDING PIRROL-OXINDOL DERIVATIVES AND THEIR USES | |
JP2011507853A (en) * | 2007-12-20 | 2011-03-10 | テバ ウィメンズ ヘルス インコーポレイテッド | Dosage regimens and pharmaceutical compositions and packages for emergency contraception |
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- 2003-06-23 AU AU2003245637A patent/AU2003245637A1/en not_active Abandoned
- 2003-06-23 RU RU2005101635/15A patent/RU2005101635A/en not_active Application Discontinuation
- 2003-06-23 EP EP03739264A patent/EP1531806A4/en not_active Withdrawn
- 2003-06-23 JP JP2004516125A patent/JP2005535623A/en active Pending
- 2003-06-23 CN CN038147807A patent/CN1662234A/en active Pending
- 2003-06-23 WO PCT/US2003/019710 patent/WO2004000225A2/en not_active Application Discontinuation
- 2003-06-23 MX MXPA04012419A patent/MXPA04012419A/en unknown
- 2003-06-23 US US10/601,438 patent/US7488734B2/en not_active Expired - Fee Related
- 2003-06-23 BR BR0312054-6A patent/BR0312054A/en not_active IP Right Cessation
- 2003-06-23 CA CA002489813A patent/CA2489813A1/en not_active Abandoned
- 2003-06-23 IL IL16539503A patent/IL165395A0/en unknown
- 2003-06-24 AR ARP030102255A patent/AR040339A1/en unknown
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2004
- 2004-11-29 NO NO20045217A patent/NO20045217L/en not_active Application Discontinuation
- 2004-12-08 CR CR7610A patent/CR7610A/en unknown
- 2004-12-23 ZA ZA200410409A patent/ZA200410409B/en unknown
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2005
- 2005-01-25 EC EC2005005574A patent/ECSP055574A/en unknown
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2008
- 2008-12-17 US US12/336,588 patent/US8242098B2/en not_active Expired - Fee Related
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JP4869221B2 (en) * | 2004-04-08 | 2012-02-08 | ワイス・エルエルシー | Thiamide derivatives as progesterone receptor modulators |
JP2007532564A (en) * | 2004-04-08 | 2007-11-15 | ワイス | Thiamide derivatives as progesterone receptor modulators |
US7358246B2 (en) | 2004-04-08 | 2008-04-15 | Wyeth | Thioamide derivatives as progesterone receptor modulators |
US7511071B2 (en) | 2004-04-08 | 2009-03-31 | Wyeth | Thioamide derivatives as progesterone receptor modulators |
US7659265B2 (en) | 2004-04-08 | 2010-02-09 | Wyeth | Thioamide derivatives as progesterone receptor modulators |
JP2007532581A (en) * | 2004-04-08 | 2007-11-15 | ワイス | Method for minimizing thioamide impurities |
US8168672B2 (en) | 2004-04-08 | 2012-05-01 | Wyeth | Thioamide derivatives as progesterone receptor modulators |
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Also Published As
Publication number | Publication date |
---|---|
CR7610A (en) | 2006-05-29 |
AU2003245637A1 (en) | 2004-01-06 |
US8242098B2 (en) | 2012-08-14 |
BR0312054A (en) | 2005-10-18 |
EP1531806A2 (en) | 2005-05-25 |
WO2004000225A3 (en) | 2004-06-10 |
RU2005101635A (en) | 2005-08-10 |
EP1531806A4 (en) | 2005-09-21 |
CA2489813A1 (en) | 2003-12-31 |
CN1662234A (en) | 2005-08-31 |
US20120220558A1 (en) | 2012-08-30 |
NO20045217L (en) | 2005-03-15 |
US20090099223A1 (en) | 2009-04-16 |
ZA200410409B (en) | 2006-05-31 |
JP2005535623A (en) | 2005-11-24 |
US7488734B2 (en) | 2009-02-10 |
TW200407124A (en) | 2004-05-16 |
ECSP055574A (en) | 2005-04-18 |
AR040339A1 (en) | 2005-03-30 |
IL165395A0 (en) | 2006-01-15 |
US20040002535A1 (en) | 2004-01-01 |
MXPA04012419A (en) | 2005-04-19 |
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