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WO2000066592A1 - Derives d'uree et d'amide cycliques - Google Patents

Derives d'uree et d'amide cycliques Download PDF

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Publication number
WO2000066592A1
WO2000066592A1 PCT/US2000/011836 US0011836W WO0066592A1 WO 2000066592 A1 WO2000066592 A1 WO 2000066592A1 US 0011836 W US0011836 W US 0011836W WO 0066592 A1 WO0066592 A1 WO 0066592A1
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WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
aryl
alkoxy
cycloalkyl
Prior art date
Application number
PCT/US2000/011836
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English (en)
Inventor
Puwen Zhang
Arthur A. Santilli
Andrew Fensome
Eugene A. Terefenko
Andrew Q. Viet
Lin Zhi
Todd K. Jones
Christopher M. Tegley
Jay E. Wrobel
James P. Edwards
Original Assignee
American Home Products Corporation
Ligand Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/552,356 external-priority patent/US6369056B1/en
Application filed by American Home Products Corporation, Ligand Pharmaceuticals, Inc. filed Critical American Home Products Corporation
Priority to AU46896/00A priority Critical patent/AU4689600A/en
Priority to CA002371642A priority patent/CA2371642A1/fr
Priority to PCT/US2000/011836 priority patent/WO2000066592A1/fr
Priority to MXPA01011291A priority patent/MXPA01011291A/es
Priority to EP00928699A priority patent/EP1173443A1/fr
Priority to JP2000615622A priority patent/JP2002543206A/ja
Publication of WO2000066592A1 publication Critical patent/WO2000066592A1/fr
Priority to HK02104860.7A priority patent/HK1043994A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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

Definitions

  • This invention relates to compounds which are agonists and antagonists of the progesterone receptor, their preparation and utility
  • Intracellular receptors form a class of structurally related gene regulators known as "hgand 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 hgand, 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/kgand 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 that inhibits the effect of the hormone is an antagonist
  • PR agonists 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 prohferative effect on the uterus that can lead to an increased risk of uterine cancers
  • Co-administration of a PR agonist reduces or ablates 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 96/19997 Al. July 4. 1996)
  • 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 endomet ⁇ osis (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 mifepnstone and onapnstone, 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)
  • the compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists and/or antagonists in functional models, either/or in-vitro and in-vivo These compounds may be used for contraception, in the treatment of fibroids, endomet ⁇ osis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy
  • A. B and D are N or CH. with the proviso that A, B and D can not all be CH.
  • R 1 and R 2 are independent substituents selected from H, Ci to C 6 alkyl substituted Ci to C 6 alkyl. C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl. C to C 6 alkynyl. substituted C 2 to C alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A .
  • R 1 and R 2 are fused to form a spirocychc ring selected from a), b) or c), each spirocychc ⁇ ng optionally substituted by from 1 to 3 C ⁇ -C 3 alkyl groups a) a 3 to 8 membered spirocychc alkyl ⁇ ng, b) a 3 to 8 membered spirocychc alkenyl ⁇ ng, or c) an optionally substituted 3 to 8 membered heterocychc ⁇ ng containing one to three heteroatoms from the group including O. S and N. the spirocychc rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine. Ci to C 6 alkyl.
  • Ci Ci to C ⁇ alkoxy .
  • R A is H. Ci to C 3 alkyl. substituted Ci to G alkyl. aryl, substituted aryl. Ci to C 3 alkoxy . substituted Ci to C ⁇ alkoxy. Ci to C ⁇ aminoalkvl. or substituted Ci to Ci aminoalkyl.
  • R B is H. Ci to C 3 alkyl. or substituted C, to C, alkyl.
  • R 3 is H. OH. NH 2 .
  • R c is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl.
  • R 4 is a t ⁇ substituted benzene ⁇ ng containing the substituents X, Y and Z as shown below
  • X is taken from the group including halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl.
  • R D is H, 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 C] to C 3 alkyl
  • Y and Z are independent substituents taken from the group including H halogen.
  • CN. NO 2 Cj to C alkoxy, Ci to C ⁇ alkyl, or Ci to C 3 thioalkoxy , or
  • R 4 is a five or six membered ⁇ ng with 1, 2, or 3 heteroatoms from the group including O, S, SO. SO 2 or NR 5 and containing one or two independent substituents from the group including H, halogen, CN. N0 2 and Cj to C 3 alkyl. Ci to C 3 alkoxy, Ci to C 3 aminoalkyl COR F , or NR G COR F .
  • R F is H, 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 Q to C 3 aminoalkvl
  • R G is H, Ci to C 3 alkyl or substituted d to C, alkyl R 5 is H or Ci to C 3 alkyl,
  • e is from the group including 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, heterocychc. substituted heterocyclic, or SO 2 CF 3 ,
  • R 7 and R 8 are independent substituents from the group including H. Ci to C 6 alkyl. substituted Ci to C 6 alkyl, C-* to C 8 cycloalkyl. substituted C 3 to C 8 cycloalkyl. aryl substituted aryl, heterocyclic, substituted heterocyc c, NO 2 , CN, or CO 2 R 9 ,
  • R 9 is C, to C 3 alkyl. or CR 7 R 8 form a six membered ring of the structure below
  • W is O or a chemical bond
  • Preferred compounds are those of Formula I
  • A. B and D are N or CH. with the proviso that A, B and D can not all be CH.
  • R 1 is H, Ci to C 6 alkyl, substituted Cj to C 6 alkyl. C 3 to C 8 cycloalkyl. substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR A , or NR B COR A ,
  • R 2 is H, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 2 to C 6 alkenyl. substituted C 2 to C 6 alkenyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl. substituted aryl, heterocychc, substituted heterocychc, COR A or NR B COR A , or
  • R 1 and R 2 are fused to form the optionally substituted 3 to 8 membered spirocychc alkyl, alkenyl or heterocychc rings described above,
  • R A is H, 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, aminoalkyl
  • R B is H, Ci to C 3 alkyl, or substituted C, to C 3 alkyl,
  • R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted C, to C 6 alkyl. C to C 6 alkenyl substituted C ⁇ to C 6 alkenyl, or COR c ,
  • R c is H. C] to C 4 alkyl, substituted Ci to C 4 alkyl aryl substituted aryl. Ci to C 4 alkoxy. substituted Ci to C 4 alkoxy, Ci to C aminoalky l or substituted Ci to C 4 aminoalkyl
  • R 4 is a t ⁇ substituted benzene ring containing the substituents X. Y and Z as shown below
  • X is selected from halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, Ci to C 3 aminoalkyl, substituted Ci to C 3 aminoalkyl, N0 2 .
  • R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl Ci to C 3 alkoxy, substituted Ci to C 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.
  • Y and Z are independent substituents selected from H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C 3 alkyl, or Ci to C 3 thioalkoxy; or
  • R 5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO. SO 2 or NR 5 and containing one or two independent substituents from the group including H. halogen, CN, NO 2 and Ci to C ? alkyl, or Ci to C 3 alkoxy,
  • R 5 is H or Ci to C 3 alkyl
  • Re is selected from 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. substituted heterocyclic. or S0 2 CF 3 .
  • R 7 and R 8 are independent substituents selected from H, Ci to C 6 alk l substituted Ci to C 6 alkyl C 3 to C 8 cycloalkyl substituted C 3 to C 8 cycloalkyl. aryl substituted aryl. heterocyclic. substituted heterocyc c. N0 2 . or CN CO 2 R 9 .
  • R 9 is Ci to C, alkyl. or CR 7 R 8 form a six membered ⁇ ng of the structure below
  • W is O or a chemical bond, or a pharmaceutically acceptable salt thereof
  • A, B and D are N or CH, with the proviso that A, B and D cannot all be CH,
  • R 1 R 2 and are selected from the group of Ci to C 3 alkyl, substituted Ci to C 3 alkyl. or spirocychc alkyl constructed by fusing R 1 and R 2 to form a 3 to 6 membered spirocychc ⁇ ng,
  • R 3 is H. OH, NH 2 , Ci to C 6 alkyl. substituted Ci to C 6 alkyl. or COR c .
  • R c is H, Ci to C 4 alkyl, or Ci to C alkoxy,
  • R 4 is a disubstituted benzene ring containing the substituents X, and Y as shown below
  • X is selected from the group of halogen, CN, Ci to C3 alkoxy, Ci to C 3 alkyl, NO 2 .
  • Ci to C 3 perfluoroalkyl 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or Ci to C3 thioalkoxy.
  • Y is a substituent on the 4' or 5'pos ⁇ t ⁇ on from the group including H. halogen. CN. N0 2 , Ci to C 3 alkoxy. C ⁇ to C 4 alkyl. or Ci to C 3 thioalkoxy, or
  • R 4 is a five membered ring with the structure
  • R 5 is H, or Ci to C 3 alkyl, or Ci to C 4 CO 2 alkyl,
  • X ' is selected from halogen, CN, N0 2 , Ci to C 3 alkyl, or Ci to C3 alkoxy,
  • Y' is selected from H and Ci to C 4 alkyl
  • R 4 is a six membered ring with the structure
  • X 2 is halogen, CN or N0 2 .
  • Rg is selected from CN.
  • R 7 and R 8 are independent substituents selected from H, Ci to C ⁇ alkyl, substituted Ci to C ⁇ alkyl, C to C 8 cycloalkyl, substituted to C 8 cycloalkyl. aryl, substituted aryl, heterocychc, substituted heterocyclic, NO 2 , CN, or CO 2 R 9 ,
  • R 9 is Ci to C 3 alkyl, or CR 7 R 8 form a six membered ring of the structure below
  • R 3 is H, OH. NH 2 . CH 3 , substituted methyl or COR c .
  • R c is H, Ci to C alkyl, or Ci to C 4 alkoxy.
  • R 4 is a disubstituted benzene ⁇ ng containing the substituents X and Y as shown below
  • X is halogen, CN, methoxy, NO 2 , or 2-th ⁇ azole.
  • Y is a substituent on the 4' or 5'pos ⁇ t ⁇ on selected from H and F, or
  • R 4 is a five membered ring of the structure
  • X' is halogen, CN, or NO 2 ;
  • Y' is H or Ci to C alkyl
  • Q is O, S, NR 6 . or CR 7 R 8 ,
  • Re is CN, Ci to C 6 alkyl. substituted Cj to C 6 alkyl, C to C 8 cycloalkyl. substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl. heterocychc, substituted heterocychc. or S0 2 CF 3 ,
  • R 7 and R 8 are independent substituents selected from H, Ci to C 6 alkyl substituted Ci to C ⁇ alkyl, to C 8 cycloalkyl substituted to C 8 cycloalkyl. aryl substituted aryl. heterocyclic, substituted heterocyc c, N0 2 . or CN CO 2 R 9 .
  • R 9 is Ci to alkyl or CR 7 R 8 form a six membered ⁇ ng of the structure
  • W is O or a chemical bond
  • 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 diastereomers While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers, 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
  • alkyl is used herein to refer to both straight- and branched-cham saturated aliphatic hydrocarbon groups having one to eight carbon atoms, preferably one to six carbon atoms
  • alkenyl is intended to include both straight- and branched- cham alkyl group with at least one carbon-carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms
  • alkynyl group is intended to cover both straight- and branched-chain alkyl group with at least one carbon-carbon triple
  • substituted alkyl refers to alkyl. alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN. OH. N0 2 . amino, aryl, heterocyclic. substituted aryl substituted heterocychc.
  • aryl is used herein to refer to an aromatic system 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
  • the aryl groups include but not limited to phenyl, naphthyl, biphenyl. anthryl tetrohydronaphthyl. phenanthryl
  • substituted aryl refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, N0 2 , amino, alkyl, cycloalkyl. alkenyl, alkynyl alkoxy. aryloxy , substituted alkyloxy, alkylcarbonyl, alkylcarboxy .
  • heterocyclic is used herein to desc ⁇ be a stable 4- to 7-membered monocyc c or a stable multicyclic heterocyc c 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
  • the heterocychc ⁇ ng also includes any multicyclic ⁇ ng in which any of above defined heterocyclic rings is fused to an aryl ⁇ ng
  • the heterocychc ⁇ ng may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable
  • Such heterocyclic groups include, for example, tetrahydrofuran.
  • substituted heterocyclic is used herein to describe the heterocyclic lust defined having one to four substituents selected from the group which includes halogen.
  • CN OH, N0 2 . amino. alkyl. substituted alkyl, cycloalkyl alkenyl. substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy . alkylamino.
  • alkoxy is used herein to refer to the OR group, where R is alkyl or substituted alkyl
  • aryloxy is used herein to refer to the OR group, where R is aryl or substituted aryl
  • alkylcarbonyl ' ' is used herein to refer to the RCO group, where R is alkyl or substituted alkyl
  • alkylcarboxy is used herein to refer to the COOR group, where R is alkyl or substituted alkyl
  • aminoalkyl refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups containing one to eight carbon atoms, which may be either same or different and the pomt of attachment is on the nitrogen atom 'Halogen” refers to Cl, Br, F, or I
  • the compounds of the present invention can be used m the form of salts de ⁇ ved from pharmaceutically or physiologically acceptable acids or bases
  • These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfu ⁇ c acid, nitric acid, phosphoric acid and, as the case may be.
  • compositions and treatments which comprise administering to a mammal a pharmaceutically effective amount of one or more compounds as described above wherein Q is oxygen as antagonists of the progesterone receptor
  • Q is S. NR 6 , or CR 7 R 8 as agonists of the progesterone receptor
  • the progesterone receptor antagonists of this invention can be utilized in methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease
  • Specific uses of the compounds and pharmaceutical compositions of invention include the treatment and/or prevention of uterine myomet ⁇ al fibroids, endomet ⁇ osis, benign prostatic hypertroph . carcinomas and adenocarcinomas of the endomet ⁇ um, ovary . breast, colon, prostate, pituitary .
  • progesterone receptor antagonists include the synchronization of the estrus in livestock
  • the progesterone receptor agonists of this invention used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometnosis, polycystic ovary syndrome, carcinomas and adenocarcinomas of the endomet ⁇ um, ovary, breast. colon, prostate
  • Additional uses of the invention include stimulation of food intake
  • the compounds When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients. for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0 05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of ste ⁇ le injectable solutions or suspensions containing from about 0 05 to 5% suspending agent in an lsotonic medium.
  • Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the earner, more usually between about 5% and 60% by weight
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the seventy of the condition being treated However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0 5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a da .
  • the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg
  • Dosage forms suitable for internal use comprise from about 0 5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable earner
  • This dosage regimen may be adjusted to provide the optimal therapeutic response For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation
  • These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are approp ⁇ ate to the nature of the active ingredient and the particular form of administration desired
  • Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents
  • active compounds may also be administered parenterally or lntrape ⁇ toneally Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms
  • the pharmaceutical forms suitable for mjectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile mjectable solutions or dispersions In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol (
  • the compounds of this invention are generally prepared by employing the suitable coupling reaction as a final step
  • nucleophihc reagent e g , Ph 3 P, l.l '-b ⁇ s(d ⁇ phenylphosph ⁇ no)ferrocene, 1,2- b ⁇ s(d ⁇ phenylphosph ⁇ no)ethane or palladium salt such as palladium acetate
  • an appropriately substituted nucleophihc reagent e g , aryl boronic acid, arylstannane.
  • oxazinones 3 is coupled with oxazinones 3 to give compounds 4
  • the commonly used bases include but not limited to sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, potassium acetate, or cesium fluoride
  • the most commonly used solvents in these reactions include benzene. DMF. isopropanol. ethanol DME, ether, acetone or a mixture of any one of these solvent and water
  • the coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95 °C
  • Oxazinones 3 can be converted into a nucleophile such as boronic acid which can be coupled with an approp ⁇ ate electrophile. e g . ary 1 bromide or aryl iodide, to yield 6 employing the coupling reaction condition as described above
  • the transformation of 3 into 5 can be effected by treating 3 with an organo metallic reagent, e g . n-BuLi. in a nonprotic solvent such as THF or ether followed by quenching the reaction solution with a suitable electrophile such as t ⁇ methyl borate.
  • organo metallic reagent e g . n-BuLi.
  • a nonprotic solvent such as THF or ether
  • Conversion of ketone 11 to carbinol 12 can be effected by treatment of 10 with an organo metallic reagent such as alkyl, alkynyl, or aryl G ⁇ gnard compound in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at -78 °C to room temperature
  • Conversion of ketone 11 to carbinol 12 can also be effected by reduction of ketone group of 11 to the carbinol moiets of 12 using an approp ⁇ ate reducing reagent such as lithium aluminum hydride, sodium borohyd ⁇ de in a suitable solvent such as THF, ether, or anhydrous alcohol under an inert atmosphere in the temperature ranging from 0 °C to the boiling point of the solvent Ring closure of carbinol 12 to produce the compounds of this invention.
  • organo metallic reagent such as alkyl, alkynyl, or aryl G ⁇ gnard compound in a nonprotic solvent
  • Condensing agents such as carbonyldiimidazole. phosgene, dimethylcarbonate. or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65 °C
  • Conversion of carbamate 13 to thiocarbamate 14 can be readilv effected by treatment of 13 with a suitable sulfur reagent such as P 2 S 5 or Lawesson ' s reagent m a suitable nonprotic solvent such as toluene, chlorobenzene, benzene, or xylene under an inert atmosphere such as argon or nitrogen at the temperature of boiling solvent.
  • ortho-amino ketone 11 can be prepared by treatment of ortho- amino nitrile 16 with an organo metallic compound such as organo lithium reagent or G ⁇ ngard reagent in a suitable solvent such as THF or ether under an mert atmosphere such as argon or mtrogen at temperatures ranging from -78 °C to room temperature as illustrated in Scheme III
  • organo metallic compound such as organo lithium reagent or G ⁇ ngard reagent
  • a suitable solvent such as THF or ether
  • mert atmosphere such as argon or mtrogen
  • the compounds of this invention were tested in the relevant assay as described below and their potency are in the range of 0 01 nM to 5 ⁇ M in the in vitro assays and 0 001 to 300 mg/kg in the in vivo assays
  • the selected example is example 4
  • the in-vitro biology is determined by (1) competitive Radiohgand Binding using the A-form of the human progesterone receptor with progesterone as the radiohgand, (2) co-transfection assay, which provides functional activity expressed as agonist EC50 and Antagonist IC50 values, (3) a T47D cell proliferation, which is a further functional assay which also provides agonist and antagonist data, and (4) T47D cell alkaline phosphatase assay, which is a further functional assay which also provides agonist and antagonist data
  • hPR Binding assay This assay is carried out in accordance with Pathirana, C . Stein, R B , Berger. T S , Femcal. W , laniro. T . Mais. D E , Torres, A , Glodman, M E , Nonsteroidal human progesterone receptor modulators from the marine alga cymopha barbata. J Steroid Biochem Mol Biol . 1992, 41. 733-738 2.
  • PRE-luciferase assay in CV-1 cells The object of this assay is to determine a compound's progestational or antiprogestational potency based on its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids
  • the matenals methods used in the assay are as follows a Medium The growth medium was as follows
  • DMEM BioWhittaker
  • fetal bovine serum containing 10% (v/v) fetal bovine serum (heat inactivated). 0 1 mM MEM non-essential amino acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL)
  • the experimental medium was as follows DMEM (BioWhittaker), phenol red-free, containing 10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0 1 mM MEM non-essential amino acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) b Cell culture, transfection. treatment, and luciferase assay Stock CV-1 cells are maintained in growth medium
  • Co-transfection is done using 1 2x10 7 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 carrier DNA in 250 ml Electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene Pulser II After electroporation.
  • Each treatment consists of at least 4 replicates Log transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agomst and antagomst modes Huber weighting is used to downweight the effects of outhers EC 50 or IC 50 values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of vanance and non-linear response analyses d Reference Compounds
  • Progesterone and t ⁇ megestone are reference progestins and RU486 is the reference antiprogestm All reference compounds are run in full dose- response curves and the EC50 or IC 50 values are calculated
  • Antiprogestational activity Compounds that decrease 3 nM progesterone induced PRE-luciferase activity significantly (p ⁇ 0 05) EC 5 o Concentration of a compound that gives half-maximal increase PRE- luciferase activity (default -nM) with SE
  • T47D cell proliferation assay The objective of this assay is the determination of progestational and antiprogestational potency by using a cell proliferation assay in T47D cells A compound's effect on DNA synthesis in T47D cells is measured
  • the materials and methods used in this assay are as follows a Growth medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovine serum (not heat- mactivated), lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) b Treatment medium.
  • MEM Minimum Essential Medium
  • BRL Minimum Essential Medium
  • penicillin 200 mg/ml streptomycin
  • 2 mM GlutaMax GIBCO, BRL
  • c Cell culture Stock T47 D cells are maintained in growth medium
  • BrdU incorporation assay cells are plated in 96-well plates (Falcon Beet on Dickinson Labware) at 10 000 cells/well in growth medium After overnight incubation, the medium is changed to treatment medium and cells are cultured for an additional 24 hr before treatment
  • Stock compounds are dissolved in appropriate vehicle (100%) ethanol or 50% ethanol/50% DMSO), subsequently diluted in treatment medium and added to the cells
  • Progestm and antiprogestm reference compounds are run in full dose-response curves The final concentration of vehicle is 0 1% In control wells, cells receive vehicle only Antiprogestins are tested m the presence of 0 03
  • T47D cell alkalme phosphatase assa* The purpose of this assay is to identify progestms or antiprogestins determmmg a compound s effect on alkalme phosphatase m T47D cells
  • the materials and methods used in this assay are as follo s a.
  • Culture medium DMEM F12 (1 1) (GIBCO. BRL) supplemented with 5% ( ⁇ / ⁇ ) charcoal stripped fetal bovme serum (not heat-mactn ated) lOOU/ml penicillin. 100 ⁇ g/ml streptomvcin. and 2 mM GlutaMax (GIBCO. BRL) b Alkalme phosphatase assay buffer
  • Frozen T47D cells were thawed in a 37°C water bath and diluted to 280.000 cells/ml m culture medium To each well m a 96-well plate (Falcon, Becton Dickinson Labware), 180 ⁇ l of diluted cell suspension was added Twenty ⁇ l of reference or test compounds diluted m the culture medium was then added to each well When testing for progestm antagonist activity, reference antiprogestins or test compounds were added m the presence of 1 nM progesterone The cells were mcubated at 37°C in a 5% CO 2 /hum ⁇ d ⁇ fied atmosphere for 24 hr d Alkalme Phosphatase Enzyme Assay
  • a dose response cu ⁇ e is generated for dose (X-axis) vs the rate of reaction (slope) (Y-axis)
  • Square root-transformed data are used for analysis of variance and nonlmear dose response cur ⁇ e fitting for both agonist and antagonist modes
  • Huber weightmg is used to downweight the effects of outliers EC50 or IC50 ⁇ alues are calculated from the retransformed values JMP software (SAS Institute.
  • the p ⁇ marv ln-vr o assay is the rat decidualization model, which be used to determine progestational effects of both agonists and antagonists
  • the secondary m- v ⁇ o assa ⁇ is the rat ovulation inhibition model, which is under development, and hence the protocol is un-available 1 Rat decidualization assay
  • the objective of this procedure is used to evaluate the effect of progestins and antiprogestins on rat ute ⁇ ne decidualization and compare the relative potencies of vanous test compounds
  • the materials and methods used in this assay are as follows a Methods: Test compounds are dissolved in 100% ethanol and mixed with corn oil (vehicle) Stock solutions of the test compounds m oil (MazolaT ) are t en prepared by heating ( ⁇ 80 °C) the mixture to evaporate ethanol Test compounds are subsequently diluted with 100% corn oil or 10% ethanol m corn oil prior to the treatment of animals No difference m decidual response was found when these
  • Ova ⁇ ectomized mature female Sprague-Dawley rats ( ⁇ 60-day old and 230g) are obtained from Taconic (Tacomc Farms, NY) following surgery Ovanectomy is performed at least 10 days pnor to treatment to reduce circulating sex steroids Animals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitum c Treatment
  • Rats are weighed and randomly assigned to groups of 4 or 5 before treatment
  • Test compounds in 0 2 ml vehicle are administered by subcutaneous mjection m the nape of the neck or by gavage usmg 0 5 ml
  • the animals are treated once daily for seven day s
  • animals are given the test compounds and a EC50 dose of progesterone (5 6 mg/kg) during the first three day s of treatment
  • Folio wmg decidual stimulation animals contmue to receive progesterone until necropsy four days later d
  • Dosing 5 6 mg/kg
  • Doses are prepared based upon mg/kg mean group weight In all studies, a control group receiving vehicle is included Determination of dose-response curves is carried out using doses with half log increases (e g 0 1. 0 3. 1 0. 3 0 mg/kg ) e Decidual mduction
  • the mcrease m weight of the decidualized uterme horn is calculated by D-horn/C-horn and loganthmic transformation is used to maximize normality and homogeneity of vanance
  • the Huber M-estimator is used to down weight the outlymg transformed observations for both dose-response curve fitting and one-way analysis of vanance JMP software (SAS Institute, Inc ) is used for both oneway ANOVA and non-linear dose-response analyses g Reference Compounds
  • Concentration Compound concentration in assay (default-mg/kg body weight) Route of admmistration Route the compound is admmistered to the animals Body weight Mean total animal body weight (default-kg) D-horn Wet weight of decidualized uterme horn (default-mg) C-horn Wet weight of control ute ⁇ ne horn (default-mg)
  • Progestational activity Compounds that mduce decidualization significantly (p ⁇ 0 05) compared to vehicle control are considered active
  • Antiprogestational activity Compounds that decrease EC 50 progesterone mduced decidualization significantly (p ⁇ 0 05)
  • IC 50 for uterine weight Concentration of compound that gives half-maximal decrease m EC 50 progesterone mduced decidual response (default-mg/kg)

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Gynecology & Obstetrics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Reproductive Health (AREA)
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Abstract

L'invention concerne des composés de formule I. Dans ladite formule, A, B et D sont N ou CH, à condition que A, B et D ne puissent pas tous être CH; R1 et R2 sont des substituants indépendants qui peuvent être H, COR?A, NRBCORA¿, ou des groupes alkyle éventuellement substitué, alcényle, alkynyle, cycloalkyle ou aryle; ou bien R1 et R2 sont fusionnés pour former une chaîne alkyle spirocyclique éventuellement substituée comprenant de 3 à 8 éléments, alcényle ou hétérocyclique; RA est H ou alkyle éventuellement substitué, aryle, alcoxy, ou aminoalkyle; RB est H, alkyle C¿1-3?, ou alkyle C1-3 substitué; R?3¿ est H, OH, NH¿2?, ou alkyle éventuellement substitué, ou alcényle, ou COR?C; RC¿ est H ou alkyle éventuellement substitué, aryle, alcoxy, ou aminoalkyle; R4 est une chaîne benzène substituée ou une chaîne à 5 ou 6 éléments comportant 1, 2 ou 3 hétéroatomes pouvant être O, S, SO, SO¿2? ou NR?5; RF¿ est H ou alkyle éventuellement substitué, aryle, alcoxy, ou aminoalkyle; RG est H, alkyle, ou alkyle substitué; R5 est H ou alkyle; Q est O, S, NR?6, ou CR7R8; R6¿ est CN, SO¿2?CF3, ou une chaîne alkyle éventuellement substituée, cycloalkyle, aryle, ou hétérocyclique; R?7 et R8¿ sont H, NO¿2?, CN CO2R?9¿, ou une chaîne alkyle éventuellement substituée, cycloalkyle, aryle, ou hétérocyclique; R9 est alkyle C¿1-3?; ou CR?7R8¿ forme une chaîne à 6 éléments dont la structure est représentée ci-dessous. W est O ou une liaison chimique. Il peut s'agir d'un sel pharmaceutiquement acceptable des dérivés considérés. L'invention concerne en outre l'utilisation de ces dérivés, et des compositions pharmaceutiques tenant lieu d'agonistes et d'antagonistes vis-à-vis du récepteur de progestérone.
PCT/US2000/011836 1999-05-04 2000-05-01 Derives d'uree et d'amide cycliques WO2000066592A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU46896/00A AU4689600A (en) 1999-05-04 2000-05-01 Cyclic urea and cyclic amide derivatives
CA002371642A CA2371642A1 (fr) 1999-05-04 2000-05-01 Derives d'uree et d'amide cycliques
PCT/US2000/011836 WO2000066592A1 (fr) 1999-05-04 2000-05-01 Derives d'uree et d'amide cycliques
MXPA01011291A MXPA01011291A (es) 1999-05-04 2000-05-01 Derivados de urea ciclica y amida ciclica.
EP00928699A EP1173443A1 (fr) 1999-05-04 2000-05-01 Derives d'uree et d'amide cycliques
JP2000615622A JP2002543206A (ja) 1999-05-04 2000-05-01 環状尿素および環状アミド誘導体
HK02104860.7A HK1043994A1 (zh) 1999-05-04 2002-06-28 環尿素及環醯胺衍生物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US60/183,037 1999-05-04
US09/552,356 US6369056B1 (en) 1999-05-04 2000-04-19 Cyclic urea and cyclic amide derivatives
US09/552,356 2000-04-19
PCT/US2000/011836 WO2000066592A1 (fr) 1999-05-04 2000-05-01 Derives d'uree et d'amide cycliques

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WO2002020526A3 (fr) * 2000-09-07 2002-05-30 Bayer Ag Amidines cycliques et acycliques et compositions pharmaceutiques contenant ces composes utilises comme agents de liaison de recepteur de progesterone
US7071205B2 (en) 2002-10-11 2006-07-04 Ligand Pharmaceuticals Incorporated 5-cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds
US7084151B2 (en) 2002-10-11 2006-08-01 Ligand Pharmaceuticals Incorporated 5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno[3,4-ƒ]quinolines as selective progesterone receptor modulator compounds
US7247625B2 (en) 2003-10-09 2007-07-24 Wyeth 6-amino-1,4-dihydro-benzo[d][1,3] oxazin-2-ones and analogs useful as progesterone receptor modulators

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020526A3 (fr) * 2000-09-07 2002-05-30 Bayer Ag Amidines cycliques et acycliques et compositions pharmaceutiques contenant ces composes utilises comme agents de liaison de recepteur de progesterone
US7071205B2 (en) 2002-10-11 2006-07-04 Ligand Pharmaceuticals Incorporated 5-cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds
US7084151B2 (en) 2002-10-11 2006-08-01 Ligand Pharmaceuticals Incorporated 5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno[3,4-ƒ]quinolines as selective progesterone receptor modulator compounds
US7247625B2 (en) 2003-10-09 2007-07-24 Wyeth 6-amino-1,4-dihydro-benzo[d][1,3] oxazin-2-ones and analogs useful as progesterone receptor modulators
US7354915B2 (en) 2003-10-09 2008-04-08 Wyeth 6-amino-1,4-dihydro-benzo[d][1,3]oxazin-2-ones and analogs useful as progesterone receptor modulators

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