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WO2000066560A1 - Derives de quinazolinone et de benzoxazine tenant lieu de modulateurs du recepteur de progesterone - Google Patents

Derives de quinazolinone et de benzoxazine tenant lieu de modulateurs du recepteur de progesterone Download PDF

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Publication number
WO2000066560A1
WO2000066560A1 PCT/US2000/011835 US0011835W WO0066560A1 WO 2000066560 A1 WO2000066560 A1 WO 2000066560A1 US 0011835 W US0011835 W US 0011835W WO 0066560 A1 WO0066560 A1 WO 0066560A1
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Prior art keywords
alkyl
substituted
alkoxy
aryl
ammoalkyl
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PCT/US2000/011835
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English (en)
Inventor
Puwen Zhang
Andrew Fensome
Eugene A. Terefenko
Lin Zhi
Todd K. Jones
Christopher M. Tegley
Jay E. Wrobel
James P. Edwards
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American Home Products Corporation
Ligand Pharmaceuticals, Inc.
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Application filed by American Home Products Corporation, Ligand Pharmaceuticals, Inc. filed Critical American Home Products Corporation
Priority to EP00930288A priority Critical patent/EP1175404A1/fr
Priority to CA002371651A priority patent/CA2371651A1/fr
Priority to PCT/US2000/011835 priority patent/WO2000066560A1/fr
Priority to JP2000615391A priority patent/JP2003524626A/ja
Priority to MXPA01011310A priority patent/MXPA01011310A/es
Priority to AU48140/00A priority patent/AU4814000A/en
Publication of WO2000066560A1 publication Critical patent/WO2000066560A1/fr
Priority to HK02104857.2A priority patent/HK1043991A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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 "ligand dependent transcnption 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)
  • PR progesterone receptor
  • ER estrogen receptor
  • AR glucocorticoid receptor
  • MR mineralocorticoid receptor
  • 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 hgands
  • a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex This complex
  • a compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist PR agonists (natural and synthetic) are known to play an important role m 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
  • 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 Nedeckis) as well as uterine and ovanan cancers PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J Chn Endo Metab , 76, 513, 1993) and endometnosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991)
  • hormone dependent breast cancers Horm Cancer, 283, pub Birkhaeuser, Boston, Mass , ed Nedeckis
  • PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J Chn Endo Metab , 76, 513, 1993) and endometnosis (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 mifep ⁇ stone and onapnstone
  • PR antagonists 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 antagomsts in functional models, either/or in-vitro and in-vivo These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovanan and prostate cancer, and post menopausal hormone replacement therapy
  • the compounds in the present invention contain a pendent aromatic substituent
  • the aromatic substituents proved to be c ⁇ tical for the resultant compounds being active as progesterone receptor modulators and have broad structural diversity which may consists of aryl, substituted aryl, heteroaryl or substituted heteroaryl group
  • R 1 , R 2 are independent substituents selected from the group which includes H,
  • Ci to C 6 alkyl substituted Ci to C 6 alkyl, C to C 6 alkenyl, substituted C 2 to C 6 alkenyl,
  • R A is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, G to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 aminoalkyl, substituted Ci to C 3 aminoalkyl,
  • R B is H, C_ to C 3 alkyl, substituted C. to C 3 alkyl
  • R 3 is H, OH, NH 2 , C, to C 6 alkyl, substituted C, to C 6 alkyl, C 3 to C 6 alkenyl, substituted G to C 6 alkenyl, alkynyl, or substituted alkynyl, COR c ,
  • R c is H, G 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, substituted Ci to C 3 aminoalkyl, R 4 is H, halogen, CN, N0 2 , C, to C 6 alkyl, substituted C, to C 6 alkyl, alkynyl, or substituted alkynyl, Ci to C 6 alkoxy, substituted Ci to C 6 alkoxy, amino, Ci to C 6 ammoalkyl, substituted Ci to C 6 aminoalkyl,
  • R 5 is a t ⁇ substituted benzene ring 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, alkynyl, or substituted alkynyl, to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, amino, Ci to C 3 aminoalkyl, substituted Ci to C 3 aminoalkyl.
  • N0 2 Ci to C 3 perfluoroalkyl, 5 or 6 membered heterocychc ⁇ ng containing 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D ,
  • R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, G to C 3 alkoxy, substituted Ci to C 3 alkoxy, G to C 3 aminoalkyl, or substituted Ci to C 3 ammoalkyl,
  • R E is H, Ci to C 3 alkyl, substituted C, to C 3 alkyl,
  • Y and Z are independent substituents taken from the group including H, halogen, CN, N0 2 , amino, aminoalkyl, 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, S0 2 or NR 6 and containing one or two independent substituents from the group including H, halogen, CN, N0 2 amino, and Ci to C 3 alkyl, Ci to C 3 alkoxy, C, to C 3 aminoalkyl, COR F , or NR G COR F , R F is H, Ci to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to
  • R G is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl,
  • R 6 is H or Ci to C 3 alkyl
  • R 7 and R 8 are independent substituents selected from H or an optionally substituted alkyl, aryl, or heterocychc moiety, or pharmaceutically acceptable salt thereof
  • Preferred compounds are those of Formula I
  • R 1 is H, Ci to C 6 alkyl, substituted G 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 an optionally substituted 3 to 8 membered spirocychc alkyl, alkenyl or heterocyclic ⁇ ng containing one to three heteroatoms from the group including O, S and N, as desc ⁇ bed 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 G to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl,
  • R B is H, Ci to C 3 alkyl, or substituted G to C 3 alkyl,
  • R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 6 alkenyl, substituted Ci to C 6 alkenyl, alkynyl, or substituted alkynyl, COR c ,
  • R c is H, Ci to C 4 alkyl, substituted Ci to C alkyl, aryl, substituted aryl, Ci to C alkoxy, substituted Ci to C 4 alkoxy, Ci to C 4 aminoalkyl, or substituted Ci to C 4 aminoalkyl,
  • R 4 is H, halogen, CN, N0 2 , C, to C 6 alkyl, substituted C. to C 6 alkyl, G to C 6 alkoxy, substituted Ci to C 6 alkoxy, ammo, Ci to C ⁇ ammoalkyl, substituted Ci to ⁇ ammoalkyl
  • R 5 is a t ⁇ substituted benzene rmg 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
  • Ci to C 3 alkoxy substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, ammo, Ci to C 3 ammoalkyl, substituted Ci to C 3 ammoalkyl, N0 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocychc ring contaimng 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D , R D is H, Ci to C 3 alkyl, substituted G to C 3 alkyl, aryl, substituted aryl, Ci to
  • R E is H, Ci to C 3 alkyl, or substituted G to C 3 alkyl,
  • Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, N0 2 , C, to C 3 alkoxy, G to C 3 alkyl, or C, to C 3 thioalkoxy, or
  • R 5 is a five or six membered rmg with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, S0 2 or NR 6 and contaimng one or two mdependent substituents from the group mcludmg H, halogen, CN, N0 2 ammo, and Ci to C 3 alkyl, C_ to C 3 alkoxy
  • R 6 is H, or C, to C 3 alkyl
  • G 2 is CO, CS, or CR 7 R 8 , with the proviso that when Gi is O, G 2 is CR 7 Rs, and Gi and G 2 cannot both be CR 7 Rs, wherem R 7 and R 8 are mdependent substituent selected from H, alkyl, substituted alkyl. aryl, substituted aryl, heterocychc, or substituted heterocychc or a pharmaceutically acceptable salt thereof
  • R 1 R 2 and are selected from G to C 3 alkyl, substituted Ci to C 3 alkyl, or spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 3 to 6 membered spirocychc ⁇ ng,
  • R 3 is H, OH, NH 2 , C, to C 6 alkyl, substituted C, to C 6 alkyl, -COH, -CO(C, to C 4 alkyl) or -CO(G to C 4 alkoxy),
  • R 4 is H, halogen, N0 2 , Ci to C 3 alkyl, substituted G to C 3 alkyl, R 5 is a disubstituted benzene rmg contaimng the substituents X, and Y as shown below
  • X is taken from the group mcludmg halogen, CN, G to C 3 alkoxy, G to C 3 alkyl, N0 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocychc ⁇ ng contaimng 1 to 3 heteroatoms, Ci to C 3 thioalkoxy,
  • Y is a substituent on the 4' or 5' position from the group mcludmg H, halogen, CN. N0 2 , Ci to C 3 alkoxy, C, to C 4 alkyl, C_ to C 3 thioalkoxy or
  • R 5 is a five membered rmg with the structure shown below
  • R 6 is H, or C, to C 3 alkyl, C, to C 4 C0 2 alkyl, X' is from the group mcludmg halogen, CN, N0 2 , Ci to C 3 alkyl and Ci to C 3 alkoxy,
  • Y' is from the group mcludmg H and Ci to C 4 alkyl or
  • R 5 is a six membered rmg with the structure shown
  • X 2 is halogen, CN, alkoxy, or N0 2
  • G 2 is CR 7 Rs, and Gi and G 2 cannot both be CR 7 R 8 , wherem R 7 and R 8 are mdependent substituents selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocychc, or substituted heterocychc, or pharmaceutically acceptable salt thereof
  • R 1 R 2 and are selected from the group which mcludes CH 3 and spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 6 membered spirocychc ⁇ ng,
  • R 3 is H, OH, NH 2 , CH 3 , substituted methyl, COR c ,
  • R c is H, Ci to C 3 alkyl, C. to C 4 alkoxy,
  • R 4 is H, halogen, C, to C 3 alkyl
  • R 5 is a disubstituted benzene ⁇ ng contaimng the substituents X, and Y as shown below
  • X is taken from the group including halogen, CN, methoxy, N0 , 2-th ⁇ azole, Y is a substituent on the 4' or 5' position from the group mcludmg H and F, or
  • R 5 is a five membered rmg with the structure shown below
  • U is O, S, or NH
  • X' is from the group including halogen, CN, N0 2
  • Y' is from the group mcludmg H and Ci to C 4 alkyl
  • G 2 is CO, CS, or CR 7 R 8 provided that when Gi is O, G 2 is CR 7 Rs, and Gi and G 2 cannot both be CR 7 Rs,
  • R 7 and Rs are mdependent substituent selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocychc, or substituted heterocychc, and pharmaceutically acceptable salts thereof
  • the compounds of this mvention may contain an asymmetnc carbon atom and some of the compounds of this mvention may contain one or more asymmetnc centers and may thus give nse to optical isomers and diastereomers While shown without respect to stereochemistry m Formula I, the present mvention mcludes such optical isomers and diastereomers, as well as the racemic and resolved, enantiome ⁇ cally pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof It will be understood by one skilled m the art that the number of substituents listed for spirocychc or heterospirocychc rings formed by fusmg R, and R 2 will be determined by the size of the spirocychc ⁇ ng
  • alkyl is used herem to refer to both straight- and branched-cham saturated aliphatic hydrocarbon groups having one to eight carbon atoms
  • alkenyl is mtended to mclude both straight- and branched-cham alkyl group with at least one carbon-carbon double bond and two to eight carbon atoms
  • alkynyl is mtended to cover both straight- and branched-cham alkyl group with at least one carbon-carbon t ⁇ ple bond and two to eight carbon atoms
  • substituted alkyl refers to alkyl, alkenyl, and alkynyl as just desc ⁇ bed having one or more substituents from the group mcludmg halogen, CN, OH, N0 2 , ammo, aryl, heterocychc, substituted aryl, substituted heterocychc, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio
  • substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety
  • aryl is used herem to refer to an aromatic system which may be a smgle rmg or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rmgs forms the conjug
  • substituted aryl refers to aryl as just defined havmg one to four substituents from the group mcludmg halogen, CN, OH, N0 2 , ammo, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio
  • heterocyclic is used herem to describe a stable 4- to 7-membered monocychc or a stable multicychc heterocychc ⁇ ng which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group mcludmg N, O, and S atoms The N and S atoms may be oxidized
  • the heterocychc ⁇ ng also mcludes any multicychc ⁇ ng m which any of
  • substituted heterocychc is used herem to desc ⁇ be the heterocychc just defined having one to four substituents selected from the group which mcludes halogen, CN. OH, N0 2 , ammo, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio
  • alkoxy refers to the OR group, where R is alkyl or substituted alkyl
  • aryloxy is used herem to mdicate the OR group, where R is aryl or substituted aryl
  • alkylcarbonyl refers to the RCO group, where R is alkyl or substituted alkyl
  • alkylcarboxy refers to the COOR group, where R is alkyl or substituted
  • the compounds of this mvention are generally prepared by employmg the suitable couphng reaction as a key step
  • the arylation of ammo carbinol 2 to yield 3 can be effected by va ⁇ ous couplmg reactions mcludmg Suzuki, Stille reactions These reactions are commonly performed in the presence of a transition metallic catalyst,
  • ortho-amino ketone 8 can be prepared by treatment of ortho- amino benzonitrile 11 with an organo metalhc compound such as organo hthium reagent or Gngnard reagent in a suitable solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at temperatures ranging from -78 °C to room temperature as illustrated in Scheme III.
  • organo metalhc compound such as organo hthium reagent or Gngnard reagent
  • a suitable solvent such as THF or ether
  • an inert atmosphere such as argon or nitrogen
  • Benzonitrile 11 can be readily prepared from an appropriately substituted benzonitrile such as bromobenzonitrile 10 using a suitable coupling reaction such as Stille or Suzuki protocol carried out in a similar fashion as described for the preparation of the Weinreb amide 7.
  • Scheme IN illustrates the synthesis of 3,4-d ⁇ hydroqu ⁇ nazohn-2-ones
  • organo metalhc compound such as an organo hthium or Gngnard reagent m a nonprotic solvent such as THF or ether under an mert atmosphere such argon or nitrogen at -78 °C to room temperature to produce an imino intermediate which is reacted with a suitable carbonate such as diethyl carbonate or dimethyl carbonate in situ at 0 °C to 60 °C to give qu ⁇ nazohn-2- ones 12
  • Protection of qu ⁇ nazohn-2-ones 12 with a suitable protective group such as a /? ⁇ r ⁇ -methoxybenzyl moiety can be effected by treating 12 with a suitable base such as potassium hyd ⁇ de, potassium t-butoxide, or sodium hyd ⁇ de followed by addition of a protective reagent such as /r ⁇ ra-
  • Removal of the protective group can be effected by treatmg 13 with a suitable deprotectmg reagent, e g for the ⁇ r ⁇ -methoxybenzyl protective group it can be removed by treatment of 13 with protic acid such as TFA or with Ce ⁇ c ammonium mtrate in a suitable solvent such as methylene chlo ⁇ de at 0 °C to room temperature under an mert atmosphere such as argon or nitrogen P ⁇ or to the removal of protective group, the alkylation of 3-n ⁇ trogen can be achieved by treatmg 13 with an appropnate base such as sodium hydride, potassium hydride, or potassium t-butoxide m a suitable solvent such as DMF followed by quenching the reaction solution with an organo iodide or an organo tnflate such as lodomethane under an mert atmosphere such as argon or mtrogen at 0 °C to room temperature
  • the compounds of the present mvention 14 can be prepared when the
  • the conversion of compounds 14 to 3,4-d ⁇ hydroqu ⁇ nazohn-2-th ⁇ ones 15 can be accomphshed by treatment of 14 with a suitable sulfur reagent such as Lawesson's reagent m a nonprotic solvent such as o-xylene, chlorobenzene, or toluene under an mert atmosphere such as argon or mtrogen at reflux
  • a suitable sulfur reagent such as Lawesson's reagent m
  • a nonprotic solvent such as o-xylene, chlorobenzene, or toluene under an mert atmosphere such as argon or mtrogen at reflux
  • the compounds 14 or 15 can be further de ⁇ vatized at position- 1 via numerous approaches leading to a vanety of the novel de ⁇ vatives mcludmg 1 -alkyl, substituted 1 -alkyl, 1-carbonyl, substituted 1-carbonyl, 1 -carboxy, substituted 1
  • 16 or 17 can be formed by treatment of carbamate 14 or 15 with a suitable base such as sodium hydride m a suitable solvent such as DMF under an mert atmosphere such as argon or nitrogen followed by addition of an appropnate electrophile such as alkyl or substituted alkyl bromide, iodide, or tnflate Such transformation of 14 or 15 to 16 or
  • 17 at position- 1 can also be effected usmg biphasic condition as mdicated m scheme N m which alkylation is executed using a biphasic catalyst such as t ⁇ butylammomum bromide in a suitable solvent such as acetonitrile
  • a biphasic catalyst such as t ⁇ butylammomum bromide in a suitable solvent such as acetonitrile
  • m position- 1 m cludes but not limited to the one depicted m scheme N m that heatmg of 14 or 15 with tnethyl orthoformate affords 1 -substituted de ⁇ vatives of compound 14 or 15
  • a solvent such as acetone, ethanol, benzene, toluene or THF.
  • a palladium catalyst such as tetrak ⁇ s(t ⁇ phenylphosph ⁇ ne) palladium (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluonde or potassium phosphate
  • the conversion of compounds 26 to thioamide 27 can be accomplished by treatment of 26 with a suitable sulfur reagent such as Lawesson's reagent m a nonprotic solvent such as o-xylene, chlorobenzene, or toluene under an mert atmosphere such as argon or mtrogen at reflux
  • a suitable sulfur reagent such as Lawesson's reagent m
  • a nonprotic solvent such as o-xylene, chlorobenzene, or toluene
  • mert atmosphere such as argon or mtrogen at reflux
  • an appropnate cychc amide such as 25, is allowed to react with ⁇ aH m THF to form the amon species and then a benzyl hahde is added to convert the starting material to the ⁇ -protected amide product, 28 Reaction of 28 with an aryl boromc acid m the presence of a palladium catalyst such as tetrak ⁇ s(t ⁇ phenylphosphme)pallad ⁇ um(0) or palladium acetate permits a couplmg of the two aromatic species to yield 29
  • the reaction is normally earned out under biphasic conditions That is, water is often employed along with an appropnate orgamc solvent, such as toluene or DMF
  • the palladium catalyst is typically added last and the reaction mixture is refluxed m the presence of an mert gas such as mtrogen
  • the product is treated with a Gngnard Reagent, an alkyl magnesium halide, m THF followed by the addition of
  • the compounds of the present mvention can be used m the form of salts denved from pharmaceutically or physiologically acceptable acids or bases
  • These salts mclude, but are not hmited to, the following salts with morgamc acids such as hydrochlo ⁇ c acid, sulfu ⁇ c acid, mt ⁇ c acid, phosphoric acid and, as the case may be, such orgamc acids as acetic acid, oxalic acid, succinic acid, and maleic acid
  • Other salts m clude salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium m the form of esters, carbamates and other conventional "pro-drug" forms, which, when admimstered m such form, convert to the active moiety in vivo
  • the progesterone receptor antagomsts of this mvention can be utilized m methods of contraception and the treatment and/or prevention of bemgn and malignant neoplastic disease
  • Specific uses of the compounds and pharmaceutical compositions of mvention mclude the treatment and/or prevention of uterine myomet ⁇ al fibroids, endometnosis, bemgn prostatic hypertrophy, carcinomas and adenocarcinomas of the endomet ⁇ um, ovary, breast, colon, prostate, pituitary, memngioma and other hormone-dependent tumors
  • Additional uses of the present progesterone receptor antagomsts mclude the synchromzation of the estrus m hvestock
  • the progesterone receptor antagomsts of the current mvention may be used either alone m a continuous administration of between 1 and 500 mg per day, or alternatively used m a different regimen which would entail 2-4 days of
  • the progesterone receptor antagomsts of this mvention can also be utihzed m methods of treatment and/or prevention of bemgn and malignant neoplastic disease
  • Specific uses of the compounds and pharmaceutical compositions of mvention mclude the treatment and/or prevention of uterine myometnal fibroids, endometnosis, bemgn prostatic hypertrophy, carcinomas and adenocarcinomas of the endometnum, ovary, breast, colon, prostate, pituitary, memngioma and other hormone-dependent tumors
  • Additional uses of the present progesterone receptor antagomsts mclude the synchronization of the estrus in hvestock
  • the progesterone receptor agonists of this mvention, used alone or m combmation can be utilized m methods of contraception and the treatment and/or prevention of dysfunctional bleedmg, uterme leiomyomata, endometnosis,
  • the progesterone receptor agomsts of the current mvention are preferably used m combmation or sequentially with an estrogen agomst (e g ethmyl estradiol)
  • the prefe ⁇ ed dose of the progesterone receptor agomst is between 0 01 and 500 mg per day
  • the compounds may be combmed with one or more pharmaceutically acceptable earners or excipients, for example, solvents, diluents and the hke, and may be admimstered orally m such forms as tablets, capsules, dispersible powders, granules, or suspensions contaimng, for example, from about 0 05 to 5% of suspendmg agent, syrups contaimng, for example, from about 10 to 50% of sugar, and elixirs contaimng, for example, from about 20 to 50% ethanol, and the hke, or parenterally m the form of ste ⁇ le injectable
  • the effective dosage of active ingredient employed may vary dependmg on the particular compound employed, the mode of administration and the severity of the condition bemg treated However, m general, satisfactory results are obtained when the compounds of the mvention are admimstered at a daily dosage of from about 0 5 to about 500 mg/kg of animal body weight, preferably given m divided doses two to four times a day, or m a sustained release form For most large marnmals, 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 m intimate admixture with a solid or liquid pharmaceutically acceptable carrier This dosage regimen may be adjusted to provide the optimal therapeutic response For example, several divided doses may be admimstered daily or the dose may be proportionally reduced as mdicated by the exigencies of the therapeutic situation
  • These active compounds may be admimstered orally as well as by mtravenous, intramuscular, or subcutaneous routes Sohd earners
  • compositions from the standpoint of ease of preparation and admimstration are sohd compositions, particularly tablets and hard- filled or hquid-filled capsules Oral admimstration of the compounds is prefe ⁇ ed
  • active compounds may also be admimstered parenterally or mtrape ⁇ toneally Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared m water suitably mixed with a surfactant such as hydroxypropylceUulose Dispersions can also be prepared m 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 injectable use mclude sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions
  • the form must be ste ⁇ le 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 contaminatmg action of microorganisms such as bacterial and fungi
  • the carrier can be a solvent or dispersion medium contaimng, for example, water, ethanol (e g , glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil
  • the reaction mixture was kept at room temperature under nitrogen for 3 hours and quenched with a mixture of a saturated aqueous ammonium chloride solution (10 mL) and IN aqueous HCl solution (5 mL). The mixture was stirred at room temperature for 20 minutes and ethyl acetate (40 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine and dried (MgS0 4 ). The solvent was removed and a half portion of the residue was dissolved in TFA (3 mL) and was stirred under nitrogen at room temperature for 72 hours.
  • TFA 3 mL
  • EXAMPLE 12 Pharmacology
  • the compounds of this mvention were tested m the relevant assay as descnbed below and their potency are m the range of 0 01 nM to 5 ⁇ M m the in vitro assays and 0 001 to 300 mg/kg m the in vivo assays The selected examples are listed below
  • the m- vitro biology is determined by (1) competitive Radiohgand Bmdmg usmg 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 Antagomst IC50 values, (3) a T47D cell proliferation, which is a further functional assay which also provides agomst and antagomst data, and (4) T47D cell alkaline phosphatase assay, which is a further functional assay which also provides agomst and antagomst data
  • hPR B dmg assay This assay is earned out in accordance with Pathirana, C , Stem, R B , Berger, T S , Femcal, W , lamro, T , Mais, D E , Tones, A , Glodman, M E , Nonsteroidal human progesterone receptor modulators from the marine alga cymopha barbata, J Steroid Biochem Mol Biol , 1992, 41, 733-738
  • PRE-luciferase assay m CN-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 m CN-1 cells co-transfected with human PR and PRE-luciferase plasmids
  • the materials methods used m the assay are as follows a Medium
  • the growth medium was as follows DMEM (BioWhittaker) contaimng 10% (v/v) fetal bovme serum (heat mactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml pemcilhn, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL)
  • the expenmental medium was as follows
  • DMEM BioWhittaker
  • phenol red-free phenol red-free, contaimng 10% (v/v) charcoal-st ⁇ pped fetal bovme serum (heat-mactivated)
  • 0 1 mM MEM non-essential ammo acids lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL)
  • GlutaMax b Cell culture, transfection. treatment, and luciferase assay
  • Each treatment consists of at least 4 replicates
  • Log transformed data are used for analysis of vanance and nonlinear dose response curve fittmg for both agomst and antagomst modes
  • Huber weightmg 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
  • Reference Compounds Progesterone and tnmegestone are reference progestms and
  • RU486 is the reference antiprogestm All reference compounds are run m full dose- response curves and the EC 50 or IC 50 values are calculated Table 2. Estimated EC50, standard error (SE), and 95% confidence intervals (CI) for reference progestins from three individual studies
  • Progestational activity Compounds that increase PRE-luciferase activity significantly (p ⁇ 0.05) compared to vehicle control are considered active.
  • Antiprogestational activity Compounds that decrease 3 nM progesterone induced PRE-luciferase activity significantly (p ⁇ 0.05)
  • EC 50 Concentration of a compound that gives half-maximal increase PRE- luciferase activity (default-nM) with SE.
  • IC 50 Concentration of a compound that gives half-maximal decrease in 3 nM progesterone induced PRE-luciferase activity (default-nM) with SE.
  • 3 T47D cell proliferation assay The objective of this assay is the determination of progestational and antiprogestational potency by usmg a cell proliferation assay m T47D cells A compound's effect on DNA synthesis m T47D cells is measured The materials and methods used this assay are as follows a Growth medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovme serum (not heat- lnactivated), lOOU/ml pemcilhn, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) b Treatment medium Minimum Essential
  • this assay is to identify progestins or antiprogestins by determinmg a compound's effect on alkahne phosphatase activity m T47D cells
  • the materials and methods used m this assay are as follows a Culture medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 5% (v/v) charcoal stnpped fetal bovme serum (not heat-mactivated).
  • Frozen T47D cells were thawed m 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 in the culture medium was then added to each well When testmg for progestm antagomst activity, reference antiprogestins or test compounds were added m the presence of 1 nM progesterone The cells were mcubated at 37°C m a 5% C0 2 /hum ⁇ d ⁇ fied atmosphere for 24 hr d Alkaline Phosphatase Enzyme Assay
  • Progesterone 1 0 839 0 030 0 706 0 996
  • Rat deciduahzation assay The objective of this procedure is used to evaluate the effect of progestins and antiprogestins on rat uterine deciduahzation and compare the relative potencies of various test compounds
  • the mate ⁇ als and methods used m this assay are as follows a Methods: Test compounds are dissolved m 100% ethanol and mixed with corn oil (vehicle) Stock solutions of the test compounds m oil (MazdaTM 1 ) re then prepared by heatmg (-80 °C) the mixture to evaporate ethanol Test compounds are subsequently diluted with 100% corn oil or 10% ethanol m corn oil p ⁇ or to the treatment of ammals No difference m decidual response was found when these two vehicles were compared b Ammals (RACUC protocol #5002)
  • Ova ⁇ ectomized mature female Sprague-Dawley rats ( ⁇ 60-day old and 230g) are obtained from Tacomc (Taconic Farms, NY) following surgery Ova ⁇ ectomy is performed at least 10 days prior to treatment to reduce circulating sex steroids Ammals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitu c Treatment
  • Rats are weighed and randomly assigned to groups of 4 or 5 before treatment
  • Test compounds m 0 2 ml vehicle are admimstered by subcutaneous mjection m the nape of the neck or by lavage usmg 0 5 ml
  • the animals are treated once daily for seven days
  • testmg antiprogestins ammals are given the test compounds and a EC50 dose of progesterone (5 6 mg/kg) dunng the first three days of treatment
  • Folio wmg decidual stimulation animals contmue to receive progesterone until necropsy four days later d
  • Doses are prepared based upon mg/kg mean group body weight In all studies, a control group receiving vehicle is included Determmation of dose-response curves is earned out using doses with half log mcreases (e g 0 1, 0 3, 1 0, 3 0 mg/kg) e Decidual mduction
  • deciduahzation is mduced in one of the uterme horns by scratching the antimesomet ⁇ al luminal epithelium with a blunt 21 G needle The contralateral horn is not scratched and serves as an unstimulated control
  • rats are sacrificed by C02 asphyxiation and body weight measured Uten are removed and trimmed of fat Deciduahzed (D-horn) and control (C-horn) uterme horns are weighed separately f Analysis of Results
  • the mcrease in weight of the deciduahzed uterme horn is calculated by D-horn/C-horn and logarithmic 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 fittmg and one-way analysis of vanance JMP software (SAS Institute, Inc ) is used for both oneway ANONA and non-hnear dose-response analyses g Reference Compounds
  • Body weight Mean total animal body weight (default-kg) D-horn Wet weight of deciduahzed uterme horn (default-mg) C-horn Wet weight of control uterme horn (default-mg) Decidual response [(D-C)/C]xl00% Progestational activity Compounds that mduce deciduahzation significantly
  • Antiprogestational activity Compounds that decrease EC50 progesterone mduced deciduahzation significantly (p ⁇ 0 05)
  • IC 50 for uterme weight Concentration of compound that gives half-maximal decrease m EC 50 progesterone mduced decidual response (default-mg/kg)
  • 2-Methyl-6-bromospiro[4H-3,l-benzoxazine-4,r-cyclopentane] was prepared using the same procedure as for 6-bromo-2,4,4-trimethyl-l,4-dihydro-2H-3,l- benzoxazine in Example 13.
  • the title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,l-benzoxazine-4,r-cyclopentane] and 5-bromo-4- methyl-2-thiophenecarbonitrile.
  • mcludmg 5-(2,4,4-Tnmethyl-l,2,3,4-tetrahydro- qumolm-6-yl)-lH-py ⁇ ole-2-carbomtnle, l-Methyl-5-(2,4,4-tnmethyl-l, 2,3,4- tetrahydro-qumolm-6-yl)-lH-pynole-2- carbomt ⁇ le , and 3-Fluoro-5-(2,4,4-tnmethyl- l,2,3,4-tetrahydro-qumolm-6-yl)-benzomt ⁇ le may be prepared usmg the methods descnbed above

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Abstract

L'invention concerne des composés qui sont des agonistes et des antagonistes vis-à-vis du récepteur de progestérone, et qui sont représentés par la structure générale (I). Dans ladite structure, R1 et R2 peuvent être indépendamment H, COR?A, ou NRBCORA¿, ou une fraction alkyle éventuellement substituée, alcényle, alkynyle, cycloalkyle, aryle, ou hétérocyclique; ou bien R1 et R2 sont fusionnés pour former une chaîne spirocyclique alkyle de 3 à 8 éléments, alcényle ou hétérocyclique; RA est H ou un groupe alkyle éventuellement substitué, aryle, alcoxy, ou aminoalkyle; RB est H, alkyle C¿1-3?, ou alkyle C1-3 substitué; R?3¿ est H, OH, NH2, CORC ou alkyle éventuellement substitué, alcényle, ou alkynyle; RC est H ou alkyle éventuellement substitué, aryle, alcoxy, ou aminoalkyle; R4 est H, halogène, CN, NO¿2?, ou alkyle éventuellement substitué, alkynyle, alcoxy, amino ou aminoalkyle; R?5¿ est une chaîne benzène éventuellement substituée à 5 ou 6 éléments comportant 1, 2, ou 3 hétéroatomes pouvant être O, S, SO, SO¿2? ou NR?6; R6¿ est H ou alkyle C¿1-3?; G1 est O, NR7, ou CR7R8; G2 est CO, CS, ou CR7R8; à condition que lorsque G1 est O, G2 soit CR7R8, et G1 et G2 ne peuvent pas être ensemble CR7R8; R7 et R8 sont H ou une fraction alkyle éventuellement substituée, aryle, ou hétérocyclique. Il peut également s'agir d'un sel pharmaceutiquement acceptable des composés considérés. L'invention concerne en outre des procédés relatifs à l'utilisation de ces composés chez les mammifères comme agonistes ou antagonistes vis-à-vis du récepteur de progestérone.
PCT/US2000/011835 1999-05-04 2000-05-01 Derives de quinazolinone et de benzoxazine tenant lieu de modulateurs du recepteur de progesterone WO2000066560A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP00930288A EP1175404A1 (fr) 1999-05-04 2000-05-01 Derives de quinazolinone et de benzoxazine tenant lieu de modulateurs du recepteur de progesterone
CA002371651A CA2371651A1 (fr) 1999-05-04 2000-05-01 Derives de quinazolinone et de benzoxazine tenant lieu de modulateurs du recepteur de progesterone
PCT/US2000/011835 WO2000066560A1 (fr) 1999-05-04 2000-05-01 Derives de quinazolinone et de benzoxazine tenant lieu de modulateurs du recepteur de progesterone
JP2000615391A JP2003524626A (ja) 1999-05-04 2000-05-01 プロゲステロンレセプタモジュレーターとしてのキナゾリノンおよびベンゾキサジン誘導体
MXPA01011310A MXPA01011310A (es) 1999-05-04 2000-05-01 Derivados de quinazolinona y benzoxazina como moduladores del receptor de progesterona.
AU48140/00A AU4814000A (en) 1999-05-04 2000-05-01 Quinazolinone and benzoxazine derivatives as progesterone receptor modulators
HK02104857.2A HK1043991A1 (zh) 1999-05-04 2002-06-28 作為黃體酮受體調節劑的喹唑啉酮及苯並噁嗪衍生物

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US60/219,339 1999-05-04
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WO2002074754A1 (fr) * 2001-03-21 2002-09-26 Warner-Lambert Company Llc Nouveaux derives spirotricycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase-7
JP2006504764A (ja) * 2002-10-30 2006-02-09 コビオン オーガニック セミコンダクターズ ゲーエムベーハー 半導体高分子製品に有用な単量体の新規な製造
WO2005105739A3 (fr) * 2004-04-27 2006-02-16 Wyeth Corp Biaryles de carbamate et thiocarbamate cycliques contenant du cyanopyrrole, et leurs procedes de preparation
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
US7429598B2 (en) 2002-09-17 2008-09-30 Warner-Lambert Company Spirocondensed quinazolinones and their use as phosphodiesterase inhibitors
CN100434425C (zh) * 2005-03-09 2008-11-19 首都师范大学 4-喹唑啉酮衍生物及其在抗肿瘤药物中的应用
WO2009103007A3 (fr) * 2008-02-13 2009-11-19 Ligand Pharmaceuticals Incorporated Composés modulateurs des récepteurs de l’hormone stéroïdienne et procédés
WO2010074807A1 (fr) * 2008-10-30 2010-07-01 Gilead Palo Alto, Inc. Dérivés 3, 4-dihydroquinolin-2 (1h) -one utilisés comme modulateurs de canaux sodiques
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
US8969351B2 (en) 2010-11-19 2015-03-03 Novartis Ag Crystalline form of an inhibitor of MDM2/4 and p53 interaction
US9365576B2 (en) 2012-05-24 2016-06-14 Novartis Ag Pyrrolopyrrolidinone compounds
US9403827B2 (en) 2013-01-22 2016-08-02 Novartis Ag Substituted purinone compounds
US9550796B2 (en) 2013-11-21 2017-01-24 Novartis Ag Pyrrolopyrrolone derivatives and their use as BET inhibitors
US9556180B2 (en) 2013-01-22 2017-01-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction
US9624247B2 (en) 2013-05-28 2017-04-18 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives as bet inhibitors and their use in the treatment of disease
US9714249B2 (en) 2013-05-28 2017-07-25 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
US9890166B2 (en) 2013-05-27 2018-02-13 Novartis Ag Imidazopyrrolidine derivatives and their use in the treatment of disease

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WO1996019458A2 (fr) * 1994-12-22 1996-06-27 Ligand Pharmaceuticals Incorporated Composes modulateurs des recepteurs des steroides et procedes d'utilisation

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CN100447136C (zh) * 2001-03-21 2008-12-31 沃尼尔·朗伯有限责任公司 螺三环衍生物及其作为磷酸二酯酶-7抑制剂的应用
WO2002076953A1 (fr) * 2001-03-21 2002-10-03 Warner-Lambert Company Llc Nouveaux derives spirotricycliques et utilisation de ces derives en tant qu'inhibiteurs de la phosphodiesterase-7
AP1699A (en) * 2001-03-21 2006-12-26 Warner Lambert Co New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors
US7214676B2 (en) 2001-03-21 2007-05-08 Warner-Lambert Company Llc Spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors
EP1801106A3 (fr) * 2001-03-21 2007-07-04 Warner-Lambert Company LLC Nouveaux dérivés spirotricycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase-7
WO2002074754A1 (fr) * 2001-03-21 2002-09-26 Warner-Lambert Company Llc Nouveaux derives spirotricycliques et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase-7
US7429598B2 (en) 2002-09-17 2008-09-30 Warner-Lambert Company Spirocondensed quinazolinones and their use as phosphodiesterase inhibitors
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
JP2006504764A (ja) * 2002-10-30 2006-02-09 コビオン オーガニック セミコンダクターズ ゲーエムベーハー 半導体高分子製品に有用な単量体の新規な製造
KR101086658B1 (ko) 2002-10-30 2011-11-24 메르크 파텐트 게엠베하 반도체 폴리머의 제조에 있어서 유용한 모노머의 신규한생산방법
JP2012072178A (ja) * 2002-10-30 2012-04-12 Merck Patent Gmbh 半導体高分子製品に有用な単量体の新規な製造
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
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
US7582755B2 (en) 2004-04-27 2009-09-01 Wyeth Cyanopyrrole-containing cyclic carbamate and thiocarbamate biaryls and methods for preparing the same
US8003784B2 (en) 2004-04-27 2011-08-23 Wyeth Llc Cyanopyrrole containing cyclic carbamate and thiocarbamate biaryls and methods for preparing the same
WO2005105739A3 (fr) * 2004-04-27 2006-02-16 Wyeth Corp Biaryles de carbamate et thiocarbamate cycliques contenant du cyanopyrrole, et leurs procedes de preparation
US8129524B2 (en) 2004-04-27 2012-03-06 Wyeth Llc Cyanopyrrole containing cyclic carbamate and thiocarbamate biaryls and methods for preparing the same
CN100434425C (zh) * 2005-03-09 2008-11-19 首都师范大学 4-喹唑啉酮衍生物及其在抗肿瘤药物中的应用
WO2009103007A3 (fr) * 2008-02-13 2009-11-19 Ligand Pharmaceuticals Incorporated Composés modulateurs des récepteurs de l’hormone stéroïdienne et procédés
WO2010074807A1 (fr) * 2008-10-30 2010-07-01 Gilead Palo Alto, Inc. Dérivés 3, 4-dihydroquinolin-2 (1h) -one utilisés comme modulateurs de canaux sodiques
US8664379B2 (en) 2008-10-30 2014-03-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8952007B2 (en) 2008-10-30 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
US9051279B2 (en) 2009-12-22 2015-06-09 Novartis Ag Substituted isoquinolinones and quinazolinones
US8969351B2 (en) 2010-11-19 2015-03-03 Novartis Ag Crystalline form of an inhibitor of MDM2/4 and p53 interaction
US9073898B2 (en) 2010-11-19 2015-07-07 Novartis Ag Crystalline form of an inhibitor of MDM2/4 and p53 interaction
US9365576B2 (en) 2012-05-24 2016-06-14 Novartis Ag Pyrrolopyrrolidinone compounds
US9403827B2 (en) 2013-01-22 2016-08-02 Novartis Ag Substituted purinone compounds
US9556180B2 (en) 2013-01-22 2017-01-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction
US9890166B2 (en) 2013-05-27 2018-02-13 Novartis Ag Imidazopyrrolidine derivatives and their use in the treatment of disease
US9624247B2 (en) 2013-05-28 2017-04-18 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives as bet inhibitors and their use in the treatment of disease
US9714249B2 (en) 2013-05-28 2017-07-25 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
US9550796B2 (en) 2013-11-21 2017-01-24 Novartis Ag Pyrrolopyrrolone derivatives and their use as BET inhibitors

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