WO2004083204A1 - 6-sulfonamide quinoline and chromene derivative as androgen receptor antagonists - Google Patents

6-sulfonamide quinoline and chromene derivative as androgen receptor antagonists Download PDF

Info

Publication number
WO2004083204A1
WO2004083204A1 PCT/IB2004/000856 IB2004000856W WO2004083204A1 WO 2004083204 A1 WO2004083204 A1 WO 2004083204A1 IB 2004000856 W IB2004000856 W IB 2004000856W WO 2004083204 A1 WO2004083204 A1 WO 2004083204A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
represented
trifluoromethyl
oxo
alkyl
Prior art date
Application number
PCT/IB2004/000856
Other languages
French (fr)
Inventor
Daniel Yunlong Du
Martin James Procter
Matthew Colin Thor Fyfe
Vilasben Kanji Shah
Geoffrey Martyn Williams
Karen Lesley Schofield
Original Assignee
Warner-Lambert Company Llc
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
Application filed by Warner-Lambert Company Llc filed Critical Warner-Lambert Company Llc
Priority to EP04721256A priority Critical patent/EP1608643A1/en
Priority to CA002517446A priority patent/CA2517446A1/en
Priority to JP2006506374A priority patent/JP2006520780A/en
Priority to MXPA05009988A priority patent/MXPA05009988A/en
Priority to BRPI0408529-9A priority patent/BRPI0408529A/en
Publication of WO2004083204A1 publication Critical patent/WO2004083204A1/en

Links

Classifications

    • 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
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D215/36—Sulfur atoms
    • 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
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to a new class of quinolin-2-ones and chromen-2-ones (hereinafter "quinolines and chromenes”), to their use as androgen receptor antagonists, to medicinals containing these compounds and to their use to alleviate conditions associated with inappropriate activation of the androgen receptor.
  • the androgen receptor is a member of the steroid receptor (SR) family of transcriptional regulatory proteins that transduces the signaling information conveyed by androgens (Chang et al., 1995 and Wilson et al., 1991).
  • SR steroid receptor
  • the androgen receptor Upon androgen binding, the androgen receptor is released from the repressive effects of an Hsp 90-based regulatory complex, allowing the receptor to either activate or inhibit transcription of target genes in a hormone-dependent manner (Suina et al., 1996; Fang et al, 1996; Fang et al., 1998; Picard et al., 1990; Segnitz et al, 1997; Jenster et al., 1991; and Jenster et al., 1992).
  • the androgen receptor plays in male sex determination, its activation plays a critical role in the development and progression of benign prostate hyperplasia, prostate cancer, seborrhea, acne, premenstrual syndrome, lung cancer, ovarian polycyclic syndrome, hirsutism, and hair loss.
  • the androgen receptor is an important target in multiple areas of drug discovery.
  • United States Patent No. 6,017,924 discloses a class of non-steroidal compounds, pyridinoquinolines that have affinity for the androgen receptor.
  • the '924 patent describes these compounds as being agonists, partial agonists, antagonists, and partial antagonists, etc.
  • the 6 924 patent provides no guidance on how to achieve a specific biological effect (i.e. agonist versus antagonist). Agonists have the ability to masculinize females, whereas antagonists feminize males. Such side effects limit the potential applicability of androgen therapy.
  • PCT applications WO 01/16133 and WO 01/16139 also disclose non- steroidal compounds that have affinity for the androgen receptor.
  • Examples of such structures include pyrazinoquinolines, oxazinoquinolines, and pyridinoquinolines.
  • the PCT application does not disclose any 6-sulfonamido- quinolin-2-ones or 6-sulfonamido-chromen-2-ones.
  • PCT application WO 01 /16108 discloses non-steroidal compounds having affinity for the androgen receptor. Like the '924 patent described above, the compounds are described as having both agonist and antagonist effects. Some of the compounds of the PCT application are quinolin-2-one derivatives. The PCT application does not disclose any 6-sulfonamido-quinolin-2-ones or 6- sulf onamido-chromen-2-ones .
  • a. M is NZ or O; b. Z is represented by H or C - C4 alkyl; c. R! is represented by hydrogen, (C ⁇ -C ⁇ alky!, optionally substituted with one or more halogens, or (C ⁇ -C2)alko y, optionally substituted with 1 or more halogens; d. R2 is absent, or may represent up to 2 substituents selected from the group consisting of halogen, nitrile, hydroxy, (C ⁇ -
  • R4 is represented by hydrogen, optionally substituted phenyl, (C ⁇ -C4)alkyl, or optionally substituted benzyl
  • R5 is represented by optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclic
  • a and B are each independently represented by a substituent selected from the group consisting of hydrogen, (C j -
  • R is represented by a substituent selected from the group consisting of nitrile, OH, optionally substituted phenyl, optionally substituted cyloalkylphenyl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted (C 3 -C 8 ) cycloalkyl, optionally substituted (C 5 -C 8 ) cycloalkenyl, SR 4 , NR 4 R 5 ; i.
  • R is absent, or is represented by a substituent selected from the group consisting of optionally substituted (C 3 -C 8 ) cycloalkyl, optionally substituted (C 5 -C 8 ) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, and optionally substituted phenyl, j.
  • R is absent, or is represented by a substituent selected from the group consisting of (C j -C 6 )alkyl optionally substituted with one or more halogens, optionally substituted (C -C 8 ) cycloalkyl, optionally substituted (C 5 -C 8 ) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl; k. m is an integer selected from 0, 1, 2, 3, or 4;
  • Y is absent, or is represented by O, C(O), C(O)O,
  • n is represented by an integer selected from 0, 1, 2, 3, or 4; n.
  • X is absent, or is represented by O, C(O), C(O)O, -CH 2 C(O)O, OH, SH or S o.
  • q is represented by an integer selected from 0, 1, 2, 3, or 4; p.
  • X 1 is represented by a substituent selected from the group consisting of optionally substituted (C 3 -C 8 ) cycloalkyl, optionally substituted (C 5 -C 8 ) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl ; q.
  • X 2 is represented by a substituent selected from the group consisting of optionally substituted (C 3 -C 8 ) cycloalkyl, optionally substituted (Cs-C 8 ) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl and; r. the pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • the compounds of Formula I are androgen receptor antagonists.
  • the compounds will inhibit, or decrease, activation of the androgen receptor by androgens.
  • the compounds can be used to treat, or alleviate, conditions associated with inappropriate activation of the androgen receptor. Examples of such conditions include, but are not limited to, acne, excess seborrhea secretion, alopecia, prostrate cancer, hirsutism, etc.
  • the invention is also directed to pharmaceutical compositions containing at least one of the compounds of Formula I, in an amount effective to decrease activation of the androgen receptor.
  • the invention is directed to an article of manufacture containing a compound of Formula I, packaged for retail distribution, in association with instructions advising the consumer on how to use the compound to alleviate a condition associated with inappropriate activation of the androgen receptor.
  • An additional embodiment is directed to the use of a compound of Formula I as a diagnostic agent to detect inappropriate activation of the androgen receptor.
  • the compounds of Formula I are used topically to induce and or stimulate hair growth and/or to slow down hair loss.
  • the compounds may also be used topically in the treatment of hyperseborrhoea and/or of acne.
  • C ⁇ - C4 alkyl and “lower alkyl” refers to a branched or straight chained alkyl group containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. b.
  • Cj- Cg alkyl refers to a branched or straight chained alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, etc.
  • halogen refers to a chlorine, fluorine or bromine atom.
  • Cj- C2 alkyl substituted with one or more halogen atoms refers to a straight chained alkyl group containing 1 or 2 carbon atoms, i.e.
  • methyl or ethyl in which at least one hydrogen atom is replaced with a halogen.
  • Examples include chloromethyl, difluoromethyl, trifluoromethyl, etc. e.
  • "lower alkoxy group” and "C]_- C4 alkoxy” refers to a straight or branched chain alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc. f .
  • C2- C4 alkenyl refers to a straight-chain or branched-chain hydrocarbon radical containing from 2 to 4 carbon atoms and 1, or more, carbon-carbon double bonds.
  • alkenyl radicals examples include ethenyl, propenyl, 1,4-butadienyl and the like.
  • C2- 6 alkenyl refers to a straight-chain or branched-chain hydrocarbon radical containing from 2 to 6 carbon atoms and 1, or more, carbon-carbon double bonds.
  • alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl, pentenyl, hexenyl and the like, h.
  • C2- C4 alkynyl refers to a straight-chain or branched-chain hydrocarbon radical containing from 2 to 4 carbon atoms and having
  • alkynyl radicals include ethynyl, propynyl, butynyl and the like, i. "C2- Cg alkynyl” refers to a straight-chain or branched-chain hydrocarbon radical containing from 2 to 6 carbon atoms and having 1 , or more, carbon-carbon triple bonds.
  • alkynyl radicals include ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like, j.
  • (Ci-C4)alkylnitrile refers to a straight-chain or branched chain alkyl group containing from 1 to 4 carbon atoms in which at least one hydrogen atom is replaced with a C ⁇ N moiety.
  • (d-C ⁇ alkanol” refers to a straight-chain or branched chained alkyl group containing from 1 to four carbon atoms group in which at least one hydrogen atom is replaced with a hydroxy function. 1.
  • optionally substituted phenyl refers to a phenyl (C6H5) which is substituted with up to 3 substituents, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (C ⁇ -C 4 )alkyl, (C 2 - C 4 )alkenyl, (C 2 - C 4 )alkynyl, (Ci-
  • substituents may be the same or different and may be located at any of the ortho, meta, or para positions, m.
  • "optionally substituted benzyl” refers to a benzyl -CH2-(C ⁇ H5) which is substituted with up to 3 substituents, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (C ⁇ -C4)alkyl, (C2- C4) alkenyl, (C2- C4) alkynyl (C ⁇ -
  • n. (C ⁇ -C2) lko y substituted with one or more halogen atoms refers to a straight chained alkoxy group containing 1 or 2 carbon atoms, ie, methoxy or ethoxy in which at least one hydrogen atom is replaced with a halogen.
  • heteroaryl refers to aromatic ring having one, or more, heteroatoms selected from oxygen, nitrogen and sulfur.
  • the 5-membered ring has 2 double bonds and the 6- membered ring has
  • heteroaryl also includes bicyclic groups in which the heteroaryl ring is fused to a benzene ring, heterocyclic ring, a cycloalkyl ring, or another heteroaryl ring.
  • heteroaryl ring systems include, but are not limited to pyrrolyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, furanyl, thienyl, imidazolyl, oxazolyl, indolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, and isoquinolinyl.
  • optionally substituted heteroaryl refers to a heteroaryl moiety as defined immediately above, in which up to 2 carbon atoms of the heteroaryl moiety may be substituted with a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (C ⁇ -C4)alkyl, (C2- C4)alkenyl, (C2-
  • heterocycle or “heterocyclic ring” refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6-, 7-, 8-, 9-, or 10- membered ring containing 1, 2, or
  • the 5-membered ring has 0 to 1 double bonds
  • the 6- and 7-membered rings have 0 to 2 double bonds
  • the 8, 9, or 10 membered rings may have 0, 1, 2, or 3 double bonds.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring, a cyclohexane or cyclopentane ring or another heterocyclic ring (for example tetrahydroquinolyl, dihydrobenzofuryl and the like).
  • Heterocyclics include: pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, azepane, azocane, morpholinyl, and quinolinyl. r.
  • optionally substituted heterocyclic refers to a heterocyclic moiety as defined immediately above, in which up to 2 carbon atoms of the heterocycle moiety may be substituted with a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (C ⁇ C4)alkyl, (C2- C4) alkenyl, (C2-
  • any nitrogen atom of the heterocyclic ring may be substituted with a (d-C 4 )alkyl.
  • C3- Cg cycloalkyl refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has about 3 to about 8 carbon atoms.
  • Examples of cyclcoalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like, t.
  • C3- Cg cycloalkyl refers to a cycloalkyl moiety as defined immediately above in which up to 3 hydrogen atoms of the cycloalkyl moiety may be replaced with a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (C ⁇ -C4)alkyl, (C2- C4)alkenyl, (C2-
  • C5- Cg cycloalkenyl refers to a partially saturated monocyclic, bicyclic or tricyclic alkyl radical containingl, or more, carbon- carbon double bonds, wherein each cyclic moiety has about 5 to about 8 carbon atoms.
  • cyclcoalkenyl radicals include cyclopentenyl, cyclohexenyl, and the like v.
  • “optionally substituted "C5- Cg cycloalkenyl” refers to a cycloalkenyl moiety as defined immediately above, in which up to 3 hydrogen atoms of the cycloalkenyl moiety may be replaced with a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (Cj-C4)alkyl, (C2-
  • cycloalkylphenyl refers to a phenyl ring in which two carbon atoms of the phenyl ring complete a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl ring.
  • Examples of such cycloalkylphenyl moieties include: indanyl, tetrahydronapfhyl, and the like.
  • cycloalkylphenyl refers to a cycloalkylphenyl moiety as described above, in which up to 3 hydrogen atoms of the cycloalkylphenyl moiety may be replaced by a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (C ⁇ -C4)alkyl, C2- C4 alkenyl, C2- C4 alkynyl, (C ⁇ -C4)alko y, (Cj-C2)alkyl substituted with one or more halogens, (C ⁇ C2)alko y substituted with one or more halogens, (C ⁇ -C4)alkylnitrile, (C ⁇ -C )alkanol, SR 4 , and
  • NR 4 R 5 . y. refers to testosterone and its precursors and metabolites, and 5 -alpha reduced androgens, including but not limited to dihydrotestosterone. Androgen refers to androgens from the testis, adrenal gland, and ovaries, as well as all forms of natural, synthetic and substituted or modified androgens.
  • pharmaceutically acceptable salts is intended to refer to either pharmaceutically acceptable acid addition salts” or “pharmaceutically acceptable basic addition salts” depending upon actual structure of the compound, aa.
  • pharmaceutically acceptable acid addition salts is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
  • Illustrative organic acids, which form suitable salts include the mono-, di-, and tricarboxylic acids.
  • Such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
  • Such salts can exist in either a hydrated or substantially anhydrous form.
  • the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points, bb.
  • pharmaceutically acceptable basic addition salts is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I, or any of its intermediates.
  • Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulas, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug
  • optical isomers Any reference in this application to one of the compounds represented by Formula I is meant to encompass either a specific optical isomer or a mixture of optical isomers (unless it is expressly excluded).
  • the specific optical isomers can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases or resolution via chiral salt formation and subsequent separation by selective crystallization. Alternatively utilization of a specific optical isomer as the starting material will produce the corresponding isomer as the final product.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • Position 1 of the quinoline nucleus contains a nitrogen atom. This nitrogen atom may be substituted with a lower alkyl group as described above. Position 6 of the quinoline ring will always be substituted with a SO2 moiety as depicted in
  • Position 4 of the quinoline nucleus may optionally be substituted with 1 of the halogenated lower alkyl or alkoxy moieties described for R! above. Typically, Position 4 will be substituted with a trifluoromethyl function.
  • Position 1 of the chromene nucleus contains an oxygen atom.
  • Position 6 of the chromene ring will always be substituted with a SO2 moiety as depicted in
  • Positions 3, 5, 7, or 8 of the chromene nucleus may optionally be substituted with a substituent from the list described for R2. Up to two of these positions may be substituted.
  • Position 4 of the chromene nucleus may optionally be substituted with one of the halogenated lower alkyl or alkoxy moieties described for R above. Typically, Position 4 will be substituted with a trifluoromethyl function.
  • M is NZ, in which Z is H; R 1 is trifluoromethyl, R ⁇ is absent, B is hydrogen, and A is represented by phenyl, which may be optionally substituted.
  • M is NZ, in which Z is H, R 1 is trifluoromethyl, R ⁇ is absent, B is hydrogen, or Cj-Cg alkyl and A is C ⁇ -Cg alkyl, more typically C j - C 3 alkyl.
  • M is NZ, in which Z is H, R is trifluoromethyl, R 2 is absent, B is hydrogen, A is d-C ⁇ alkyl R 6 , and more specifically a d-C 3 alkylphenyl ring.
  • M is NZ, in which Z is H, R 1 is trifluoromethyl, R 2 is absent, B is hydrogen, A is d-C 6 alkylR 6 , and R 6 is phenyl, which has been substituted with trifluoromethyl, or d-C 4 alkyl, more specifically ethyl.
  • M is NZ in which Z is H, R is trifluoromethy, R 2 is absent, B is hydrogen, A is d-C 6 alkylR 6 , and R 6 is cycloalkenyl, typically cyclohexenyl.
  • M is NZ in which Z is H, R 1 is trifluoromethyl, R 2 is absent, B is hydrogen, A is d-C 6 alkylR 6 , and R 6 is cycloalkylphenyl.
  • M is NZ in which Z is H, R 1 is trifluoromethyl, R 2 is absent, B is hydrogen, A is d-C 6 alkylR 6 , and R 6 is heterocyclic.
  • M is NZ in which Z is H, Rl is trifluoromethyl, R 2 is absent, B is hydrogen, A is -C ⁇ alkylR 6 , and R 6 is heteroaryl.
  • one of the starting materials is an appropriately substituted quinolin-2-one or 2-oxo-chromene (i.e. R 1 , R ⁇ , and M are as in desired compound) that has been functionalized at the 6-position with a sulfonyl chloride moiety (Formula LT).
  • R 1 , R ⁇ , and M are as in desired compound
  • a sulfonyl chloride moiety (Formula LT).
  • These compounds may be produced by introducing the sulfonyl chloride moiety into the 6-postion of the quinolin-2-ones and 2-oxo- chromenes by chlorosulfonation with chlorosulfonic acid at about 140°C. These reactions are described in more detail in the working examples. The reader's attention is also directed to Furniss et al, Nogel's Textbook of Practical Organic Chemistry, 5 th Edition, pages 877-879, where such reactions are described in detail.
  • the other starting material is an appropriately substituted amine as described by Formula III (i.e. A and B are as in final compound).
  • These amines can typically be purchased from Aldrich, which has an office located in St. Louis, Mo. USA. Further information may be obtained from Aldrich at, www.sigmaaldrich.com
  • the sulfonamides derivatives of Formula I are prepared by reacting the sulfonyl chloride derivative of Formula II with the appropriate amine as described by Formula HI in the presence of a non-nucleophilic base, such as pyridine or diisopropylethylamine, at about room temperature in an aprotic solvent, such as,
  • N,N'-dimethylformamide N,N'-dimethylformamide.
  • the reaction is allowed to proceed to completion, which is typically accomplished in from 2 to 24 hours.
  • the compounds can be isolated and purified using techniques known in the art such as extraction and flash chromatography. These reactions are described in detail in the working examples.
  • the compounds of Formula I are androgen receptor antagonists. They can be used to alleviate any condition associated with inappropriate activation of the androgen receptor. Examples of such conditions include prostate carcinomas, benign hyperplasia of the prostate, acne, hirsutism, seborrhoea, alopecia, premenstrual syndrome, lung cancer, and precocious puberty.
  • the compounds need to be administered in a quantity sufficient to inhibit activation of the androgen receptor.
  • This antagonistic amount can vary depending upon the particular disease/condition being treated, the severity of the patient's disease/condition, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc.
  • the compounds When administered systemically, the compounds typically exhibit their effect at a dosage range of from about 0.1 mg/kg/day to about 100 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.
  • the compounds of the present invention may be administered by a variety of routes. They are effective if administered orally.
  • the compounds may also be administered parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally), rectally, or topically.
  • the compounds are administered topically. Topical administration is especially appropriate for hirsutism, alopecia, acne and hyperseborhhea.
  • the dose will vary, but as a general guideline, the compound will be present in a dermatologically acceptable carrier in an amount of from 0.1 to 10 w/w% and the dermatological preparation will be applied to the affected area from 1 to 4 times daily.
  • Dermatologically acceptable refers to a carrier which may be applied to the skin or hair, and which will allow the drug to diffuse to the site of action. More specifically, it refers to the site where inhibition of activation of an androgen receptor is desired.
  • the compounds are used topically to relieve alopecia, especially androgenic alopecia.
  • Androgens have a profound effect on both hair growth and hair loss.
  • androgens stimulate hair growth by prolonging the growth phase of the hair cycle (anagen) and increasing follicle size.
  • Hair growth on the scalp does not require androgens but, paradoxically, androgens are necessary for balding on the scalp in genetically predisposed individuals (androgenic alopecia) where there is a progressive decline in the duration of anagen and in hair follicle size.
  • Men castrated before puberty fail to grow beards and do not go bald. If subsequently treated with testosterone about one third of male castrates will show balding.
  • Androgeneic alopecia is also common in women where it usually present as a diffuse hair loss rather than showing the patterning seen in men.
  • alopecia refers to partial or complete hair loss on the scalp.
  • the compounds will typically be used to alleviate androgenic alopecia. This condition afflicts both men and women. In males, the hair loss begins in the lateral frontal areas or over the vertex. For females, it is typically associated with thinning of the hair in the frontal and parietal regions. Complete hair loss in females is rare.
  • the compounds will most typically be used to alleviate androgenic alopecia, the invention is not limited to this specific condition.
  • the compounds may be used to alleviate any type of alopecia.
  • non-androgenic alopecia include alopecia areata, alopecia due to radiotherapy or chemotherapy, scarring alopecia, stress related alopecia, etc.
  • the compounds can be applied topically to the scalp and hair to prevent, or alleviate balding. Further, the compound can be applied topically in order to induce or promote the growth of hair on the scalp:
  • a compound of Formula I is applied topically in order to prevent the growth of hair in areas where such hair growth is not desired.
  • One such use will be to alleviate hirsutism. Hirsutism is excessive hair growth in areas that typically do not have hair (i.e. a female face). Such inappriate hair growth occurs most commonly in women and is frequently seen at menopause. The topical administration of the compounds will alleviate this condition leading to a reduction, or elimination of this inappropriate, or undesired, hair growth.
  • the compounds may also be used topically to decrease seborrhea production and more specifically to alleviate hyperseborrhoea (oily skin). Likewise the compounds can be used topically alleviate acne.
  • the compounds can be administered directly without any carrier.
  • compositions designed for administration directly to the skin or hair can be manufactured utilizing techniques known in the art. Typically an antagonistic amount of the compound will be admixed with a pharmaceutically/cosmetically acceptable carrier.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions.
  • Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
  • the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.
  • Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent, which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
  • the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension.
  • suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin.
  • the pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art.
  • the compounds When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid as is known in the art.
  • the compounds of this invention will typically be administered topically.
  • topical refers to application of the compounds (and optional carrier) directly to the skin or hair.
  • the topical composition according to the present invention can be in the form of solutions, lotions, salves, creams, ointments, liposomes, sprays, gels, roller sticks, or any other method using micelles and pharmaceutically acceptable penetration enhancers
  • compositions in particular dermatological compositions, which comprise at least one of the compounds corresponding to Formula I above.
  • Such dermatological compositions will contain from 0.001% to 10% w/w% of the compounds in admixture with a dermatologically acceptable carrier, and more typically, from 0.1 to 5 w/w% of the acompounds.
  • Such compositions will typically be applied from 1 to 4 times daily.
  • the compositions according to the invention can also consist of solid preparations constituting cleansing soaps or bars. These compositions are prepared according to the usual methods.
  • the compounds can also be used for the hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions or mousses, or alternatively in the form of aerosol compositions also comprising a propellant under pressure.
  • the composition according to the invention can also be a hair care composition, and in particular a shampoo, a hair-setting lotion, a treating lotion, a styling cream or gel, a dye composition (in particular an oxidation dye composition) optionally in the form of coloring shampoos, restructuring lotions for the hair, a permanent-waving composition (in particular a composition for the first stage of a permanent-waving operation), a lotion or gel for preventing hair loss, etc.
  • the amounts of the various constituents in the dermatological compositions according to the invention are those conventionally used in the fields considered.
  • the medicinals and cosmetics containing the compounds of the invention will typically be packaged for retail distribution (i.e. an article of manufacture). Such articles will be labeled and packaged in a manner to instruct the patient how to use the product. Such instructions will include the condition, which may be treated, duration of treatment, dosing schedule, etc.
  • the compounds of Formula I may also be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the serum, urine, etc., of the patient as is known in the art. The compounds may also be used as a research tool.
  • reaction mixture was diluted with EtOAc (70 mL), before being washed with H 2 O (30 mL), 1 M HC1 (30 mL), H 2 O (30 mL), saturated aqueous NaHCO 3 (30 mL), H 2 O (30 mL), & brine (30 mL).
  • BIOLOGICAL DATA The compounds ability to antagonize the effects of androgen on the androgen receptor were determined in the protocol described immediately below. The results are shown in Table 3.
  • MDA-MB453-MMTV clone 54-19 This cell line is a stable transfected cell line with MDA-MB453 cell background (human breast tumor cell expressing high level of androgen receptor).
  • MDA-MB453 cell background human breast tumor cell expressing high level of androgen receptor.
  • a MMTN minimal promoter containing ARE was first cloned in front of a firefly luciferase reporter gene. Then the cascade was cloned into transfection vector pUN120puro. Electroporation method was used for transfecting MDA-MB-453 cell. Puromycin resistant stable cell line was selected.
  • DMEM high glucose, Gibco cat #: 11960-044
  • 10%FBS 10%FBS
  • Plating medium DMEM (phenol red free), 10% charcoal treated HyClone serum, 1% L-glutamine
  • Assay medium DMEM (phenol red free), 1% charcoal treated HyClone serum, 1% L-glutamine, and 1% penicillin/streptomycin 3X luciferase buffer: 2% beta-mercaptoethanol, 0.6% ATP, 0.0135% luciferine in cell lysis buffer
  • test compounds 10,000 cells/well are plated to opaque 96 cell culture plate in 100 ul/well plating medium, culture for overnight at 37°C in cell culture incubator

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

The present invention is directed to 6-sulfonamide quinoline and chromene derivatives of the formula (I) with the definitions of M, R1, R2, A and B according to claim 1 and to their use as androgen antagonists.

Description

6-SULF0NAMIDE QUINOLINE AND CHROMENE DERIVATIVES AS ANDROGEN RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
The present invention is directed to a new class of quinolin-2-ones and chromen-2-ones (hereinafter "quinolines and chromenes"), to their use as androgen receptor antagonists, to medicinals containing these compounds and to their use to alleviate conditions associated with inappropriate activation of the androgen receptor.
BACKGROUND OF THE INVENTION
The androgen receptor (AR) is a member of the steroid receptor (SR) family of transcriptional regulatory proteins that transduces the signaling information conveyed by androgens (Chang et al., 1995 and Wilson et al., 1991). Upon androgen binding, the androgen receptor is released from the repressive effects of an Hsp 90-based regulatory complex, allowing the receptor to either activate or inhibit transcription of target genes in a hormone-dependent manner (Suina et al., 1996; Fang et al, 1996; Fang et al., 1998; Picard et al., 1990; Segnitz et al, 1997; Jenster et al., 1991; and Jenster et al., 1992). In addition to the role the androgen receptor plays in male sex determination, its activation plays a critical role in the development and progression of benign prostate hyperplasia, prostate cancer, seborrhea, acne, premenstrual syndrome, lung cancer, ovarian polycyclic syndrome, hirsutism, and hair loss. Thus, the androgen receptor is an important target in multiple areas of drug discovery.
United States Patent No. 6,017,924 discloses a class of non-steroidal compounds, pyridinoquinolines that have affinity for the androgen receptor. The '924 patent describes these compounds as being agonists, partial agonists, antagonists, and partial antagonists, etc. The 6924 patent provides no guidance on how to achieve a specific biological effect (i.e. agonist versus antagonist). Agonists have the ability to masculinize females, whereas antagonists feminize males. Such side effects limit the potential applicability of androgen therapy. PCT applications WO 01/16133 and WO 01/16139 also disclose non- steroidal compounds that have affinity for the androgen receptor. Examples of such structures include pyrazinoquinolines, oxazinoquinolines, and pyridinoquinolines. The PCT application does not disclose any 6-sulfonamido- quinolin-2-ones or 6-sulfonamido-chromen-2-ones.
PCT application WO 01 /16108 discloses non-steroidal compounds having affinity for the androgen receptor. Like the '924 patent described above, the compounds are described as having both agonist and antagonist effects. Some of the compounds of the PCT application are quinolin-2-one derivatives. The PCT application does not disclose any 6-sulfonamido-quinolin-2-ones or 6- sulf onamido-chromen-2-ones .
While the prior art describes compounds having affinity for the androgen receptor, it does not describe how to achieve selectivity with respect to this affinity (i.e. agonist or antagonist). The physiological impact of this affinity is often an undesirable side effect, depending upon the gender of the patient. Thus a need exists in the art for androgen receptor antagonists.
SUMMARY OF THE INVENTION
In accordance with the present invention a new class of androgen antagonists have been discovered. These compounds may be represented by the following formula:
Figure imgf000003_0001
in which: a. M is NZ or O; b. Z is represented by H or C - C4 alkyl; c. R! is represented by hydrogen, (C^-C^alky!, optionally substituted with one or more halogens, or (Cι-C2)alko y, optionally substituted with 1 or more halogens; d. R2 is absent, or may represent up to 2 substituents selected from the group consisting of halogen, nitrile, hydroxy, (C^-
C4)alkyl, (C2-C4)al enyl, (C2-C4)alkynyl, (Cι-C4)alkoxy,
(Cι-C2)alkyl substituted with 1 or more halogens, (C -
C2)alkoxy substituted with one or more halogens, SR^, and NR4R5; e. R4 is represented by hydrogen, optionally substituted phenyl, (Cχ-C4)alkyl, or optionally substituted benzyl; f. R5 is represented by optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclic; g. A and B are each independently represented by a substituent selected from the group consisting of hydrogen, (Cj-
Cg)alkyl optionally substituted with one or more halogens,
(C2-C6)alkenyl, (C2-C6)alkynyl, optionally substituted (C3- C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, optionally substituted phenyl, optionally substituted cycloalkylphenyl, optionally substituted heterocyclic, optionally substituted heteroaryl, (CrC6)alkylR6, -(CH2)m-R7-Y[-CH2] n-X- R8,
Figure imgf000004_0001
h. R is represented by a substituent selected from the group consisting of nitrile, OH, optionally substituted phenyl, optionally substituted cyloalkylphenyl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted (C3-C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, SR4, NR4R5 ; i. R is absent, or is represented by a substituent selected from the group consisting of optionally substituted (C3-C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, and optionally substituted phenyl, j. R is absent, or is represented by a substituent selected from the group consisting of (Cj-C6)alkyl optionally substituted with one or more halogens, optionally substituted (C -C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl; k. m is an integer selected from 0, 1, 2, 3, or 4;
1. Y is absent, or is represented by O, C(O), C(O)O,
CH2C(O)O, OH, SH, or S; m. n is represented by an integer selected from 0, 1, 2, 3, or 4; n. X is absent, or is represented by O, C(O), C(O)O, -CH2C(O)O, OH, SH or S o. q is represented by an integer selected from 0, 1, 2, 3, or 4; p. X1 is represented by a substituent selected from the group consisting of optionally substituted (C3-C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl ; q. X2 is represented by a substituent selected from the group consisting of optionally substituted (C3-C8) cycloalkyl, optionally substituted (Cs-C8) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl and; r. the pharmaceutically acceptable salts, solvates, and prodrugs thereof.
The compounds of Formula I are androgen receptor antagonists. The compounds will inhibit, or decrease, activation of the androgen receptor by androgens. The compounds can be used to treat, or alleviate, conditions associated with inappropriate activation of the androgen receptor. Examples of such conditions include, but are not limited to, acne, excess seborrhea secretion, alopecia, prostrate cancer, hirsutism, etc.
The invention is also directed to pharmaceutical compositions containing at least one of the compounds of Formula I, in an amount effective to decrease activation of the androgen receptor. In a further embodiment, the invention is directed to an article of manufacture containing a compound of Formula I, packaged for retail distribution, in association with instructions advising the consumer on how to use the compound to alleviate a condition associated with inappropriate activation of the androgen receptor. An additional embodiment is directed to the use of a compound of Formula I as a diagnostic agent to detect inappropriate activation of the androgen receptor.
In a further embodiment, the compounds of Formula I are used topically to induce and or stimulate hair growth and/or to slow down hair loss. The compounds may also be used topically in the treatment of hyperseborrhoea and/or of acne.
DETAILED DESCRIPTION OF THE INVENTION
The headings within this document are only being utilized expediate its review by the reader. They should not be construed as limiting the invention or claims in any manner. Definitions and Exemplification
As used throughout this application, including the claims, the following terms have the meanings defined below, unless specifically indicated otherwise. The plural and singular should be treated as interchangeable, other than the indication of number: a. "Cι- C4 alkyl" and "lower alkyl" refers to a branched or straight chained alkyl group containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. b. "Cj- Cg alkyl" refers to a branched or straight chained alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, etc. c. "halogen" refers to a chlorine, fluorine or bromine atom. d. "Cj- C2 alkyl substituted with one or more halogen atoms" refers to a straight chained alkyl group containing 1 or 2 carbon atoms, i.e. methyl or ethyl, in which at least one hydrogen atom is replaced with a halogen. Examples include chloromethyl, difluoromethyl, trifluoromethyl, etc. e. "lower alkoxy group" and "C]_- C4 alkoxy" refers to a straight or branched chain alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc. f . "C2- C4 alkenyl" refers to a straight-chain or branched-chain hydrocarbon radical containing from 2 to 4 carbon atoms and 1, or more, carbon-carbon double bonds. Examples of alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like. g. "C2- 6 alkenyl" refers to a straight-chain or branched-chain hydrocarbon radical containing from 2 to 6 carbon atoms and 1, or more, carbon-carbon double bonds. Examples of alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl, pentenyl, hexenyl and the like, h. "C2- C4 alkynyl" refers to a straight-chain or branched-chain hydrocarbon radical containing from 2 to 4 carbon atoms and having
1, or more, carbon-carbon triple bonds. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like, i. "C2- Cg alkynyl" refers to a straight-chain or branched-chain hydrocarbon radical containing from 2 to 6 carbon atoms and having 1 , or more, carbon-carbon triple bonds. Examples of alkynyl radicals include ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like, j. "(Ci-C4)alkylnitrile" refers to a straight-chain or branched chain alkyl group containing from 1 to 4 carbon atoms in which at least one hydrogen atom is replaced with a C≡N moiety. k. "(d-C^alkanol" refers to a straight-chain or branched chained alkyl group containing from 1 to four carbon atoms group in which at least one hydrogen atom is replaced with a hydroxy function. 1. "optionally substituted phenyl" refers to a phenyl (C6H5) which is substituted with up to 3 substituents, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (Cι-C4)alkyl, (C2- C4)alkenyl, (C2- C4)alkynyl, (Ci-
C4)alkoxy, (C j-C2)alkyl substituted with one or more halogens,
(Cl-C2)alko y substituted with one or more halogens,
(C1-C )alkylnitrile , (d-C4)alkanol, SR4, and NR4R5. These substituents may be the same or different and may be located at any of the ortho, meta, or para positions, m. "optionally substituted benzyl" refers to a benzyl -CH2-(CβH5) which is substituted with up to 3 substituents, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (Cι-C4)alkyl, (C2- C4) alkenyl, (C2- C4) alkynyl (Cι -
C4)alkoxy, (Cι-C2)alkyl substituted with one or more halogens, (Cj -C2)alkoxy substituted with one or more halogens,
(C1-C4)alkylnitrile, (Q-G alkanol, SR4, and NR4R5. These substituents may be the same or different and may be located at any of the ortho, meta, or para positions. n. (Cχ-C2) lko y substituted with one or more halogen atoms refers to a straight chained alkoxy group containing 1 or 2 carbon atoms, ie, methoxy or ethoxy in which at least one hydrogen atom is replaced with a halogen. o. "heteroaryl" refers to aromatic ring having one, or more, heteroatoms selected from oxygen, nitrogen and sulfur. More specifically, it refers to a 5- or 6-, membered ring containing 1, 2, or 3 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2 nitrogen atoms and 1 oxygen atom; or 2 nitrogen atoms and 1 sulfur atom. The 5-membered ring has 2 double bonds and the 6- membered ring has
3 double bonds. The term heteroaryl also includes bicyclic groups in which the heteroaryl ring is fused to a benzene ring, heterocyclic ring, a cycloalkyl ring, or another heteroaryl ring. Examples of such heteroaryl ring systems include, but are not limited to pyrrolyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, furanyl, thienyl, imidazolyl, oxazolyl, indolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, and isoquinolinyl. p. "optionally substituted heteroaryl" refers to a heteroaryl moiety as defined immediately above, in which up to 2 carbon atoms of the heteroaryl moiety may be substituted with a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (Cι-C4)alkyl, (C2- C4)alkenyl, (C2-
C4)alkynyl , (Cι-C4)alkoxy, (Cι~C2)alkyl substituted with one or more halogens, (Cι~C2)alkoxy substituted with one or more halogens, (Cι -C4)alkylnitrile , (Q-C^alkanol, SR4, and NR4R5. Further, any nitrogen atom of the heterocyclic ring may be substituted with a (d-C )alkyl. q. "heterocycle" or "heterocyclic ring" refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6-, 7-, 8-, 9-, or 10- membered ring containing 1, 2, or
3 nitrogen atoms; 1 oxygen atom; 1 sulfur atom; 1 nitrogen and 1 sulfur atom; 1 nitrogen and 1 oxygen atom; 2 oxygen atoms in non-adjacent positions; 1 oxygen and 1 sulfur atom in non-adjacent positions; or 2 sulfur atoms in non-adjacent positions. The 5-membered ring has 0 to 1 double bonds, the 6- and 7-membered rings have 0 to 2 double bonds, and the 8, 9, or 10 membered rings may have 0, 1, 2, or 3 double bonds. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring, a cyclohexane or cyclopentane ring or another heterocyclic ring (for example tetrahydroquinolyl, dihydrobenzofuryl and the like). Heterocyclics include: pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, azepane, azocane, morpholinyl, and quinolinyl. r. "optionally substituted heterocyclic" refers to a heterocyclic moiety as defined immediately above, in which up to 2 carbon atoms of the heterocycle moiety may be substituted with a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (Cι~C4)alkyl, (C2- C4) alkenyl, (C2-
C4)alkynyl, (C^-C4)alkoxy, (C;[-C2)alkyl substituted with one or more halogens, (Cι-C2)alkoxy substituted with 1 or more halogens,
(C1-C4)alkylnitrile , (d-C4)alkanol, (=O), SR4, and NR4R5.
Further, any nitrogen atom of the heterocyclic ring may be substituted with a (d-C4)alkyl. s. "C3- Cg cycloalkyl" refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has about 3 to about 8 carbon atoms. Examples of cyclcoalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like, t. "optionally substituted "C3- Cg cycloalkyl" refers to a cycloalkyl moiety as defined immediately above in which up to 3 hydrogen atoms of the cycloalkyl moiety may be replaced with a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (Cι-C4)alkyl, (C2- C4)alkenyl, (C2-
C4)alkynyl , (Cι-C4)alko y, (Cj-C2)alkyl substituted with one or more halogens, (Cι~C2)alkoxy substituted with one or more halogens, (C1-C )alkylnitrile, (d-C4)alkanol, SR4, and NR4R5. u. "C5- Cg cycloalkenyl" refers to a partially saturated monocyclic, bicyclic or tricyclic alkyl radical containingl, or more, carbon- carbon double bonds, wherein each cyclic moiety has about 5 to about 8 carbon atoms. Examples of cyclcoalkenyl radicals include cyclopentenyl, cyclohexenyl, and the like v. "optionally substituted "C5- Cg cycloalkenyl" refers to a cycloalkenyl moiety as defined immediately above, in which up to 3 hydrogen atoms of the cycloalkenyl moiety may be replaced with a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (Cj-C4)alkyl, (C2-
C4)alkenyl, (C2- C4)alkynyl , (C1-C4)alkoxy, (Ci^^lkyl substituted with one or more halogens, (Cι-C2)alkoxy substituted with one or more halogens, (Cι-C4)alkylnitrile, (d-C )alkanol,
SR4, and NR4R5. w. "cycloalkylphenyl" refers to a phenyl ring in which two carbon atoms of the phenyl ring complete a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl ring. Examples of such cycloalkylphenyl moieties include: indanyl, tetrahydronapfhyl, and the like. x. "optionally substituted cycloalkylphenyl" refers to a cycloalkylphenyl moiety as described above, in which up to 3 hydrogen atoms of the cycloalkylphenyl moiety may be replaced by a substituent, each substituent is independently selected from the group consisting of halogen, nitrile, hydroxy, (Cι-C4)alkyl, C2- C4 alkenyl, C2- C4 alkynyl, (Cι-C4)alko y, (Cj-C2)alkyl substituted with one or more halogens, (Cι~C2)alko y substituted with one or more halogens, (Cι-C4)alkylnitrile, (Cι-C )alkanol, SR4, and
NR4R5. y. "androgen" refers to testosterone and its precursors and metabolites, and 5 -alpha reduced androgens, including but not limited to dihydrotestosterone. Androgen refers to androgens from the testis, adrenal gland, and ovaries, as well as all forms of natural, synthetic and substituted or modified androgens. z. "pharmaceutically acceptable salts" is intended to refer to either pharmaceutically acceptable acid addition salts" or "pharmaceutically acceptable basic addition salts" depending upon actual structure of the compound, aa. "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids, which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points, bb. "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formula I, or any of its intermediates.
Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. cc. "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulas, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug
Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference, dd. "compound of Formula I" "compounds of the invention" and "compounds" are used interchangeably throughout the application and should be treated as synonoms. ee. "patient" refers to warm blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans. ff. "treat" refers to the ability of the compounds to either relieve, alleviate, or slow the progression of the patient's disease (or condition) or any tissue damage associated with the disease.
Some of the compounds of Formula I will exist as optical isomers. Any reference in this application to one of the compounds represented by Formula I is meant to encompass either a specific optical isomer or a mixture of optical isomers (unless it is expressly excluded). The specific optical isomers can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases or resolution via chiral salt formation and subsequent separation by selective crystallization. Alternatively utilization of a specific optical isomer as the starting material will produce the corresponding isomer as the final product.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
Some of the compounds of Formula I are based upon a 6-sulfonamido- quinolin-2-one nucleus. To further exemplify the invention this ring is depicted below along with its numbering system:
Figure imgf000014_0001
Position 1 of the quinoline nucleus contains a nitrogen atom. This nitrogen atom may be substituted with a lower alkyl group as described above. Position 6 of the quinoline ring will always be substituted with a SO2 moiety as depicted in
Figure 1. Any of positions 3, 5, 7, or 8 of the quinoline nucleus may optionally be substituted with a substituent from the list described for R^. Up to two of these positions may be substituted. Position 4 of the quinoline nucleus may optionally be substituted with 1 of the halogenated lower alkyl or alkoxy moieties described for R! above. Typically, Position 4 will be substituted with a trifluoromethyl function.
The remaining compounds of Formula I are based upon a 6-sulfonamido- 2-oxo-chromene nucleus. To further exemplify the invention, this ring is depicted below along with its numbering system:
Figure imgf000014_0002
Position 1 of the chromene nucleus contains an oxygen atom. Position 6 of the chromene ring will always be substituted with a SO2 moiety as depicted in
Figure 1. Any of Positions 3, 5, 7, or 8 of the chromene nucleus may optionally be substituted with a substituent from the list described for R2. Up to two of these positions may be substituted. Position 4 of the chromene nucleus may optionally be substituted with one of the halogenated lower alkyl or alkoxy moieties described for R above. Typically, Position 4 will be substituted with a trifluoromethyl function.
More specific embodiments of the invention ..are directed to compounds of
Formula I in which:
a. M is NZ, in which Z is H; R1 is trifluoromethyl, R^ is absent, B is hydrogen, and A is represented by phenyl, which may be optionally substituted. b. M is NZ, in which Z is H, R1 is trifluoromethyl, R^ is absent, B is hydrogen, or Cj-Cg alkyl and A is C^-Cg alkyl, more typically Cj - C3 alkyl. c. M is NZ, in which Z is H, R is trifluoromethyl, R2 is absent, B is hydrogen, A is d-Cβ alkyl R6, and more specifically a d-C3 alkylphenyl ring. d. M is NZ, in which Z is H, R1 is trifluoromethyl, R2 is absent, B is hydrogen, A is d-C6 alkylR6, and R6 is phenyl, which has been substituted with trifluoromethyl, or d-C4alkyl, more specifically ethyl. e. M is NZ in which Z is H, R is trifluoromethy, R2 is absent, B is hydrogen, A is d-C6 alkylR6, and R6 is cycloalkenyl, typically cyclohexenyl. f. M is NZ in which Z is H, R1 is trifluoromethyl, R2 is absent, B is hydrogen, A is d-C6 alkylR6, and R6 is cycloalkylphenyl. M is NZ in which Z is H, R1 is trifluoromethyl, R2 is absent, B is hydrogen, A is d-C6 alkylR6, and R6 is heterocyclic. M is NZ in which Z is H, Rl is trifluoromethyl, R2 is absent, B is hydrogen, A is -Cβ alkylR6, and R6 is heteroaryl.
Synthesis
The compounds of formula can be prepared using methods analogous to those known in the art for the preparation of sulfonamides. The reader's attention is directed to J. March, Advanced Organic Chemistry, 3rd edition, page 445, John Wiley & Sons (1985) for a more detailed discussion of such synthesis. Scheme I below provides a general overview:
Scheme 1
Figure imgf000016_0001
As depicted above, one of the starting materials is an appropriately substituted quinolin-2-one or 2-oxo-chromene (i.e. R1, R^, and M are as in desired compound) that has been functionalized at the 6-position with a sulfonyl chloride moiety (Formula LT). These compounds may be produced by introducing the sulfonyl chloride moiety into the 6-postion of the quinolin-2-ones and 2-oxo- chromenes by chlorosulfonation with chlorosulfonic acid at about 140°C. These reactions are described in more detail in the working examples. The reader's attention is also directed to Furniss et al, Nogel's Textbook of Practical Organic Chemistry, 5th Edition, pages 877-879, where such reactions are described in detail.
The other starting material is an appropriately substituted amine as described by Formula III (i.e. A and B are as in final compound). These amines can typically be purchased from Aldrich, which has an office located in St. Louis, Mo. USA. Further information may be obtained from Aldrich at, www.sigmaaldrich.com
The sulfonamides derivatives of Formula I are prepared by reacting the sulfonyl chloride derivative of Formula II with the appropriate amine as described by Formula HI in the presence of a non-nucleophilic base, such as pyridine or diisopropylethylamine, at about room temperature in an aprotic solvent, such as,
N,N'-dimethylformamide. The reaction is allowed to proceed to completion, which is typically accomplished in from 2 to 24 hours. If desired, the compounds can be isolated and purified using techniques known in the art such as extraction and flash chromatography. These reactions are described in detail in the working examples.
Medical and Cosmetic Uses
The compounds of Formula I are androgen receptor antagonists. They can be used to alleviate any condition associated with inappropriate activation of the androgen receptor. Examples of such conditions include prostate carcinomas, benign hyperplasia of the prostate, acne, hirsutism, seborrhoea, alopecia, premenstrual syndrome, lung cancer, and precocious puberty.
In order to exhibit the therapeutic properties described above, the compounds need to be administered in a quantity sufficient to inhibit activation of the androgen receptor. This antagonistic amount can vary depending upon the particular disease/condition being treated, the severity of the patient's disease/condition, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc. When administered systemically, the compounds typically exhibit their effect at a dosage range of from about 0.1 mg/kg/day to about 100 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above. The compounds of the present invention may be administered by a variety of routes. They are effective if administered orally. The compounds may also be administered parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally), rectally, or topically.
In a typical embodiment, the compounds are administered topically. Topical administration is especially appropriate for hirsutism, alopecia, acne and hyperseborhhea. The dose will vary, but as a general guideline, the compound will be present in a dermatologically acceptable carrier in an amount of from 0.1 to 10 w/w% and the dermatological preparation will be applied to the affected area from 1 to 4 times daily. "Dermatologically acceptable" refers to a carrier which may be applied to the skin or hair, and which will allow the drug to diffuse to the site of action. More specifically, it refers to the site where inhibition of activation of an androgen receptor is desired. In a further embodiment, the compounds are used topically to relieve alopecia, especially androgenic alopecia. Androgens have a profound effect on both hair growth and hair loss. In most body sites, such as the beard and pubic skin, androgens stimulate hair growth by prolonging the growth phase of the hair cycle (anagen) and increasing follicle size. Hair growth on the scalp does not require androgens but, paradoxically, androgens are necessary for balding on the scalp in genetically predisposed individuals (androgenic alopecia) where there is a progressive decline in the duration of anagen and in hair follicle size. Men castrated before puberty fail to grow beards and do not go bald. If subsequently treated with testosterone about one third of male castrates will show balding. Androgeneic alopecia is also common in women where it usually present as a diffuse hair loss rather than showing the patterning seen in men.
As used in this application "alopecia" refers to partial or complete hair loss on the scalp. The compounds will typically be used to alleviate androgenic alopecia. This condition afflicts both men and women. In males, the hair loss begins in the lateral frontal areas or over the vertex. For females, it is typically associated with thinning of the hair in the frontal and parietal regions. Complete hair loss in females is rare.
While the compounds will most typically be used to alleviate androgenic alopecia, the invention is not limited to this specific condition. The compounds may be used to alleviate any type of alopecia. Examples of non-androgenic alopecia include alopecia areata, alopecia due to radiotherapy or chemotherapy, scarring alopecia, stress related alopecia, etc.
Thus, the compounds can be applied topically to the scalp and hair to prevent, or alleviate balding. Further, the compound can be applied topically in order to induce or promote the growth of hair on the scalp:
In a further embodiment of the invention, a compound of Formula I is applied topically in order to prevent the growth of hair in areas where such hair growth is not desired. One such use will be to alleviate hirsutism. Hirsutism is excessive hair growth in areas that typically do not have hair (i.e. a female face). Such inappriate hair growth occurs most commonly in women and is frequently seen at menopause. The topical administration of the compounds will alleviate this condition leading to a reduction, or elimination of this inappropriate, or undesired, hair growth.
The compounds may also be used topically to decrease seborrhea production and more specifically to alleviate hyperseborrhoea (oily skin). Likewise the compounds can be used topically alleviate acne.
Formulations If desired, the compounds can be administered directly without any carrier.
However, to ease administration, they will typically be formulated into pharmaceutical carriers. Likewise, they will most typically be formulated into dermatological, or cosmetic carriers. In this application the terms "dermatological carrier" and "cosmetic" carrier are being used interchangeably. They refer to formulations designed for administration directly to the skin or hair. Pharmaceutical and cosmetic compositions can be manufactured utilizing techniques known in the art. Typically an antagonistic amount of the compound will be admixed with a pharmaceutically/cosmetically acceptable carrier.
For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent, which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art. When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid as is known in the art. The compounds of this invention will typically be administered topically.
As used herein, topical refers to application of the compounds (and optional carrier) directly to the skin or hair. The topical composition according to the present invention can be in the form of solutions, lotions, salves, creams, ointments, liposomes, sprays, gels, roller sticks, or any other method using micelles and pharmaceutically acceptable penetration enhancers
Thus, a further embodiment relates to cosmetic or pharmaceutical compositions, in particular dermatological compositions, which comprise at least one of the compounds corresponding to Formula I above. Such dermatological compositions will contain from 0.001% to 10% w/w% of the compounds in admixture with a dermatologically acceptable carrier, and more typically, from 0.1 to 5 w/w% of the acompounds. Such compositions will typically be applied from 1 to 4 times daily. The compositions according to the invention can also consist of solid preparations constituting cleansing soaps or bars. These compositions are prepared according to the usual methods.
The compounds can also be used for the hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions or mousses, or alternatively in the form of aerosol compositions also comprising a propellant under pressure. The composition according to the invention can also be a hair care composition, and in particular a shampoo, a hair-setting lotion, a treating lotion, a styling cream or gel, a dye composition (in particular an oxidation dye composition) optionally in the form of coloring shampoos, restructuring lotions for the hair, a permanent-waving composition (in particular a composition for the first stage of a permanent-waving operation), a lotion or gel for preventing hair loss, etc. The amounts of the various constituents in the dermatological compositions according to the invention are those conventionally used in the fields considered. The medicinals and cosmetics containing the compounds of the invention will typically be packaged for retail distribution (i.e. an article of manufacture). Such articles will be labeled and packaged in a manner to instruct the patient how to use the product. Such instructions will include the condition, which may be treated, duration of treatment, dosing schedule, etc. The compounds of Formula I may also be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the serum, urine, etc., of the patient as is known in the art. The compounds may also be used as a research tool.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention. The following examples and biological data is being presented in order to further illustrate the invention. This disclosure should not be construed as limiting the invention in any manner.
EXAMPLES
Materials and Methods
Column chromatography was carried out on Siθ2 (40-63 mesh). LCMS data were obtained using a Phenomenex Mercury Luna 3 μ Cjg column
(2 x 10 mm, flow rate = 1.5 mL mmr1) eluting with a 5% MeCN in H2θ-MeCN solution (4:1 to 1:4) containing 0.1% HCO2H over 2.55 minutes and diode array detection. The mass spectra were obtained employing an electrospray ionisation source in the positive (ES+) & negative (ES-) ion modes. Preparative mass- directed liquid chromatographic purification was carried out utilizing a Waters
Xterra 5 μ Cjg column (19 x 50 mm, flow rate = 20 mL min~l) eluting with a 5% MeCN in H2θ-MeCN solution (4: 1 to 1 :4) containing 0.1 % HCO2H over
7 minutes and diode array detection. 1H NMR spectra were recorded at 400 MHz on a Narian Mercury spectrometer at 27°C. The deuterated solvent was used as the lock, while the residual solvent peak was employed as internal reference. Acronyms: DMAP = 4-Dimethylaminopyridine; HATU = 0-(7~Azabenzotriazol- l-yl)-N,N,N',N'-tetι-amethyluronium hexafluorophosphate; ΝMP = l-Methyl-2- pyrrolidinone; PE = Petroleum ether (B.p. = 60-80°C); RT = Retention time. Preparation of Starting Materials Preparation 1: l-Methyl-2-oxo-4-trifIuoromethyl-l,2-dihydroquinoIine-6- sulfonyl chloride
Figure imgf000023_0001
KOH (10.54 g, 188.0 mmol) was added to a solution of 4-trifluoromethyl- lH-quinolin-2-one (4.00 g, 18.8 mmol) in DMF (160 mL). After 1 hour, the mixture was treated with Mel (11.7 mL, 188.0 mmol), then stirring was continued overnight. EtOAc (200 mL) was added, followed by saturated aqueous NΗ4CI to adjust the aqueous pH to 6.5. After separation of the layers, the aqueous phase was extracted further with EtOAc (2 x 200 mL). The combined organic extracts were washed with H2O (200 mL) and brine (200 mL), before being dried
(MgSO4). Filtration, solvent evaporation, and column chromatography (PE- EtOAc, 4:1 to 7:3) yielded l-methyl-4-trifluoromethyl-lH-quinolin-2-one (4.00 g, 94%): δΗ ((CD3)2SO) = 3.65 (s, 3H), 7.10 (s, 1H), 7.40 (t, 1H), 7.65-7.80 (m, 3H). This compound (8.70 g, 38.3 mmol) was added portionwise with stirring over 20 min to fuming H2SO4 (30% oleum, 17.5 mL) at 84°C . The bath temperature was raised to 120°C for 1 hour, before being cooled back down to 20°C. Thereupon, the mixture was added slowly to saturated aqueous NaCl (60 mL) and stirred for 30 min. The solid produced was collected & dried under vacuum at 50 °C to give sodium l-methyl-2-oxo-4-trifluoromethyl-l,2- dihydroquinoline-6-sulfonate: δπ ((CD3)2SO) = 3.65 (s, 3H), 7.10 (s, 1H), 7.65
(d, 1H), 7.95 (dd, 1H), 8.00 (d, 1H). This compound was suspended in MeCN- sulfolane (1:1, 52 mL), before being treated with POCI3 (18.8 mL, 201.7 mmol).
The mixture was heated to 88°C for 1.5 hours, before being cooled to 20°C over 0.5 hour. On cooling to <5°C, ice cold H2O (128 mL) was added, the temperature being maintained below 7°C. The mixture was stirred at 0°C for 20 minutes, then the solid formed was collected and washed with H2O to afford, after drying, the title compound (9.62 g, 73%): δH (CDCI3) = 3.80 (s, 3H), 7.25 (s, IH), 7.65 (d, IH), 8.25 (dd, IH), 8.50 (d, IH).
Preparation 2: 2-Oxo-4-trifluoromethyi-2Jϊ-elιromene-6-sulfonyl chloride
Figure imgf000024_0001
Sulfonation of 4-trifluoromethylchromen-2-one (5.00 g, 23.3 mmol), followed by NaCl treatment, as described in Preparation 1, produced sodium 2-oxo-4-trifluorόmethyϊ~2H-chromene-6-sulfonate: δjj ((CD3)2SO) = 7.10 (s, 1Η), 7.45 (d, 1Η), 7.90 (dd, 1Η), 7.95 (d, 1Η). Reaction of this compound with POCI3 (10.3 mL, 110.5 mmol) provided the title compound (5.48 g, 75%): δjj (CDCI3) = 7.00 (s, 1Η), 7.70 (d, 1Η), 8.30 (dd, 1Η), 8.40 (d, 1Η).
Preparation 3: 2-Oxo-4-trifluoromethyl-l,2-dihydroquinoline-6-sulfonyl chloride
Figure imgf000024_0002
4-Trifluoromethyl-lH-quinolin-2-one (5.00 g, 23.5 mmol) was treated with CISO3Η (3.1 mL, 47.0 mmol) at 0°C. The mixture was then heated with stirring to 140°C for 7 hours. On cooling, ice-cold H2O (50 mL) was added. The solid produced was collected and dried to give the title compound (2.93 g, 41%): δH (CDCI3) = 7.20 (s, IH), 7.60 (d, IH), 8.20 (dd, IH), 8.50 (d, IH).
Preparation of Compounds of Formula I EXAMPLE 1 l-MethyI-2-oxo-4-trifluoromethyl-l,2-dihydroquinoIine-6-suIfonic acid phenylamide
Figure imgf000025_0001
A solution of l-methyl-2-oxo-4-trifluoromethyl-l,2-dihydroquinoline-6-sulfonyl chloride (Preparation 1, 65 mg, 200 /Λnol) in anhydrous DMF (1.5 mL) was contacted with PhNH2 (19 μL, 210 /Λnol), employing pyridine (17 μL, 220 Λnol) as base), before being stirred overnight under N2. The reaction mixture was diluted with EtOAc (70 mL), before being washed with H2O (30 mL), 1 M HC1 (30 mL), H2O (30 mL), saturated aqueous NaHCO3 (30 mL), H2O (30 mL), & brine (30 mL). After drying (MgSO4), the organic phase was filtered & concentrated to give a residue that was recrystallised from EtOAc-PE to furnish the title compound (39 mg, 50%): & ((CD3)2SO) = 3.60 (s, 3H), 7.00 (s, IH), 7.10 (d, 2H), 7.15-7.20 (m, 3H), 7.80 (d, IH), 8.00-8.05 (m, 2H); mlz (ES+) = 383.1 [M + H]+.
Example 2: 2-Oxo-4-trifluoromethyl-l,2-dihydroquinoline-6-sulfonic acid phenylamide
Figure imgf000025_0002
Following the same procedure as Example 1, condensation of 2-oxo-4- trifluoromethyl-l,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 50 mg, 160 mol) with PhNH2 (15 μL, 168 /Λnol), employing pyridine (14 μL, 168 /Λnol) as base, gave the title compound (11 mg, 17%): & ((CD3)2SO) = 7.00 (s, IH), 7.05-7.10 (m, 3H), 7.20 (m, 2H), 7.50 (d, IH), 7.90 (dd, IH), 8.00 (d,
Figure imgf000025_0003
[M + H]+.
Example 3: 2-Oxo-4-trifluoromethyl-l,2-dihydroquinoline-6-sulfonic acid benzylamide
Figure imgf000026_0001
Condensation of 2-oxo-4-trifluoromethyl-l ,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 16 mg, 51 /Λnol) with BnNH2 (7 μL, 54 /Λnol), employing NEt (8 μL, 57 /Λnol) as base as delineated in Example 1, gave the title compound (18 mg, 90%): δ_ ((CD3)2SO) = 4.00 (d, 2H), 7.05 (s, IH), 7.10-7.20 (m, 5H), 7.50 (d, IH), 7.95 (dd, IH), 8.00 (d, IH), 8.30 (t, IH); mlz (ES-) = 381.0 [M - HT.
EXAMPLE 4-67 l-Methyl-2-oxo-4-trifluoromethyl-l,2-dihydroquinoline-6-sulfonic acid amides, 2-oxo-4-trifluoromethyl-2H-chromene-6-sulfonic acid amides, (Table 1)
Figure imgf000026_0002
These compounds were prepared by solution phase parallel synthesis. The appropriate amine as described by Formula HI (30 μL of a 0.33 M solution in NMP, 9.9 μmol), i-Pr2NEt (20 μL of a 0.50 M solution in NMP, 10.0 μmol), & the sulfonyl chloride of Formula II (50 μL of a 0.20 M solution in NMP, 10.0 μmol) were mixed together in 1 well of a 96-well plate using an automated liquid handler. After agitating for 66 h, the solvents were evaporated off under reduced pressure & DMF (50 μL) was added. To ensure dissolution, the mixture was shaken, before being treated with EtOAc (450 μL). Using automated liquid-liquid extraction equipment, the solution was washed with H2O (150 μL) & 1% aqueous NaHCO3 (150 μL). The organic layer was concentrated to furnish the compounds displayed in Table 1. Example CHEMISTRY Name RT Base Peak
Figure imgf000027_0001
acid butylethylamide
1-Methyl-2-oxo-4- trifluoromethyl-1 ,2- dihydroquinoIine-6-sulfonic 1.70 407.2 [M + Hf
Figure imgf000027_0002
acid butyl(2-hydroxyethyl)- amide
1 -Methyl-2-oxo-4- trifluoromethyl-1 ,2- di ydroquinoline-6-sulfonic 1.72 441.2 [M + H]+
Figure imgf000027_0003
acid benzyl(2-hydroxyethyl)- amide
1-Met yl-2-oxo-4- trifluoromet yl-1 ,2- dihydroquinoline-6-sulfonic 1.78 421.2 [M + H]+
Figure imgf000027_0004
acid (2-hydroxyethyi)- pentylamide
Figure imgf000027_0005
acid butylmethylamide
Figure imgf000027_0006
Figure imgf000028_0001
acid benzylethylamide
Figure imgf000028_0002
acid met ylphenethylamide
Figure imgf000028_0003
acid methylphenylamide
Figure imgf000028_0004
acid m-tolylamide
Figure imgf000028_0005
acid p-tolylamidθ
Figure imgf000028_0006
acid (4-ethynylphenyl)amide
Figure imgf000028_0007
acid (3-ethylp enyl)amide
Figure imgf000029_0001
18 ulfonic 1.85 409.2 [M - Hf
Figure imgf000029_0002
dimethylphenyl)amide
19 sulfonic 1.61 411.2 [M-Hr
Figure imgf000029_0003
ydroxymethylphenyl)amide
20 suifonic 1.78 411.2 [M-Hr
Figure imgf000029_0004
methoxyphenyl)amide
21 sulfonic 1.70 420.2 [M-H
Figure imgf000029_0005
cyanomet ylphenyl)amide
Figure imgf000029_0006
acid indan-5-ylamide
Figure imgf000029_0007
acid indan-4-ylamide
Figure imgf000030_0001
acid (3-acetylphenyl)amide
25 ulfonic 2.00 423.2 [M - Hf
Figure imgf000030_0002
isopropylphenyl)amide
1-Methyl-2-oxo-4- trifluoromethyl-1 ,2-
26 dihydroquinoline-6-sulfonic 1.75 425.1 [M - Hf
Figure imgf000030_0003
acid benzo[1 ,3]dioxol-5- ylamide
1-Methyl-2-oxo-4- trifiuoromethyl-1 ,2-
27 di ydroquinoline-6-sulfonic 2.00 471.2 [M - H]"
Figure imgf000030_0004
acid (4-methylbiphenyl-3- yl)amide
1-Methyl-2-oxo-4- trifluoromethyl-1 ,2-dihydro-
28 quinoline-6-sulfonic acid [3- 1.55 425.2 [M - Hf
Figure imgf000030_0005
(1 -hydroxyethyl)phenyl]- amide
29 ulfonic 1.85 427.1 [M - Hf
Figure imgf000030_0006
methylsulfanylp enyl)amide
Figure imgf000030_0007
methylphenyl)amide
Figure imgf000031_0001
acid (4-chlorophenyl)amide
Figure imgf000031_0002
acid isoquinolin-3-ylamide
Figure imgf000031_0003
acid quinolin-3-ylamide
Figure imgf000031_0004
acid quinolin-8-ylamide
Figure imgf000031_0005
methylsulfanyl-2 V-pyrazol-3- yl)amide
1 -Methyl-2-oxo-4- trifluoromethyl-1 ,2-
36 dihydroquinoline-6-sulfonic 1.77 441.2 [M - Hf
Figure imgf000031_0006
acid (3,5-dimethoxyphenyl)- amide 1-Methyl-2-oxo-4- trifluoromethyl-1 ,2-
37 dihydroquinoline-6-sulfonic 1.88 439.2 [M - Hf
Figure imgf000032_0001
acid (3-isopropoxyphenyl)- amide
1-Methyl-2-oxo-4- trifluoromethyl-1 ,2-
38 dihydroquinoline-6-sulfonic 1.85 447.1 [M - Hf
Figure imgf000032_0002
acid (3-difluoromethoxy- phenyl)amide
39 sulfonic 1.90 449.1 [M - Hf
Figure imgf000032_0003
trifluoromethylphenyl)-amide
1 -Methyl-2-oxo-4- trifluoromethyl-1 ,2-
40 dihydroquinoline-6-sulfonic 1.72 463.2 [M - Hf
Figure imgf000032_0004
acid (4-methyl-2-oxo-2 -- c romen-7-yl)amide
1-Methyl-2-oxo-4- trifluoromethyl-1 ,2-
41 dihydroquinoiine-6-sulfoπic 1.96 465.1 [M - Hf
Figure imgf000032_0005
acid (3-trifluoromethoxy- phenyl)amide
[4-(1-Methyl-2-oxo-4- trifluoromethyl-1 ,2-
42 dihydroquinoline-6- 1.79 467.2 [M - Hf
Figure imgf000032_0006
sulfonylamino)phenyl]acetic acid ethyl ester
Figure imgf000032_0007
acid (3-benzylphenyl)amide
Figure imgf000033_0001
acid (4-ethoxyphenyl)amide
1 -Melhyl-2-oxc~4- trifluoromethyl-1 ,2-
45 dihydroquinoline-6-sulfonic 2.26 493.3 [M - Hf
Figure imgf000033_0002
acid (3,5-d erf- butylphenyl)amide
1-Methyl-2-oxo-4- trifluoromethyl-1 ,2-
46 dihydroquinoiine-6-sulfonic 2.03 503.2 [M + Hf
Figure imgf000033_0003
acid benzyl(4-methoxy- phenyl)amide
Figure imgf000033_0004
trifluoromethylpyrazol-1 - yl)phenyl]amide
48 sulfonic 1.76 411.2 [M - Hf
Figure imgf000033_0005
methoxyphenyl)amide
49 sulfonic 1.89 389.2 [M - Hf
Figure imgf000033_0006
dimethylbutyl)amide
Figure imgf000033_0007
acid phenethylamide
Figure imgf000034_0001
acid 4-methylbenzylamide
Figure imgf000034_0002
acid 2-methylbenzylamide
1 -Methyl-2-oxo-4- trifluoromethyl-1 ,2- dihydroquinoline-6-sulfonic 1.97 413.2 [M - Hf
Figure imgf000034_0003
acid (2-cyclohex-1 - enylethyl)amide
1 -Methyl-2-oxo-4- trifluoromethyl-1 ,2- dihydroquinoline-6-sulfonic 1.78 415.1 [M - Hf
Figure imgf000034_0004
acid (2-thiophen-2- ylethyl)amide
Figure imgf000034_0005
acid indan-1-ylamide
Figure imgf000034_0006
acid (2-phenylpropyl)amide
Figure imgf000034_0007
acid (4-phenylbutyl)amide -4- 1 ,2- e-6-sulfonic 1.85 439.2 [M - Hf
Figure imgf000035_0001
methoxyphenyl)ethyl]amide
1 -Methyl-2-oxo-4- trifluoromethyl-1 ,2- dihydroquinoline-6-suIfonic 1.85 447.1 [M - Hf
Figure imgf000035_0002
acid 5-chloro-2- fluorobenzylamide
1-Methyl-2-oxo-4- trifluoromethyl-1 ,2- dihydroquinoline-6-sulfonic 1.75 448.2 [M - Hf
Figure imgf000035_0003
acid [2-(1 H-indol-3- yl)ethyl]amide
ulfonic 1.87 421.2 [M - Hf
Figure imgf000035_0004
butylsulfanylethyl)amide
1-Methyl-2-όxo-4- trifluoromethyl-1 ,2- dihydroquinoline-6-sulfonic 1.88 463.2 [M - Hf
Figure imgf000035_0005
acid 2-trifluoromethyl- benzylamide
Figure imgf000035_0006
fluorobenzylsulfanyl)ethyl]- amide
2-Oxo-4-trifluoromethyl-2H- chromene-6-sulfonic acid 1.18 385.1 [M + H]
Figure imgf000035_0007
(pyridin-3-ylmethyl)amide 2-Oxo-4-trifluoromethyl-2A7-
65 chromene-6-sulfonic acid (1 - 1.95 410.2 [M - Hf
Figure imgf000036_0001
methyl-1 -phenylethyl)amide
2-Oxo-4-trifluoromethyl-2H-
66 chromenβ-6-sulfonic acid 2- 1.95 428.1 [M - H]"
Figure imgf000036_0002
methylsulfanylbenzylamide
2-Oxo-4-trifluoromethyl-2H-
67 chromene-6-sulfonic acid [2- 1.87 435.2 [M - Hf
Figure imgf000036_0003
(1 H-indol-3-yl)ethyl]amide
Examples 68-160 2-Oxo-4-trifluoromethyl-l,2-dihydroquinoIine-6-sulfonic acid amides (Table
2)
Figure imgf000037_0001
Employing the procedure described above for Examples 4-67, the appropriate amine of Formula III (120 μL of a 0.33 M solution in NMP, 39.6 μmol) was reacted with 2-oxo-4-trifluoromethyl-l,2-dihydroquinoline-6-sulfonyl chloride (200 μL of a 0.20 M solution in NMP, 40.0 /ztnol) in the presence of /-Pr2NEt (80 μL of a 0.50 M solution in NMP, 40.0 μm i). Following evaporation of the NMP, the residues were dissolved in DMSO (450 μL), before being subjected to preparative mass-directed liquid chromatographic purification to provide the compounds illustrated in Table 2.
Table 2 Example CHEMISTRY Name RT Base Peak
2-Oxo-4-trifluoromethyl-1 ,2-
68 dihydroquinoline-6-sulfonic acid 2.01 405.2 [M + Hf
Figure imgf000037_0002
dibutylamide
2-Oxo-4-trifluoromethyl-1 ,2-
69 dihydroquinoline-6-sulfonic acid 1.87 377.2 [M + Hf
Figure imgf000037_0003
butylethylamide
2-Oxo-4-trifluoromethyl-1 ,2-
70 dihydroquinoline-6-sulfonic acid 1.66 347.2 [M - Hf
Figure imgf000037_0004
isopropylmethylamide 2-Oxo-4-trifluoromethyl-1 ,2-
71 dihydroquιnoline-6-sulfonic acid 1.65 425.2 [M - Hf
Figure imgf000038_0001
benzyl(2-hydroxyelhyl)amide
Figure imgf000038_0002
quinolin-2-one
2-Oxo-4-trifluoromethyl-1 ,2-
73 dihydroquinoline-6-sulfonic acid 1.87 389.2 [M + Hf
Figure imgf000038_0003
cyclopropylmethyl-propylamide
2-Oxo-4-trifluoromethyl-1 ,2-
74 dihydroquinoline-6-sulfonic acid 1.68 405.2 [M - Hf
Figure imgf000038_0004
(2-hydroxyethyl)-pentylamide
2-Oxo-4-trifluoromethyl-1 ,2-
75 dihydroquinoline-6-sulfonic acid 1.86 389.2 [M + Hf
Figure imgf000038_0005
cyclohexylmethylamide
2-Oxo-4-trifluoromethyl-1 ,2-
76 dihydroquinoline-6-sulfonic acid 1.81 361.2 [M - Hf
Figure imgf000038_0006
butylmethylamide
2-Oxo-4-trifluoromethyl-1 ,2-
77 dihydroquinoline-6-sulfonic acid 1.49 358.2 [M - Hf
Figure imgf000038_0007
(2-cyanoethyl)methylamide 2-Oxo-4-trifluoromethyl-1 ,2-
78 dihydroquinoline-6-sulfonic acid 1.86 411.2 [M + H]+ methylphenethylamide
2-Oxo-4-trifluoromethyl-1 ,2-
79 dihydroquinoline-6-sulfonic acid 1.88 411.2 [M + Hf
Figure imgf000039_0002
benzylethylamide
2-Oxo-4-trifluoromethyl-1 ,2-
80 dihydroquinoline-6-sulfonic acid 1.57 409.1 [M + Hf
Figure imgf000039_0003
bis(2-methoxyethyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
81 dihydroquinoline-6-sulfonic acid 1.34 370.1 [M + Hf
Figure imgf000039_0004
pyridin-3-ylamide
2-Oxo-4-trifluoromethyl-1 ,2-
82 dihydroquinoline-6-sulfonic acid 1.73 381.1 [M - Hf
Figure imgf000039_0005
m-tolylamide
2-Oxo-4-trifluoromethyl-1 ,2-
83 dihydroquinoline-6-sulfonic acid 1.71 381.1 [M - Hf
Figure imgf000039_0006
p-tolylamide
2-Oxo-4-trifluoromethyl-1 ,2-
84 dihydroquinoline-6-sulfonic acid 1.68 385.1 [M - Hf
Figure imgf000039_0007
(4-fluorophenyl)amide
Figure imgf000040_0001
yl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
86 dihydroquiπoline-6-sulfonic acid 1.74 391.1 [M - Hf
Figure imgf000040_0002
(4-elhynylphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
87 dihydroquinoline-6-sulfonic acid 1.62 392.1 [M - Hf
Figure imgf000040_0003
(3-cyanophenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
88 dihydroquinoline-6-sulfonic acid 1.75 395.2 [M - Hf
Figure imgf000040_0004
(3-ethylphenyl)amide
1 ,2-
89 nic acid 1.80 395.2 [M - Hf
Figure imgf000040_0005
2-Oxo-4-trifluoromethyl- ,2-
90 dihydroquinoline-6-sulfonic acid 1.68 395.1 [M - Hf
Figure imgf000040_0006
(2,6-dimethylphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
91 dihydroquinoline-6-sulfoπic acid 1.46 397.2 [M - Hf
Figure imgf000040_0007
(3-hydroxymethylphenyl)arnide 2-Oxo-4-trifluoromethyl-1 ,2-
92 dihydroquinoline-6-sulfonic acid 1.63 397.1 [M - Hf
Figure imgf000041_0001
(2-methoxyphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
93 dihydroquinoline-6-sulfonic acid 1.30 420.2 [M + Hf
Figure imgf000041_0002
quinolin-6-ylamide
2-Oxo-4-trifluoromethyl-1 ,2-
94 dihydroquinoline-6-sulfonic acid 1.69 403.1 [M - Hf
Figure imgf000041_0003
(2,4-difluorophenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
95 dihydroquinoline-6-sulfonic acid 1.55 406.1 [M - Hf
Figure imgf000041_0004
(4-cyanomethylphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
96 dihydroquinoline-6-sulfonic acid 1.81 407.2 [M - Hf
Figure imgf000041_0005
indan-5-ylamide
2-Oxo-4-trifluoromethyl~1 ,2-
97 dihydroquinoline-6-sulfonic acid 1.85 409.2 [M - Hf
Figure imgf000041_0006
(4-isopropylphenyl)am ide
2-Oxo-4-trifluoromethyl-1 ,2-
98 dihydroquinoline-6-sulfonic acid 1.61 411.1 [M - Hf
Figure imgf000041_0007
ben∑o[1 ,3]dioxol-5-ylamide 2-Oxo-4-trifluoromethyl-1 ,2-
99 dihydroquinoline-6-sulfonic acid 1.92 457.2 [M - Hf
Figure imgf000042_0001
(4-methylbiphenyl-3-yl)amide
Figure imgf000042_0002
hydroxyethyl)phenyl]amide
2-Oxo-4-trifluoromethyl-1 ,2-
101 dihydroquinoline-6-sulfonic acid 1.74 413.1 [M - Hf
Figure imgf000042_0003
(3-methylsulfanylphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
102 dihydroquinoline-6-sulfonic acid 1.65 427.1 [M - Hf
Figure imgf000042_0004
(2,5-dimethoxyphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
103 dihydroquinoline-6-sulfonic acid 1.68 427.1 [M - Hf
Figure imgf000042_0005
(3,5-dimethoxyphenyl)amide
Figure imgf000042_0006
pyrazol-3-yl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
105 dihydroquinoline-6-sulfonic acid 1.80 425.2 [M - Hf
Figure imgf000042_0007
(3-isopropoxyphenyl)amide
Figure imgf000043_0001
difluoromethoxyphenyl)amide
Figure imgf000043_0002
yl)amide
2-Oxo-4-trifluoromethyl-1 ,2- dihydroquinoline-6-sulfonic acid 1.46 435.1 [M + Hf
Figure imgf000043_0003
(3-methylcinnolin-5-yl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
109 dihydroquinoline-6-sulfonic acid 1.80 435.1 [M - Hf
Figure imgf000043_0004
(3-trifluoromethylphenyl)amide
2-Oxo-4-trifluorom ethyl- 1 ,2-
110 dihydroquinoline-6-sulfonic acid 1.72 449.0 [M + Hf
Figure imgf000043_0005
(2-bromophenyl)amide
Figure imgf000043_0006
yl)amide
Figure imgf000043_0007
trifluoromethoxyphenyl)amide
Figure imgf000044_0001
hydroxyethyl)phenyl]amide
2-Oxo-4-trifluoromethyl-1 ,2- dihydroquinoline-6-sulfonic acid 1.90 473.1 [M - Hf
Figure imgf000044_0002
(3-benzyloxyphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
115 dihydroquinoline-6-sulfonic acid 1.93 475.1 [M - Hf
Figure imgf000044_0003
(2-phenylsulfanylphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
116 dihydroquinoline-6-sulfonic acid 1.66 397.1 [M - Hf
Figure imgf000044_0004
(3-methoxyphenyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
117 dihydroquinoline-6-sulfonic acid 1.43 333.1 [M - Hf
Figure imgf000044_0005
isopropylamide
2-Oxo-4-trifluoromethyl-1 ,2-
118 dihydroquinoline-6-sulfonic acid 1.57 387.1 [M - Hf
Figure imgf000044_0006
(thiophen-2-ylmethyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
119 dihydroquinoline-6-sulfonic acid 1.31 392.1 [M + H + MeC
Figure imgf000044_0007
(2-methoxyethyl)amide 2-Oxo-4-trifluoromethyl-1 ,2-
120 dihydroquinoline-6-sulfonic acid 1.57 359.1 [M - Hf
Figure imgf000045_0001
cyclopentylamide
2-Oxo-4-trifluoromethyl-1 ,2-
121 dihydroquinoline-6-sulfonic acid 1.68 361.1 [M - Hf
Figure imgf000045_0002
(3-methylbutyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
122 dihydroquinoline-6-sulfonic acid 1.73 375.2 [M - Hf
Figure imgf000045_0003
(3,3-dimethylbutyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
123 dihydroquinoline-6-sulfonic acid 1.77 387.2 [M - Hf
Figure imgf000045_0004
cyclohexylmethylamide
2-Oxo-4-trifluoromethyl-1 ,2-
124 dihydroquinoline-6-sulfonic acid 1.63 395.1 [M - Hf
Figure imgf000045_0005
2-methylbenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
125 dihydroquinoline-6-sulfonic acid 1.62 395.1 [M - Hf
Figure imgf000045_0006
(l-phenylethyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
126 dihydroquinoline-6-sulfonic acid 1.72 387.2 [M - Hf
Figure imgf000045_0007
cycloheptylamide 2-Oxo-4-trifluoromethyl-1 ,2-
127 dihydroquinoline-6-sulfonic acid 1.53 391.2 [M - Hf
Figure imgf000046_0001
(3-isopropoxypropyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
128 dihydroquinoline-6-sulfonic acid 1.63 395.2 [M - Hf
Figure imgf000046_0002
phenethylamide
2-Oxo-4-trifluoromethyl-1 ,2-
129 dihydroquinoline-6-sulfonic acid 1.59 399.1 [M - Hf
Figure imgf000046_0003
4-fluorobenzylamide
2-Oxo-4-trifluorom ethyl- 1 ,2-
130 dihydroquinoline-6-sulfonic acid 1.72 407.2 [M - Hf
Figure imgf000046_0004
indan-1-ylamide
2-Oxo-4-trifluoromethyl-1 ,2-
131 dihydroquinoline-6-sulfonic acid 1.74 409.2 [M - Hf
Figure imgf000046_0005
(2-phenylpropyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
132 dihydroquinoline-6-sulfonic acid 1.79 399.2 [M - Hf
Figure imgf000046_0006
(2-cyclohex-1-enylethyl)amide
2-Oxo-4-trifluoromethyl-1 ,2-
133 dihydroquinoline-6-sulfonic acid 1.64 401.1 [M - Hf
Figure imgf000046_0007
(2-thiophen-2-ylethyl)amide
Figure imgf000047_0001
yl)elhyl]amide
Figure imgf000047_0002
methoxyphenyl)ethyl]amide
2-Oxo-4-trifluoromethyl-1 ,2-
136 dihydroquinoline-6-sulfonic acid 1.73 425.2 [M - Hf
Figure imgf000047_0003
2-ethoxy benzylam ide
2-Oxo-4-trifluoromethyl-1 ,2-
137 dihydroquinoline-6-sulfonic acid 1.68 413.1 [M - Hf
Figure imgf000047_0004
5-fluoro-2-methylbenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
138 dihydroquinoline-6-sulfonic acid 1.68 415.1 [M - Hf
Figure imgf000047_0005
3-chlorobenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
139 dihydroquinoline-6-sulfonic acid 1.60 417.1 [M - Hf
Figure imgf000047_0006
2,6-difluorobenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
140 dihydroquinoline-6-sulfonic acid 1.69 433.1 [M - Hf
Figure imgf000047_0007
2-chloro-4-fluorobenzylamide 2-Oxo-4-trifluoromethyl-1 ,2-
141 dihydroquinoline-6-sulfonic acid 1.66 433.1 [M - Hf
Figure imgf000048_0001
3-chloro-2-fluorobenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
142 dihydroquinoline-6-sulfonic acid 1.62 433.1 [M - Hf
Figure imgf000048_0002
2-chloro-6-fluorobenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
143 dihydroquinoline-6-sulfonic acid 1.68 427.1 [M - Hf
Figure imgf000048_0003
2-methylsulfanylbenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
144 dihydroquinoline-6-sulfonic acid 1.68 429.1 [M - Hf
Figure imgf000048_0004
2-chloro-6-methylbenzylamide
Figure imgf000048_0005
methylbenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
146 dihydroquinoline-6-sulfonic acid 1.68 433.1 [M - Hf
Figure imgf000048_0006
5-chloro-2-fluorobenzylamide
2-Oxo-4-trifluoromethyl-1 ,2-
147 dihydroquinoline-6-sulfonic acid 1.60 436.1 [M + Hf
Figure imgf000048_0007
[2-(1 H-indol-3-yl)ethyl]amide
Figure imgf000049_0001
-2-yl)
2-Oxo-4-trifluoromethyl-1 ,2-
149 dihydroquinoline-6-sulfonic acid 1.59 484.1 [M + H + MeCN]'
Figure imgf000049_0002
3,5-dimethoxybenzylamide
150
Figure imgf000049_0003
dimethylethyQamide
2-Oxo-4-trifluoromethyl-1 ,2-
151 dihydroquinoline-6-sulfonic acid 1.66 447.1 [M - Hf
Figure imgf000049_0004
2-difluoromethoxybenzylamide
Figure imgf000049_0005
methylbenzylamide
2-Oxo-4-trifluorom ethyl- 1 ,2-
153 dihydroquinoline-6-sulfonic acid 1.75 449.1 [M - Hf
Figure imgf000049_0006
2-trifluoromethylbenzylamide
Figure imgf000049_0007
fluorobenzylsulfanyl)ethyl]amide
Figure imgf000050_0001
nzylamide
2-Oxo-4-tπfluoromethyl-1 ,2-
156 dιhydroquιnolιne-6-sulfonιc acid 1 70 461 0 [M - Hf
Figure imgf000050_0002
2-bromobenzylamιde
2-Oxo-4-trιfliJθromethyl-1 ,2-
157 dιhydroquιnoiιne-6-sulfonιc acid 1 21 351 1 [M + Hf
Figure imgf000050_0003
(3-hydroxypropyl)amιde
Figure imgf000050_0004
tπfluoromethylbenzylamide
2-Oxo-4-trιfluoromethyl-1 ,2-
159 dιhydroquιnolιne-6-sulfonιc acid 1 84 471 2 [M - Hf
Figure imgf000050_0005
(2,2-dιphenylethyl)amιde
2-Oxo-4-tπfluoromethyl-1 ,2-
160 dιhydroquιnolιne-6-sulfonιc acid 1 82 522 2 [M + H + MeCN]
Figure imgf000050_0006
(2-benzyloxycyclohexyl)am ide EXAMPLE 162
BIOLOGICAL DATA The compounds ability to antagonize the effects of androgen on the androgen receptor were determined in the protocol described immediately below. The results are shown in Table 3.
Experimental procedure for AR antagonist cell assay
Cell line: MDA-MB453-MMTV clone 54-19. This cell line is a stable transfected cell line with MDA-MB453 cell background (human breast tumor cell expressing high level of androgen receptor). A MMTN minimal promoter containing ARE was first cloned in front of a firefly luciferase reporter gene. Then the cascade was cloned into transfection vector pUN120puro. Electroporation method was used for transfecting MDA-MB-453 cell. Puromycin resistant stable cell line was selected.
Cell culture media and reagents:
Culture medium: DMEM (high glucose, Gibco cat #: 11960-044), 10%FBS, and l% L-glutamine
Plating medium: DMEM (phenol red free), 10% charcoal treated HyClone serum, 1% L-glutamine
Assay medium: DMEM (phenol red free), 1% charcoal treated HyClone serum, 1% L-glutamine, and 1% penicillin/streptomycin 3X luciferase buffer: 2% beta-mercaptoethanol, 0.6% ATP, 0.0135% luciferine in cell lysis buffer
Assay procedure:
1. Cells are maintained in culture medium, splitting cells when they reach 80-
90% confluence 2. To test compounds, 10,000 cells/well are plated to opaque 96 cell culture plate in 100 ul/well plating medium, culture for overnight at 37°C in cell culture incubator
3. Carefully remove plating medium, then add 80 ul/well of pre-warmed assay medium, add 10 ul/well testing compound (final concentration at 10 uM or 1 uM), incubate at 37°C for 30 minutes
4. Add 10 ul/well freshly prepared DHT (final concentration at 100 pM) to each well, incubate at 37°C for 17 hr (overnight)
5. Add 50 ul/well 3X luciferase buffer, incubate at room temperature for 5 minutes, then count on Luminometer
The fold induction over background by 100 pM DHT in the absence of testing compounds is standardized as 100% and experimental result is expressed as percentage of inhibition by testing compounds.
TABLE 3
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001

Claims

CLAΓMS
What is claimed is:
A compound of the formula:
Figure imgf000057_0001
in which; a. M is NZ or O; b. Z is represented by H or (C^- C4)alkyl ; c. R! is represented by hydrogen, (Cι-C2)al yl, optionally substituted with one or more halogens, or (Cι-C2)alkoxy, optionally substituted with 1 or more halogens; d. R2 is absent, or may represent up to 2 substituents selected from the group consisting of halogen, nitrile, hydroxy, (Cj-
C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (Cι-C4)alkoxy,
(Cj-C2)alkyl substituted with 1 or more halogens, (Cj-
C2)alkoxy substituted with one or more halogens, SR^, and
NR4R5; e. R4 is represented by hydrogen, optionally substituted phenyl, (Cι-C4)alkyl, or optionally substituted benzyl; f. R^ is represented by optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclic; g. A and B are each independently represented by a substituent selected from the group consisting of hydrogen, (Cj-
C6)alkyl optionally substituted with one or more halogens, (C2-C6)alkenyl, (C2-C6)alkynyl, optionally substituted (C3-
C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, optionally substituted phenyl, optionally substituted cycloalkylphenyl, optionally substituted heterocyclic, optionally substituted heteroaryl,
(CrC6)alkylR6, -(CH2)m-R7-Y[-CH2] n-X- R8, and
-(CH2)qCHX1X2; h. R is represented by a substituent selected from the group consisting of nitrile, OH, optionally substituted phenyl, optionally substituted cyloalkylphenyl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted (C3-C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, SR4, and NR4R5; i. R7 is absent, or is represented by a substituent selected from the group consisting of optionally substituted (C3-C8) cycloalkyl, optionally substituted (Cs-C8) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, and optionally substituted phenyl; j. R8 is absent, or is represented by a substituent selected from the group consisting of (Cj-C6)alkyl optionally substituted with one, or more, halogens, optionally substituted (C3-C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl; k. m is an integer selected from 0, 1, 2, 3, or 4; 1. Y is absent, or is represented by O, C(O), C(O)O,
CH2C(O)O, OH, SH, or S; m. n is represented by an integer selected from 0, 1, 2, 3, or 4; n. X is absent, or is represented by O, C(O), C(O)O,
CH2C(O)O, OH, SH, or S; o. q is represented by an integer selected from 0, 1, 2, 3, or 4; p. X1 is represented by a substituent selected from the group consisting of optionally substituted (C3-C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl; q. X2 is represented by a substituent selected from the group consisting of optionally substituted (C3-C8) cycloalkyl, optionally substituted (C5-C8) cycloalkenyl, optionally substituted heteroaryl, optionally .substituted heterocyclic, optionally substituted phenyl, and optionally substituted cycloalkylphenyl and; r. the pharmaceutically acceptable salts, solvates, and prodrugs thereof.
2. A compound according to any one of claims 1, or 3-10 in which R1 is represented by trifluoromethyl, R2 is hydrogen, and M is NZ in which Z is hydrogen or CH3.
3. A compound according to any one of claims 1, 2 or 4-10 in which A is represented by optionally substituted phenyl, (C1-C6)alkyl, -
C4 alkanol, or ( -C^alkylR6 in which R6 is optionally substituted phenyl.
4. A compound according to any of claims 1, 2, 3, or 5-10 in which B is hydrogen or (C1-C6)alkyl.
5. Use of a compound according to any one of claims 1-4 as a medicine.
6. Use of a compound according to anyone of claims 1-4 in the manufacture of a medicament for inhibiting activation of the androgen receptor.
7. Use of a compound according to anyone claims 1-4 in the manufacture of a medicament for the alleviating a condition selected from the group consisting of alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia.
8. A pharmaceutical composition comprising a compound according to anyone of claims 1-4 in admixture with 1, or more, pharmaceutically acceptable excipients.
9. A topical pharmaceutical formulation comprising a compound according to any one of claims 1-4 in admixture with 1, or more, pharmaceutically acceptable excipients suitable for dermal application.
10. An article of manufacture comprising a compound according to any one of claims 1-4 packaged for retail distribution, which advises a consumer how to utilize the compound to alleviate a condition selected from the group consisting of acne, alopecia, and oily skin.
PCT/IB2004/000856 2003-03-20 2004-03-17 6-sulfonamide quinoline and chromene derivative as androgen receptor antagonists WO2004083204A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP04721256A EP1608643A1 (en) 2003-03-20 2004-03-17 6-sulfonamide quinoline and chromene derivative as androgen receptor antagonists
CA002517446A CA2517446A1 (en) 2003-03-20 2004-03-17 6-sulfonamide quinoline and chromene derivative as androgen receptor antagonists
JP2006506374A JP2006520780A (en) 2003-03-20 2004-03-17 6-sulfonamide derivatives of quinoline and chromene as androgen receptor antagonists
MXPA05009988A MXPA05009988A (en) 2003-03-20 2004-03-17 6-sulfonamide quinoline and chromene derivative as androgen receptor antagonists.
BRPI0408529-9A BRPI0408529A (en) 2003-03-20 2004-03-17 quinoline and chromene 6-sulfonamide derivatives as androgen receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45631603P 2003-03-20 2003-03-20
US60/456,316 2003-03-20

Publications (1)

Publication Number Publication Date
WO2004083204A1 true WO2004083204A1 (en) 2004-09-30

Family

ID=33030093

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/000856 WO2004083204A1 (en) 2003-03-20 2004-03-17 6-sulfonamide quinoline and chromene derivative as androgen receptor antagonists

Country Status (7)

Country Link
US (1) US7009052B2 (en)
EP (1) EP1608643A1 (en)
JP (1) JP2006520780A (en)
BR (1) BRPI0408529A (en)
CA (1) CA2517446A1 (en)
MX (1) MXPA05009988A (en)
WO (1) WO2004083204A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006024741A2 (en) * 2004-07-30 2006-03-09 Palumed S.A. Hybrid qa molecules wherein q is an aminoquinoline and a is an antibiotic residue, their synthesis and their uses as antibacterial agent
FR2874922A1 (en) * 2004-07-30 2006-03-10 Palumed Sa New aminoquinoline-antibiotic hybrids, useful as antibacterials in human and veterinary medicine, disinfectants and in agriculture
US9212182B2 (en) 2013-06-12 2015-12-15 Amgen Inc. Bicyclic sulfonamide compounds as sodium channel inhibitors
WO2016034512A1 (en) * 2014-09-01 2016-03-10 Ucl Business Plc Quinolones as inhibitors of class iv bromodomain proteins
WO2016092326A1 (en) * 2014-12-12 2016-06-16 Cancer Research Technology Limited 2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of parg
CN109793737A (en) * 2017-03-01 2019-05-24 浙江大学 Benzsulfamide structure type androgen receptor antagonists and its application
US10508086B2 (en) 2014-12-19 2019-12-17 Cancer Research Technology Limited PARG inhibitory compounds
WO2023067192A1 (en) * 2021-10-21 2023-04-27 Consejo Superior De Investigaciones Cientificas (Csic) Methods for improving abiotic stress resistance

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006124744A1 (en) * 2005-05-16 2006-11-23 Vertex Pharmaceuticals Incorporated Bicyclic derivatives as modulators of ion channels
KR20090018911A (en) * 2006-05-18 2009-02-24 다우 글로벌 테크놀로지스 인크. Polyurethane-urea polymers derived from cyclohexane dimethanol
US8362142B2 (en) * 2007-12-26 2013-01-29 Dow Global Technologies Llc Polyurethane dispersions and coatings produced therefrom
WO2015109056A1 (en) * 2014-01-17 2015-07-23 The Board Of Trustees Of The Leland Stanford Junior University 6,7-TRANS CEPHALOSPORIN-BASED PROBES FOR DETECTING BACTERIA EXPRESSING A METALLO-β-LACTAMASE

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023038A1 (en) * 1992-05-20 1993-11-25 Merck & Co., Inc. 17-AMINO SUBSTITUTED 4-AZASTEROID 5α-REDUCTASE INHIBITORS
US5494907A (en) * 1993-06-17 1996-02-27 Roussel Uclaf 11-β substituted-19-nor steroids
WO2001016108A2 (en) * 1999-08-27 2001-03-08 Ligand Pharmaceuticals Incorporated Bicyclic androgen and progesterone receptor modulator compounds and methods
WO2001092227A1 (en) * 2000-05-31 2001-12-06 Astrazeneca Ab Chemical compounds
US20030022905A1 (en) * 2000-07-18 2003-01-30 Michael Harter Substituted amidoalkyl-uracils and their use

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6017924A (en) 1996-06-27 2000-01-25 Ligand Pharmaceuticals Incorporated Androgen receptor modulator compounds and methods
AU6941200A (en) 1999-08-27 2001-03-26 Ligand Pharmaceuticals Incorporated 8-substituted-6-trifluoromethyl-9-pyrido(3,2-g)quinoline compounds as androgen receptor modulators
BR0013597A (en) 1999-08-27 2002-07-16 Ligand Pharm Inc Androgen receptor modulating compounds and methods
EP1392434A4 (en) 2001-05-17 2008-07-02 Conocophillips Co Pressure swing catalyst regeneration procedure for fischer-tropsch catalyst

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023038A1 (en) * 1992-05-20 1993-11-25 Merck & Co., Inc. 17-AMINO SUBSTITUTED 4-AZASTEROID 5α-REDUCTASE INHIBITORS
US5494907A (en) * 1993-06-17 1996-02-27 Roussel Uclaf 11-β substituted-19-nor steroids
WO2001016108A2 (en) * 1999-08-27 2001-03-08 Ligand Pharmaceuticals Incorporated Bicyclic androgen and progesterone receptor modulator compounds and methods
WO2001092227A1 (en) * 2000-05-31 2001-12-06 Astrazeneca Ab Chemical compounds
US20030022905A1 (en) * 2000-07-18 2003-01-30 Michael Harter Substituted amidoalkyl-uracils and their use

Non-Patent Citations (32)

* Cited by examiner, † Cited by third party
Title
AFINIDAD , 44(411), 431-3 CODEN: AFINAE; ISSN: 0001-9704, 1987 *
AFINIDAD , 52(456), 133-6 CODEN: AFINAE; ISSN: 0001-9704, 1995 *
AFINIDAD , 52(459), 344-6 CODEN: AFINAE; ISSN: 0001-9704, 1995 *
AFINIDAD , 55(473), 67-71 CODEN: AFINAE; ISSN: 0001-9704, 1998 *
AFINIDAD , 57(487), 217-221 CODEN: AFINAE; ISSN: 0001-9704, 2000 *
ANALYTICAL SCIENCES , 17(4), 539-543 CODEN: ANSCEN; ISSN: 0910-6340, 2001 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ABD EL-ALEEM, ABD EL-ALEEM HASSAN: "Reactions with coumarin-3,6-disulfonyl chloride", XP002283735, retrieved from STN Database accession no. 1995:541056 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ABD EL-BARY, H. ET AL: "Reactions with coumarin. II", XP002283736, retrieved from STN Database accession no. 1995:541055 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ABDEL BARY, HAMED M. ET AL: "Reaction with coumarin. IV", XP002283733, retrieved from STN Database accession no. 1995:1004606 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ABDEL-BARY, HAMED M.: "Reactions with coumarin: synthesis and reactions of coumarin sulfonamides", XP002283731, retrieved from STN Database accession no. 1998:264267 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; AL-KINDY, SALMA M. Z. ET AL: "Fluorescence enhancement of coumarin-6-sulfonyl chloride amino acid derivatives in cyclodextrin media", XP002283729, retrieved from STN Database accession no. 2001:296041 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ALY, F. M. ET AL: "Some reactions with coumarins sulfonyl chloride and their antibacterial activities", XP002283741, retrieved from STN Database accession no. 1988:55829 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BADRAN, M. M. ET AL: "Coumarin derivatives (part II). Synthesis and antimicrobial activity of certain sulfonamide, sulfonylhydrazine and sulfonyl azide derivatives of 4-methyl-7-hydroxycoumarin", XP002283738, retrieved from STN Database accession no. 1994:409227 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; CREMLYN, RICHARD J. ET AL: "The chemistry of sulfonylcoumarin derivatives", XP002283739, retrieved from STN Database accession no. 1989:57464 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; EL-MAGHRABY, A. A. ET AL: "Synthesis of coumarin sulfonamides, sulfonates, and related compounds", XP002283742, retrieved from STN Database accession no. 1986:608723 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; EL-NAGGAR, A. M. ET AL: "Synthesis and antimicrobial activity of some new N-coumarin-6-sulfonyl amino acid and dipeptide derivatives", XP002283740, retrieved from STN Database accession no. 1988:167952 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HAN, YING ET AL: "Synthesis and Bioactivity of Coumarin-6-sulfonylureas", XP002283728, retrieved from STN Database accession no. 2002:811377 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; IBRAHIM, T M. ET AL: "Synthesis and antimicrobial activity of some new 7-methoxy-4-methylcoumarin-6-sulfonylamino acid derivatives", XP002283737, retrieved from STN Database accession no. 1995:136611 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ISLAM, A. M. ET AL: "Synthesis and biological activity of coumarin sulfonamides and related compounds", XP002283743, retrieved from STN Database accession no. 1983:34463 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ISMAIL, I. IMAM ET AL: "Reactions with coumarin. III", XP002283734, retrieved from STN Database accession no. 1995:593518 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ISMAIL, IMAM ET AL: "Reactions with coumarin. V.", XP002283730, retrieved from STN Database accession no. 2000:540400 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MANDOUR, A. H. ET AL: "Synthesis, antimicrobial and antiaflatoxigenic activities of new coumarin derivatives", XP002283732, retrieved from STN Database accession no. 1996:235932 *
EGYPTIAN JOURNAL OF CHEMISTRY , VOLUME DATE 1984, 27(4), 459-69 CODEN: EGJCA3; ISSN: 0367-0422, 1985 *
EGYPTIAN JOURNAL OF PHARMACEUTICAL SCIENCES , 33(5-6), 1081-98 CODEN: EJPSBZ; ISSN: 0301-5068, 1992 *
EGYPTIAN JOURNAL OF PHARMACEUTICAL SCIENCES , 36(1-6), 71-85 CODEN: EJPSBZ; ISSN: 0301-5068, 1995 *
INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY , 21B(5), 487-9 CODEN: IJSBDB; ISSN: 0376-4699, 1982 *
JOURNAL OF THE CHEMICAL SOCIETY OF PAKISTAN , 10(1), 97-104 CODEN: JCSPDF; ISSN: 0253-5106, 1988 *
MODELLING, MEASUREMENT & CONTROL, C: ENERGETICS, CHEMISTRY, EARTH, ENVIRONMENTAL & BIOMEDICAL PROBLEMS , 47(1), 43-8 CODEN: MMCPE5; ISSN: 1259-5977, 1995 *
MODELLING, MEASUREMENT & CONTROL, C: ENERGETICS, CHEMISTRY, EARTH, ENVIRONMENTAL & BIOMEDICAL PROBLEMS , 47(1), 49-54 CODEN: MMCPE5; ISSN: 1259-5977, 1995 *
ORIENTAL JOURNAL OF CHEMISTRY , 3(1), 76-82 CODEN: OJCHEG; ISSN: 0970-020X, 1987 *
PROCEEDINGS OF THE INDIAN NATIONAL SCIENCE ACADEMY, PART A: PHYSICAL SCIENCES , 60(2), 433-9 CODEN: PIPSBD; ISSN: 0370-0046, 1994 *
ZHONGGUO YAOKE DAXUE XUEBAO , 33(2), 93-97 CODEN: ZHYXE9; ISSN: 1000-5048, 2002 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006024741A2 (en) * 2004-07-30 2006-03-09 Palumed S.A. Hybrid qa molecules wherein q is an aminoquinoline and a is an antibiotic residue, their synthesis and their uses as antibacterial agent
FR2874922A1 (en) * 2004-07-30 2006-03-10 Palumed Sa New aminoquinoline-antibiotic hybrids, useful as antibacterials in human and veterinary medicine, disinfectants and in agriculture
WO2006024741A3 (en) * 2004-07-30 2006-06-22 Palumed Sa Hybrid qa molecules wherein q is an aminoquinoline and a is an antibiotic residue, their synthesis and their uses as antibacterial agent
US9458152B2 (en) 2013-06-12 2016-10-04 Amgen Inc. Bicyclic sulfonamide compounds as sodium channel inhibitors
US9212182B2 (en) 2013-06-12 2015-12-15 Amgen Inc. Bicyclic sulfonamide compounds as sodium channel inhibitors
WO2016034512A1 (en) * 2014-09-01 2016-03-10 Ucl Business Plc Quinolones as inhibitors of class iv bromodomain proteins
WO2016092326A1 (en) * 2014-12-12 2016-06-16 Cancer Research Technology Limited 2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of parg
CN107207467A (en) * 2014-12-12 2017-09-26 癌症研究科技有限公司 It is used as the sulfamide derivative of 2,4 dioxo quinazoline 6 of PARG inhibitor
US10239843B2 (en) 2014-12-12 2019-03-26 Cancer Research Technology Limited 2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of PARG
US10508086B2 (en) 2014-12-19 2019-12-17 Cancer Research Technology Limited PARG inhibitory compounds
US10995073B2 (en) 2014-12-19 2021-05-04 Cancer Research Technology Limited PARG inhibitory compounds
CN109793737A (en) * 2017-03-01 2019-05-24 浙江大学 Benzsulfamide structure type androgen receptor antagonists and its application
WO2023067192A1 (en) * 2021-10-21 2023-04-27 Consejo Superior De Investigaciones Cientificas (Csic) Methods for improving abiotic stress resistance

Also Published As

Publication number Publication date
CA2517446A1 (en) 2004-09-30
US7009052B2 (en) 2006-03-07
US20050004367A1 (en) 2005-01-06
JP2006520780A (en) 2006-09-14
BRPI0408529A (en) 2006-03-07
MXPA05009988A (en) 2005-11-04
EP1608643A1 (en) 2005-12-28

Similar Documents

Publication Publication Date Title
EP0934276B1 (en) Anthranilic acid derivatives as multi drug resistance modulators
JP2000256323A (en) 2-oxoquinoline compound and its medicinal use
AU2007311046A1 (en) Quinoline compounds
US7064207B2 (en) Androgen receptor antagonists
US7009052B2 (en) Sulfonamide derivatives
CA2486764A1 (en) Tetrahydroisoquinoline derivatives
CA2617703A1 (en) Androgen modulators
US7098340B2 (en) Benzyl sulfonamide derivatives
US7057048B2 (en) Androgen receptor antagonists
US7074933B2 (en) Urea and thiourea derivatives
US7115745B2 (en) Benzyl urea and thiourea derivatives
WO2023242598A1 (en) Bifunctional molecules for targeted protein degradation
RU2195454C2 (en) Derivatives of anthranilic acid, methods of their synthesis and pharmaceutical composition based on thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2517446

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2005/009988

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2006506374

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2004721256

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2004721256

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0408529

Country of ref document: BR

WWW Wipo information: withdrawn in national office

Ref document number: 2004721256

Country of ref document: EP