Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems

Definitions

• This invention relates to compounds that act as agonists and antagonists of the progesterone receptor, their preparation, and utility
• Intracellular receptors form a class of structurally related genetic regulators known as "ligand dependent transcription factors" (R M Evans, Science, 240, 889, 1988)
• the steroid receptor family is a subset of the IR family, includmg progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR)
• the natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as gands
• 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 then translocates to the nucleus of the cell where it binds to a specific gene or genes present in the cell's DNA Once bound to a specific DNA sequence the complex modulates the production of the mRNA and protein encoded by that gene
• a compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist
• PR agonists 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 (in non- hysterectomized women) which can lead to an increased ⁇ sk of ute ⁇ ne cancers
• Co- administration of a PR agonist reduces or ablates that risk PR antagonists may also be used in contraception In this context they may be administered alone (Ulmann, et al, Ann N Y Acad Sci , 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 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 Nedeckis) 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)
• 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 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 m combination with a partial ER antagonist such as tamoxifen (US 5719136)
• PR antagonists such as Mifep ⁇ stone have also been shown to have bone sparing effects in rodents, and as such may be useful in the treatment of osteoporosis associated with the menopause (Barengolts, et al, Bone, 17, 21, 1995)
• PR antagonists such as mifep ⁇ stone and onap ⁇ stone, 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 Ac ⁇ d Sci , 761, 224, 1995)
• This invention provides compounds of Formula I
• a and B are independent substituents selected from S, CH or N,
• A is S, B is CH or N, provided that and A and B cannot both be CH, and when A and B both equal N, one N may be optionally substituted with an Ci to C ⁇ alkyl group,
• Ri and R 2 are independent substituents selected from the group of H, Ci to C ⁇ alkyl, substituted Ci to C 6 alkyl, C 2 to C ⁇ alkenyl, substituted C to C 6 alkenyl, C 2 to C ⁇ alkynyl, substituted C 2 to C6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A , or R 1 and R 2 are fused to form a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring, preferably a 3 to 6 membered spirocyclic alkyl ring, or b) an optionally substituted 3 to 8 membered spirocyclic alkenyl ring, preferably a 3 to 6 membered spirocyclic alkenyl ring, or c)
• R A is H, C] 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 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 Ci to C 6 alkyl, C 3 to C 6 alkenyl, substituted Ci to C ⁇ alkenyl, alkynyl, or substituted alkynyl, or COR c ,
• R c is HL, 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 4 is a t ⁇ substituted benzene ⁇ ng 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 thioalkyl, substituted Ci to C 3 thioalkyl, Ci to C 3 aminoalkyl, substituted Ci to C 3 aminoalkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ⁇ ng contammg 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D ,
• R D is H, Ci to C 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 ammoalkyl, 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 independently selected from H, halogen. CN,
• R 4 is a five or six membered ⁇ ng with 1, 2, or 3 heteroatoms from the group mcluding O S, SO, SO 2 or NR 5 and contammg one or two independent substituents from the group mcluding H, halogen, CN, NO 2 and Ci to C 3 alkyl,
• R G is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl
• R 5 is H, or Ci to C 3 alkyl
• R 6 is from the group mcluding CN, Ci to C ⁇ alkyl, substituted Ci to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO 2 CF 3
• R 7 and R 8 are mdependent substituents from the group mcludmg H, Ci to C ⁇ alkyl, substituted Ci to C ⁇ alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , or CN CO 2 R 9 ,
• R 9 is Ci to C 3 alkyl, or CR 7 R 8 may comprise a six membered ⁇ ng of the structure below
• W is O or a chemical bond or a pharmaceutically acceptable salt thereof
• a and B are mdependent substituents S, CH or N, provided that when A is S. B is CH or N, and when B is S, A is CH or N, and A and B cannot both be CH, and when A and B both equal N, one N may be optionally substituted with an Ci to C ⁇ alkyl group, R 1 is H, 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, COR A , or NR B COR A ,
• R 2 is H, Ci to Ce alkyl, substituted d to Ce alkyl, C 2 to C 6 alkenyl, substituted C 2 to C ⁇ alkenyl, C 2 to C ⁇ alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A , or R 1 and R 2 are fused to form a) an optionally substituted 3 to 8 membered spirocyclic alkyl ⁇ ng, or b) an optionally substituted 3 to 8 membered spirocyclic alkenyl ⁇ ng, or c) an optionally substituted 3 to 8 membered spirocyclic ⁇ ng contammg one to three heteroatoms selected from the group of O, S and N,
• 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 ammoalkyl, or substituted Ci to C 3 aminoalkyl,
• R B is H, Ci to C 3 alkyl, or substituted d 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, or COR c
• R c is H, Ci 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 4 ammoalkyl, or substituted Ci to C 4 ammoalkyl
• R 4 is a t ⁇ substituted benzene ⁇ ng containing the substituents X, Y and
• X is taken from the group including halogen, CN, Ci to C 3 alkyl, substituted d to C 3 alkyl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to
• C 3 thioalkyl substituted Ci to C 3 thioalkyl, to C 3 ammoalkyl, substituted Ci to C 3 ammoalkyl, NO 2 , Ci to C 3 perfluoro alkyl, 5-membered heterocyclic ⁇ ng contammg 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, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C ammoalkyl,
• R E is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl, Y and Z are mdependent substituents taken from the group including
• R 4 is a five or six membered ⁇ ng with 1 , 2, or 3 heteroatoms from the group mcluding O, S, SO, SO 2 or NR 5 and contammg one or two mdependent substituents from the group mcluding H, halogen, CN, NO 2 and Ci to C 3 alkyl, or Ci to C 3 alkoxy,
• R 5 is H or Ci to C 3 alkyl
• R 6 is from the group including CN, Ci to G. 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 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 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , or CN CO 2 R 9 ,
• R 9 is Ci to C 3 alkyl, or CR 8 R 9 compnse a six membered ring as shown by the structure below W is O or a chemical bond or a pharmaceutically acceptable salt thereof
• R 1 R 2 and are selected from the group which includes Ci to C 3 alkyl, substituted Ci to C 3 alkyl, or spirocyclic alkyl constructed by fusmg R 1 and R 2 to form a 3 to 6 membered spirocyclic ⁇ ng,
• R 3 is H, OH, NH 2 , Ci to Ce alkyl, substituted Ci to C 6 alkyl, or COR c , R c is H, Ci to C 4 alkyl, or Ci to C 4 alkoxy,
• R 4 is a disubstituted benzene ⁇ ng contammg the substituents X and Y as shown below
• X is selected from the group includmg halogen, CN, Ci to C 3 alkoxy, Ci to C 3 alkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocyclic ⁇ ng contammg 1 to 3 heteroatoms, or Ci to C 3 thioalkyl
• Y is a substituent on the 4 ' or 5' position selected from the group of H, halogen, CN, NO 2 , Ci to C 3 alkox>, Ci to C 4 alkyl, or Ci to C 3 thioalkyl, or
• R 4 is a five membered ⁇ ng with the structure shown below
• R 5 is H, or Ci to C 3 alkyl, or d to C 4 CO 2 alkyl, X' is selected from halogen, CN, NO 2 , Ci to C 3 alkyl or Ci to C 3 alkoxy,
• Y' is H or Ci to C 4 alkyl
• R 4 is a six membered ⁇ ng with the structure
• X 2 is halogen, CN or NO 2 ,
• R 6 is selected from the group mcluding CN, Ci to C 6 alkyl, substituted Ci to C ⁇ alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl. aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO 2 CF ,
• R 7 and R 8 are independent substituents selected from the group of H, Ci to C 6 alkyl, substituted Ci to C ⁇ alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , or CN CO 2 R 9 , R 9 is Ci to C 3 alkyl, or CR 7 R 8 comprise a six membered rmg of the structure
• W is O or a chemical bond, or a pharmaceutically acceptable salt thereof
• Each of the gene ⁇ c and subgene ⁇ c groups of compounds herem may further be divided into two further subgroups, one m which Q is oxygen and another wherem Q is selected from S, NR 6 , or CR 7 R 8
• the compounds of this invention have been shown to bind to the PR and act as agonists and/or antagonists m functional models, either in-vitro and/or in-vivo These compounds may be used for contraception, m the treatment of fibroids, endomet ⁇ osis, breast, ute ⁇ ne, ova ⁇ an and prostate cancer, osteoporosis and post menopausal hormone replacement therapy
• the compounds m the present mvention contain a pendent aromatic substituent which may consist of aryl, substituted aryl, heteroaryl or substituted heteroaryl groups
• the compounds of this invention may contain an asymmet ⁇ c carbon atom and some of the compounds of this invention may contam one or more asymmet ⁇ c centers and may thus give ⁇ se to optical isomers and diastereomers While shown without respect to stereochemistry m Formula I, II, and III, the present invention includes 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
• alkyl is used herein to refer to both straight- and branched-cham saturated aliphatic hydrocarbon groups having from one to 8 carbon atoms, preferably from 1 to 6 carbon atoms
• alkenyl is mtended to include both straight- and branched-cham alkyl group having from 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, with at least one carbon-carbon double bond
• alkynyl is intended to cover both straight- and branched-cham alkyl group havmg from 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, with at least one carbon-carbon t ⁇ ple bond
• substituted alkyl refers to alkyl, alkenyl, and alkynyl as just desc ⁇ bed having one or more substituents from the group mcludmg halogen, CN, OH, NO 2 , ammo, aryl, heterocyclic, substituted aryl, substituted heterocyclic, 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 here to refer to an aromatic system which may be a smgle ⁇ ng or multiple aromatic rings fused or linked together as such that at least one part of the fused or lmked rings forms the conjugated aromatic system
• the aryl groups mclude but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl
• substituted aryl refers to aryl as just defined having one or more substituents from the group mcludmg halogen, CN, OH, NO 2 , ammo, alkyl, cycloalkyl, alkenyl,
• heterocyclic is used herem to desc ⁇ be a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ⁇ ng which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group includmg N, O, and S atoms
• the N and S atoms may be oxidized
• the heterocyclic rmg also mcludes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ⁇ ng
• the heterocyclic ⁇ ng may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable
• Such heterocyclic groups mclude, for example, tetrahydrofuran, pipe ⁇ dmyl, piperazmyl.
• substituted heterocyclic is used herem to describe the heterocyclic just defined having one or more substituents selected from the group which mcludes halogen, CN, OH, NO 2 , ammo, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylammo, or arylthio
• alkoxy is used herem to refer to the OR group, where R is alkyl or substituted alkyl
• aryloxy is used herem to refer to the OR group, where R is aryl or substituted aryl
• ammo thiophene ester 2 was prepared accordmg to a literature procedure mvolvmg the Gewald reaction (see Comprehensive Heterocyclic Chemistry II A Review of the Literature 1982-1995 A R Kat ⁇ tsky et al Nol 2 page 639), l e the reaction of a suitably substituted aromatic acetaldehyde with sulfur and methyl cyanoacetate in refluxmg methanol (Scheme 1) Reaction of the 2-ammo group with a suitable chloroformate or carbonate affords the protected amine 3 This can be accomplished by allowing 2 to react with a chloroformate or carbonate derivative such as methyl chloroformate, ethyl chloroformate, allyl chloroformate, 2-
• the carbamate protecting group present in 4 may be removed under conditions approp ⁇ ate for its removal to afford 6 (Scheme 2)
• a reagent such as phosgene, carbonyldnmidazole or dimethyl carbonate
• an approp ⁇ ate solvent tetrahydrofuran, dichloromethane, benzene, etc
• compound 4 may be dehydrated to afford the isopropene derivative 7 (Scheme 3).
• Suitable conditions for the dehydration would be the use of a reagent such as acetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethane sulfonyl chloride or anhydride, in a solvent such as pyridine, tetrahydrofuran, dichloromethane or benzene.
• the reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent and may require the presence of a base such as 4- dimethylaminopyridine, triethylamine, pyridine or di-isopropyl ethylamine. Exposure of 7 to acidic conditions would then afford ring closure to give 5. Suitable conditions would be the use of an acid such as p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in a solvent such as dichloromethane, benzene, toluene or tetrahydrofuran.
• the reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent.
• a reagent such as an alkyl lithium or lithium amide m an
• ammo thiophene compounds 15 are prepared accordmg to a literature procedure (Comprehensive Heterocyclic Chemistry II A Review of the Literature 1982-1995 A R Katnsky et al , Nol 2, page 639) which mvolves treating a suitably substituted aromatic methyl ketone 13 with phosphorus oxychlo ⁇ de m ⁇ , ⁇ - dimethyl formamide to afford the chloro cyano olefin de ⁇ vative 14.
• the reaction can be earned out under an mert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent and may require the presence of a base such as 4- dimethylammopy ⁇
• the carbamate protectmg group present in 17 may be removed under conditions approp ⁇ ate for its removal to afford 19 (Scheme 7) Subsequent ⁇ ng closure of 19 with a reagent such as phosgene, carbonyldiimidazole or dimethyl carbonate m an approp ⁇ ate solvent (tetrahydrofuran, dichloromethane, benzene, etc ) also will provide access to 18
• a reagent such as phosgene, carbonyldiimidazole or dimethyl carbonate
• an approp ⁇ ate solvent tetrahydrofuran, dichloromethane, benzene, etc
• compound 17 may be dehydrated to afford the isopropene derivative 20 (Scheme 8).
• Suitable conditions for the dehydration would be the use of a reagent such as acetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethane sulfonyl chloride or anhydride, in a solvent such as pyridine, tetrahydrofuran, dichloromethane or benzene.
• the reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent and may require the presence of a base such as 4- dimethylaminopyridine, triethylamine, pyridine or di-isopropyl ethylamine. Exposure of 20 to acidic conditions would then afford ring closure to give 18. Suitable conditions would be the use of an acid such as p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in a solvent such as dichloromethane, benzene, toluene or tetrahydrofuran.
• the reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent.
• a reagent such as an alkyl lithium or lithium amide m an mert solvent such as
• Thiophene thiocyclocarbamates 26 and 27 may be obtained directly by treating 5 and 18 respectively with phosphorus pentasulfide in refluxing pyridine.
• 5 and 18 may be treated with Lawesson's reagent ([2,4-bis(4-methoxyphenyl)-l,3- dithia-2,4-diphosphetane-2,4-disulfide]) in refluxing pyridine to afford 26 and 27, respectively.
• the carbamate protecting group present m compound 30 may be removed under conditions approp ⁇ ate for its removal to afford compound 32 as taught by T W Greene and P G M Wuts, Protective Groups m Organic Synthesis, second ed , Wiley-Interscience (1991) Subsequent ⁇ ng closure of compound 32 with a reagent such as phosgene, carbonyl dnmidazole or dimethyl carbonate in an approp ⁇ ate solvent (THF, dichloromethane, benzene, etc) will also provide access to compound 31
• compound 30 is a tertiary alcohol then it may be dehydrated to afford the isopropene denvative 33, scheme 3 Suitable conditions for the dehydration would the use of a reagent such as acetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethane sulfonyl chlonde or anhyd ⁇ de, m a solvent such as py ⁇ dine, THF, dichloromethane or benzene
• the reaction can be earned out under an mert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent and may require the presence of a base such as 4-d ⁇ methylammopy ⁇ d ⁇ ne, t ⁇ ethylamme, py ⁇ dine or di-isopropyl ethylamme Exposure of compound 33 to acidic conditions would then afford ring closure to give compound 31
• Compound 31 may then be converted mto the bromide 34, scheme 15 Suitable conditions would be exposure to bromine or N-bromosuccmimide in a solvent such as dichloromethane, THF or acetic acid, the reaction can be earned out under an inert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent m the presence of an additive such as silica gel Subsequent reaction of compound 34 with an aryl or heteroaryl boronic acid, boronic acid anhydride or t ⁇ alkyl stannane then provides access to the desired biaryl compound 35 The reaction can be earned out in a solvent such as acetone, ethanol, benzene, toluene or THF, under an mert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent, m the presence of a palladium catalyst such as tetrak ⁇ s(tnphenylphosph ⁇ ne) palladium
• a reagent such as an alkyl lithium or lithium amide m an mert solvent such as THF
• the amine 37 is converted mto a carbamate, such as a tert-butyl carbamate as descnbed m scheme 1 for the preparation of compound 2
• Hydrolysis of the ester 38 under basic conditions, for example lithium or sodium hydroxide in THF or methanol at room temperature then gives the acid 39
• Conversion of the acid 39 mto the acid chloride 40 is accomplished under standard conditions, thionyl chlonde or oxalyl chloride either neat or in the presence of a solvent such as dichloromethane and an additive such as a catalytic amount of N,N-d ⁇ methylformam ⁇ de
• Compound 40 is then reacted with diazomethane or t ⁇ methylsilyldiazomethane m an mert solvent such as THF or dichloromethane, and the product diazoketone 41 is then rearranged in the presence of silver (I) oxide to afford the acid 42
• thione de ⁇ vative, compound 53 may be obtained directly by treatmg 52 with phosphorus pentasulfide m refluxing py ⁇ dme Alternatively 52 may be treated with Lawesson's reagent m refluxing pyridine to afford 53.
• the compounds of the present mvention can be used m the form of salts derived 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, sulfunc acid, nitnc acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succimc acid, and maleic acid
• Other salts mclude 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 admmistered in such form, convert to the active moiety in vivo
• This mvention mcludes pharmaceutical compositions and treatments which comp ⁇ se administering to a mammal a pharmaceutically effective amount of one or more compounds as descnbed above wherein Q is oxygen as antagonists of the progesterone receptor
• the mvention
• the progesterone receptor antagonists of this invention can be utilized m 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 mclude the treatment and/or prevention of ute ⁇ ne myometnal fibroids, endometnosis, benign prostatic hypertrophy, carcinomas and adenocarcinomas of the endomet ⁇ um, ovary, breast, colon, prostate, pituitary, menmgioma and other hormone-dependent tumors
• Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus m livestock
• the progesterone receptor agonists of this invention, used alone or m combination can be utilized m methods of contraception and the treatment and/or prevention of dysfunctional bleeding, ute ⁇ ne leiomyomata, endomet ⁇ osis, polycystic ovary syndrome, carcinomas and adenocarcinomas of the endomet ⁇ um,
• the effective dosage of active ingredient employed may vary dependmg on the particular compound employed, the mode of adrmmstration and the seventy of the condition being treated However, m general, satisfactory results are obtained when the compounds of the invention are admmistered 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 mammals, 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 mtimate 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 admmistered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation
• Solid carriers include starch, lactose, dicalcium phosphate, microcrystal ne cellulose, sucrose and kaolm, while liquid earners mclude 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 m the preparation of pharmaceutical compositions may be advantageously mcluded, such as flavoring agents, colo ⁇ ng agents, preserving agents, and antioxidants, for example, vitamm E, ascorbic acid, BHT and BHA
• compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules Oral administration of the compounds is preferred
• active compounds may also be administered parenterally or mtrapentoneally
• 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 hydroxypropylcellulose Dispersions can also be prepared m glycerol, liquid, polyethylene glycols and mixtures thereof in oils Under ordinary conditions of storage and use, these preparations contam a preservative to prevent the growth of microorganisms
• the pharmaceutical forms suitable for injectable use mclude ste ⁇ le aqueous solutions or dispersions and stenle powders for the extemporaneous preparation of sterile injectable solutions or dispersions
• the form must be stenle and must be fluid to the extent that easy synnge 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 contaimng, for example, water, ethanol (e g , glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil
• ethanol e g , glycerol, propylene glycol and liquid polyethylene glycol
• Example 3 Pharmacology The progestational activity of the current mvention was evaluated in the PRE-luciferase assay in CV-1 cells, desc ⁇ bed below In-vitro potencies can be m the range 0 01nM-10,000nM In vivo potencies are anticipated to be m the range 1 mg/kg to 30 mg/kg
• 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 CV-1 cells co-transfected with human PR and PRE-luciferase plasrmds
• the mate ⁇ als methods used m the assay are as follows a Medium
• the growth medium was as follows DMEM (BioWhittaker) contammg 10% (v/v) fetal bovine serum (heat inactivated), 0 1 raM MEM non-essential ammo acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL)
• the expenmental medium was as follows DMEM (BioWhittaker), phenol red-free, contammg 10% (v/v) charcoal- stripped fetal bovine serum (heat-inactivated), 0 1 mM MEM non-essential ammo
• Each treatment consists of at least 4 replicates Log transformed data are used for analysis of va ⁇ ance and nonlinear dose response curve fitting for both agonist and antagonist modes Huber weighting is used to downweight the effects of outliers EC50 or IC50 values are calculated from the retransformed values JMP software (SAS Institute, Ine ) is used for both one-way analysis of va ⁇ ance and non-linear response analyses d Reference Compounds
• Progesterone and t ⁇ megestone are reference progestins and RU486 is the reference antiprogestin All reference compounds are run m full dose- response curves and the EC50 or IC50 values are calculated
• Progestational activity Compounds that mcrease PRE-luciferase activity significantly (p ⁇ 0 05) compared to vehicle control are considered active
• Antiprogestational activity Compounds that decrease 3 nM progesterone mduced PRE-luciferase activity significantly (p ⁇ 0 05)

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Applications Claiming Priority (5)

Publications (1)

Family

ID=26878651

Family Applications (1)

Country Status (6)

Families Citing this family (1)

• 2000
  • 2000-05-01 MX MXPA01011288A patent/MXPA01011288A/es unknown
  • 2000-05-01 AU AU46888/00A patent/AU4688800A/en not_active Abandoned
  • 2000-05-01 CA CA002371632A patent/CA2371632A1/en not_active Abandoned
  • 2000-05-01 JP JP2000615621A patent/JP2002543205A/ja active Pending
  • 2000-05-01 EP EP00928691A patent/EP1185535A1/en not_active Withdrawn
  • 2000-05-01 CN CN 00807140 patent/CN1349538A/zh active Pending

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events