EP1175422A2 - Composes modulateurs de recepteur de progesterone tetracycliques et procedes - Google Patents

Composes modulateurs de recepteur de progesterone tetracycliques et procedes

Info

Publication number
EP1175422A2
EP1175422A2 EP00926495A EP00926495A EP1175422A2 EP 1175422 A2 EP1175422 A2 EP 1175422A2 EP 00926495 A EP00926495 A EP 00926495A EP 00926495 A EP00926495 A EP 00926495A EP 1175422 A2 EP1175422 A2 EP 1175422A2
Authority
EP
European Patent Office
Prior art keywords
compound
optionally substituted
fluoro
compounds
haloalkyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP00926495A
Other languages
German (de)
English (en)
Inventor
Lin Zhi
Todd K. Jones
Christopher M. Tegley
Andrew Fensome
Puwen Zhang
Jay E Wrobel
James P Edwards
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Ligand Pharmaceuticals Inc
Original Assignee
Ligand Pharmaceuticals Inc
American Home Products Corp
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 US09/552,353 external-priority patent/US6358947B1/en
Application filed by Ligand Pharmaceuticals Inc, American Home Products Corp filed Critical Ligand Pharmaceuticals Inc
Publication of EP1175422A2 publication Critical patent/EP1175422A2/fr
Ceased legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic 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
    • C07D498/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/24Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32Antioestrogens

Definitions

  • This invention relates to nonsteroidal tetracychc compounds that are modulators (I e agonists and antagonists) of progesterone receptors, and to methods for the making and use of such compounds
  • Progesterone receptor (PR) modulators have been widely used in regulation of female reproduction systems and in treatment of female hormone dependent diseases
  • the effectiveness of known steroidal PR modulators is often tempered by their undesired side- effect profile, particularly during long-term administration
  • the effectiveness of synthetic progestins, such as norgestrel, as female birth control agents must be weighed against the increased ⁇ sk of breast cancer and heart disease to women takmg such agents
  • the progesterone antagonist, mifep ⁇ stone (RU486) if administered for chronic indications, such as uterine fibroids, endomet ⁇ osis and certain hormone-dependent cancers, could cause homeostatic imbalances in a patient due to its inherent cross-reactivity as a glucocorticoid receptor (GR) antagonist Accordingly, identification of compounds that have good specificity for PR, but have reduced or no cross-reactivity for other steroid receptors, would be of significant value in the improvement of women's health
  • Nonsteroidal molecules that contain a di- or tetrahydroquinoline ⁇ ng as the core pharmacophore have been desc ⁇ bed as steroid receptor modulator compounds ⁇ See for example "Preparation of Quinolines and Fused Quinolines as Steroid Receptor Modulators", T K. Jones, M E Goldman, C L F Pooley, D T Winn, J P Edwards, S J West, C M Tegley, L Zhi, L G Harnann, R L Davis, L J Farmer, PCT Int Appl Pub No WO 96/19458, "Steroid Receptor Modulator Compounds and Methods", T K.
  • the present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by PR More particularly, the invention relates to nonsteroidal compounds and compositions that are high affinity, high specificity agonists, partial agomsts (l e , partial activators and/or tissue-specific activators) and antagonists for progesterone receptors Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis
  • alkyl, alkenyl, alkynyl and allyl include optionally substituted straight- chain, branched-chain, cyclic, saturated and or unsaturated structures, and combinations thereof
  • haloalkyl refers to alkyl structures, including straight-chain, branched-chain, or cyclic structures, or combinations thereof, that are substituted with one or more fluorines, chlorines, bromines or iodines, or combinations thereof
  • heteroalkyl includes straight-chain, branched-chain, cyclic, saturated and/or unsaturated structures, or combinations thereof, in which one or more skeletal atoms is oxygen, nitrogen, sulfur, or combinations thereof
  • aryl refers to an optionally substituted six-membered aromatic ⁇ ng
  • heteroaryl refers to an optionally substituted, aromatic five-membered heterocyclic ⁇ ng containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, or to an optionally substituted, aromatic six-membered heterocyclic ⁇ ng containing one or more nitrogens
  • substituents of an "optionally substituted" structure include, but are not limited to, one or more of the following prefe ⁇ ed substitutents F, Cl, Br, I, CN, N0 2 , NH 2 , NCH 3 , Compounds of the present invention are defined as those having the formula
  • R 1 through R 6 are independently hydrogen, F, Cl, Br, I, N0 2 , CN, OR 10 , NR 10 R ⁇ , SR 10 , COR 12 , C0 2 R 12 , CONR 10 R n , optionally substituted Ci to C 6 alkyl or heteroalkyl, Ci to ⁇ haloalkyl, optionally substituted C 3 to Cs cycloalkyl, optionally substituted C2 to C ⁇ alkenyl or alkynyl, optionally substituted allyl, optionally substituted aryl or heteroaryl, or optionally substituted arylmethyl, where R 10 and R 11 are independently hydrogen, Ci to C alkyl or heteroalkyl or haloalkyl, aryl, heteroaryl, optionally substituted allyl, optionally substituted arylmethyl, COR 13 , S0 2 R 13 or S(0)R 13 , where R 12 is hydrogen, Ci to C6 alkyl or heteroalkyl or haloalkyl,
  • R 8 and R 9 are independently hydrogen, Ci to C alkyl or haloalkyl or heteroalkyl, optionally substituted C 2 to C alkenyl or alkynyl, optionally substituted allyl, optionally substituted arylmethyl, optionally substituted aryl or optionally substituted heteroaryl, X is OCH 2 , SCH 2; NHCH 2 , OC(O), SC(O), NHC(O), CH 2 0, CH 2 S, CH 2 NH, C(0)0, C(0)S or C(0)NH,
  • Y is O, S or NR 10 , where R 10 has the same definition given above, and Z is O, S, NR 14 , CR 14 R 15 , CR ,4 R 15 CR 16 R 17 , OCR 14 R 15 , SCR 1 R 15 , CR 14 R 15 S,
  • R 14 through R ⁇ each independently are hydrogen, Ci to C ⁇ alkyl or haloalkyl or heteroalkyl, optionally substituted C _ to C ⁇ alkenyl or alkynyl, optionally substituted allyl, optionally substituted arylmethyl, optionally substituted aryl or optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof
  • the present invention provides a pharmaceutical composition comp ⁇ sing an effective amount of an progesterone receptor modulating compound of formula I or formula II shown above wherein R 1"17 , X, Y and Z all have the same definitions as given above
  • the present invention compnses a method of modulating processes mediated by progesterone receptors comp ⁇ sing administering to a patient an effective amount of a compound of formula I or formula II shown above, wherein R 1"17 , X,
  • pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluo ⁇ c, sulfu ⁇ c, citric, maleic, acetic, lactic, mcotinic, succinic, oxalic, phospho ⁇ c, malonic, salicylic, phenylacetic, stea ⁇ c, py ⁇ dine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnarnic, methylamino, methanesulfonic, pic ⁇ c, tarta ⁇ c, t ⁇ ethylamino, dimethylamino, and t ⁇ s(hydroxymethyl)am ⁇ nomethane Additional pharmaceutically acceptable salts are known to those skilled in the art
  • the PR agonist, partial agonist and antagonist compounds of the present invention are particularly useful for female hormone replacement therapy and as modulators of fertility (e g , as contraceptives or contragestational agents), either alone or in conjunction with estrogen receptor modulators
  • the PR modulator compounds are also used in the treatment of dysfunctional uterine bleeding, dysmeno ⁇ hea, endomet ⁇ osis, leiomyomas (uterine fibroids), hot flashes, mood disorders, memngiomas as well as in various hormone-dependent cancers, including, without limitation, cancers of ova ⁇ es, breast, endomet ⁇ um and prostate
  • the compounds of the present invention can be used in a wide va ⁇ ety of combination therapies to treat the conditions and diseases desc ⁇ bed above
  • the compounds of the present invention can be used in combination with other hormones and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, lmmunological modifiers such as interferons, lnterleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy
  • Representative PR modulator compounds (1 e , agonists, partial agomsts and antagonists) according to the present invention include 7-fluoro-4,4-d ⁇ methyl-5H- chromeno[3,4-
  • Scheme II desc ⁇ bes a four-step, selective D- ⁇ ng modification procedure, in which reduction of lactone 7 with a reducing agent such as L1BH 4 provides diol 10 and then NBS bromination of diol 10 in the presence of a base such as t ⁇ ethylamine followed by a selective methylation and NaH mediated nucleophilic cychzation in DMF affords compound 11
  • a reducing agent such as L1BH 4
  • NBS bromination of diol 10 in the presence of a base such as t ⁇ ethylamine followed by a selective methylation and NaH mediated nucleophilic cychzation in DMF affords compound 11
  • Treatment of compound 11 with more than one equivalent of an acid such as TsOH in refluxing dichloroethane provides compound 12
  • Scheme III involves selective D- ⁇ ng functional group conversion from R 1"4 to R 7"10 by known substituent group conversions such as converting bromo to aldehyde by metal- halogen exchange followed by nucleophihc addition to DMF, or converting an aldehyde to an oxime by hydroxylamine treatment of the aldehyde, or converting an oxime to a cyano group by treatment of the oxime with thionyl chlo ⁇ de Scheme III
  • the compounds of the present invention also include racemates, stereoisomers and mixtures of said compounds, including lsotopically-labeled and radio-labeled compounds
  • Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography
  • any of the PR modulator compounds of the present invention can be combined in a mixture with a pharmaceutically acceptable earner to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and more preferably, in human patients
  • the particular earner employed in these pharmaceutical compositions may take a wide va ⁇ ety of forms depending upon the type of administration desired, e g , intravenous, oral, topical, suppository or parenteral
  • compositions in oral liquid dosage forms e g , suspensions, elixirs and solutions
  • typical pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like
  • earners such as starches, sugars, diluents, granulating agents, lub ⁇ cants, binders, disintegrating agents and the like will be employed Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention
  • the earner will typically comp ⁇ se sterile water, although other ingredients that aid in solubility or serve as preservatives may also be included
  • injectable suspensions may also be prepared, in which case approp ⁇ ate liquid earners, suspending agents and the like will be employed
  • the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams
  • suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions such as Euce ⁇ nTM (Beiersdorf)
  • suitable cream bases are NiveaTM Cream (Beiersdorf), cold cream (USP), Purpose CreamTM (Johnson & Johnson), hydroph ⁇ ic ointment (USP), and Lub ⁇ dermTM (Warner-Lambert)
  • compositions and compounds of the present invention will generally be administered in the form of a dosage unit (e g , tablet, capsule etc ) at from about 1 ⁇ g/kg of body weight to about 500 mg/kg of body weight, more preferably from about 10 ⁇ g/kg to about 250 mg/kg, and most preferably from about 20 ⁇ g/kg to about 100 mg/kg
  • a dosage unit e g , tablet, capsule etc
  • the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug
  • the compounds of this invention also have utility when radio- or lsotopically-labeled as hgands for use in assays to determine the presence of PR in a cell background or extract They are particularly useful due to their ability to selectively activate progesterone receptors, and can therefore be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors
  • these compounds can be used to pu ⁇ fy samples of steroid receptors in vitro Such purification can be earned out by mixing samples containing steroid receptors with one or more of the compounds of the present invention so that the compounds bind to the receptors of choice, and then separating out the bound ligand/receptor combination by separation techniques that are known to those of skill in the art These techniques include column separation, filtration, cent ⁇ fugation, tagging and physical separation, and antibody complexing, among others
  • the compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroid modulator compounds
  • the compounds are extremely potent activators of PR, preferably displaying 50% maximal activation of PR at a concentration of less than 100 nM, more preferably at a concentration of less than 50 nM, more preferably yet at a concentration of less than 20 nM or less
  • the selective compounds of the present invention generally do not display undesired cross-reactivity with other steroid receptors, as is seen with the compound mifep ⁇ stone (RU486, Roussel Uclaf), a known PR antagonist that displays an undesirable cross reactivity on GR, thereby limiting its use in long-term, chronic administration
  • the compounds of the present invention as small organic molecules, are easier to synthesize, provide greater stability and can be more easily administered in oral dosage forms than other known steroidal compounds
  • the cotransfection assay provides a method for identifying functional agonists and partial agonists that mimic, or antagonists that inhibit, the effect of native hormones, and for quantifying their activity for responsive intracellular receptor (IR) proteins
  • the cotransfection assay mimics an in vivo system in the laboratory
  • activity in the cotransfection assay co ⁇ elates very well with known in vivo activity, such that the cotransfection assay functions as a qualitative and quantitative predictor of a tested compound's in vivo pharmacology
  • Boerger "Interaction of Glucocorticoid Analogues with the Human Glucocorticoid Receptor"
  • the cotransfection assay can detect small molecule agonists or antagonists of target IRs Exposing the transfected cells to an agonist hgand compound increases reporter activity in the transfected cells This activity can be conveniently measured, e g , by increasing luciferase production, which reflects compound-dependent, IR-mediated increases in reporter transcnption
  • the cotransfection assay is earned out in the presence of a constant concentration of an agonist to the target IR (e g , progesterone for PR) known to induce a defined reporter signal
  • concentrations of a suspected antagonist will decrease the reporter signal (e g , luciferase production)
  • the cotransfection assay is therefore useful to detect both agonists and antagonists of specific IRs Furthermore, it determines not only whether a compound interacts with a particular IR, but whether this interaction mimics (agonizes) or blocks (antagonizes) the effects of the native regulatory molecules on target gene expression, as well as the specificity and strength of
  • Table 1 Agonist, antagonist and binding activity of progesterone receptor modulator compounds of present invention and the reference agonist compound, progesterone (Prog), and reference antagonists compound,RU486 and ZK299.
  • na not active (i.e. efficacy of ⁇ 20 and potency of >10,000)
  • nt not tested
  • the PR modulator compounds of the present invention can be readily utilized in pharmacological apphcations where PR antagomst or agomst activity is desired, and where it is desired to minimize cross reactivities with other steroid receptor related IRs
  • In vivo apphcations of the invention include admimstration of the disclosed compounds to mammalian subjects, and in particular to humans
  • the following Example provides illustrative pharmaceutical composition formulations EXAMPLE 7
  • Hard gelatin capsules are prepared using the following ingredients
  • a tablet is prepared using the mgredients below
  • Tablets each containing 60 mg of active ingredient, are made as follows
  • Suppositones each containing 225 mg of active ingredient, may be made as follows
  • An intravenous formulation may be prepared as follows
  • COMPOUND 26 100 mg Isotomc saline 1,000 mL
  • the compound is dissolved in the glycerol and then the solution is slowly diluted with isotomc saline The solution of the above ingredients is then administered intravenously at a rate of 1 mL per minute to a patient

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne des composés non stéroïdes qui sont des modulateurs à affinité et sélectivité élevées pour les récepteurs de progestérone, ainsi que des compositions pharmaceutiques renfermant lesdits composés. L'invention concerne en outre des procédés relatifs à l'utilisation de ces composés et de ces compositions pour le traitement de patients nécessitant une thérapie à base d'agoniste, d'agoniste partiel ou d'antagoniste de récepteur de progestérone, ainsi que des intermédiaires utiles dans la préparation des composés considérés et des procédés relatifs à l'élaboration des composés en question.
EP00926495A 1999-05-04 2000-05-01 Composes modulateurs de recepteur de progesterone tetracycliques et procedes Ceased EP1175422A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US304614 1994-09-12
US30461499A 1999-05-04 1999-05-04
US09/552,353 US6358947B1 (en) 1999-05-04 2000-04-19 Tetracyclic progesterone receptor modulator compounds and methods
US552353 2000-04-19
PCT/US2000/011750 WO2000066590A2 (fr) 1999-05-04 2000-05-01 Composes modulateurs de recepteur de progesterone tetracycliques et procedes

Publications (1)

Publication Number Publication Date
EP1175422A2 true EP1175422A2 (fr) 2002-01-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP00926495A Ceased EP1175422A2 (fr) 1999-05-04 2000-05-01 Composes modulateurs de recepteur de progesterone tetracycliques et procedes

Country Status (6)

Country Link
EP (1) EP1175422A2 (fr)
CN (1) CN1353717A (fr)
AU (1) AU4501800A (fr)
CA (1) CA2371273A1 (fr)
HK (1) HK1043788A1 (fr)
WO (1) WO2000066590A2 (fr)

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CN1353717A (zh) 2002-06-12
HK1043788A1 (zh) 2002-09-27

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