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WO2003027107A1 - 3-pyridyl oxazoles substitues, inhibiteurs de la c17,20 lyase - Google Patents

3-pyridyl oxazoles substitues, inhibiteurs de la c17,20 lyase Download PDF

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WO2003027107A1
WO2003027107A1 PCT/US2002/030834 US0230834W WO03027107A1 WO 2003027107 A1 WO2003027107 A1 WO 2003027107A1 US 0230834 W US0230834 W US 0230834W WO 03027107 A1 WO03027107 A1 WO 03027107A1
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alkyl
lyase
compounds
compound
subject
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Barry Hart
Donald Bierer
Chengzhi Zhang
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Bayer AG
Bayer Pharmaceuticals Corp
Bayer Corp
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Bayer AG
Bayer Pharmaceuticals Corp
Bayer Corp
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    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Steroid biosynthesis begins in cells of the adrenal gland where the initial product in sterol biosynthesis, cholesterol, is converted into the adrenal steroid hormones aldosterone, hydrocortisone, and corticosterone by a series of P 450 -mediated hydroxylation steps.
  • the cholesterol side-chain cleavage activity that represents the first step in steroid honnone biosynthesis is a P 450 -mediated oxidation and cleavage of a pair of adjacent methylene groups to two carbonyl fragments, pregnenolone and isocaprylaldehyde (see Walsh (1979) Enzymatic Reaction Mechanisms; W.H. Freeman and Company, pp. 474-77).
  • CYP17 17-alpha- hydroxylase-17,20-lyase
  • P 450 17 17-alpha- hydroxylase-17,20-lyase
  • CYP17 is a bifunctional enzyme which possesses both a C17,20-lyase activity and a C17-hydroxylase activity.
  • these two alternative enzymatic activities of CYP17 result in the formation of critically different intermediates in steroid biosynthesis and each activity appear to be differentially and developmentally regulated (see e.g. l'Allemand et al. (2000) Eur. J. Clin. Invest. 30: 28-33).
  • DHEA dehydroepiandrosterone
  • DHT dihydrotestosterone
  • Estradiol and estrone are key intermediates in the synthesis of not only the androgens testosterone and dihydrotestosterone (DHT), but also the estrogens 17-beta-estradiol and estrone.
  • DHT dihydrotestosterone
  • adrenal and ovarian estrogens are the main sources of estrogens in postmenopausal women (see e.g. Harris et al. (1988) Br. J.
  • the C 17-hydroxylase activity of CYP 17 catalyzes the conversion of the common intermediate progesterone to 17-hydroxyprogesterone, a precursor of cortisol. Therefore the first activity of CYP 17, the Cl 7-hydroxylase activity, promotes the formation of glucocorticoids while the second activity of CYP 17, the C17,20-lyase activity, promotes the formation of sex hormones - particularly androgens including testosterone as well as estrogens.
  • Prostate cancer is currently one of the most frequently diagnosed forms of cancer in men in the U.S. and Europe. Prostate cancer is typically androgen-dependent and, accordingly, the reduction in androgen production via surgical or pharmacological castration remains the major treatment option for this indication. However, complete rather than partial withdrawal of androgens may be more effective in treating prostate cancer (Labrie, F. et al., Prostate, 1983, 4, 579 and Crawford, E.D. et al, N. Engl. J. Med., 1989, 321, 419).
  • CYP17 Pharmacological inhibition of CYP17 may be a promising alternative treatment to antiandrogens and LHRH agonists in that testicular, adrenal, and peripheral androgen biosynthesis would be reduced rather than only testicular androgen production (Njar V, et al., J. Med. Chem., 1998, 41, 902).
  • One such CYP 17 inhibitor, the fungicide ketoconazole has been used previously for prostate cancer treatment (Trachtenberg, J., J. Urol, 1984, 132, 61 and Williams, G. et al., Br. J. UroL, 1986, 58, 45).
  • this drug is a relatively non-selective inhibitor of cytochrome P450 (CYP) enzymes, has weak CYP 17 activity, and has a number of notable side effects associated with it including liver damage (De Coster, R. et al, J. Steroid Biochem. Mol. Biol., 1996, 56, 133 and Lake- Bakaar, G. etal, Br. Med. J., 1987, 294, 419).
  • CYP cytochrome P450
  • ketoconazole In postmenopausal patients with advanced breast cancer, treatment with high doses of ketoconazole resulted in suppression of both testosterone and estradiol levels, implicating CYP17 as a potential target for hormone therapy (Harris, A. L. et al, Br. J. Cancer, 1988, 58, 493).
  • Chemotherapy is usually not highly effective, and is not a practical option for most patients with prostate cancer because of the adverse side effects which are particularly detrimental in older patients.
  • Current treatment by orchidectomy or administration of gonadotropin-releasing honnone (GnRH) agonists results in reduced androgen production by the testis, but does not interfere with androgen synthesis by the adrenals.
  • the invention provides substituted 3-pyridyl oxazole compounds which inhibit the lyase activity of enzymes, e.g., 17 ⁇ -hydroxylase-C 17,20 lyase.
  • Compounds of the invention have the formula
  • R 4 is selected from C 1-6 alkyl, C 3-5 cycloalkyl, CF 3 , and
  • R 5 is H or C 1-4 alkyl; and m is 0, 1, or 2; or
  • R 3 is other than a pyridyl or an N-oxide-containing group
  • R 6 is selected from C 1-4 alkyl, CF 3 , OCHF 2 , CN, NO 2 , and halogen; and n is 0, 1, or 2.
  • R 2 represents H, C 1-6 alkyl, halogen, or tolyl.
  • R 7 is selected from the group consisting of
  • R 8 is H or C 1-4 alkyl, and p is O, 1, or 2;
  • R 1 is other than a pyridyl or an N-oxide-containing group
  • R 1 and R 3 are a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • Pharmaceutically acceptable salts of these compounds are also within the scope of the invention.
  • the invention also provides pharmaceutical compositions for inhibiting lyase activity, comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the invention also provides methods for inhibiting lyases, comprising contacting the lyase with a compound of the invention. More particularly, the invention provides a method of inhibiting a 17 ⁇ -hydroxylase-C 17,20 lyase, comprising contacting a 17 ⁇ - hydroxylase-C 17,20 lyase with a compound of the invention.
  • the invention further provides methods for treating diseases which can benefit from an inhibition of a lyase enzyme.
  • diseases are lyase-associated diseases, e.g., diseases resulting from an excess of androgens or estrogens.
  • the invention provides a method for treating cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the invention, such that the cancer is treated.
  • the method of treatment may be applied where the subject is equine, canine, feline, or a primate, in particular, a human.
  • the cancer may, for example, be prostate or breast cancer.
  • a method for treating prostate cancer in a subject comprises administering to the subject a therapeutically effective amount of a compound of the invention, such that the prostate cancer in the subject is treated.
  • a method for treating breast cancer in a subject comprises administering to the subject a therapeutically effective amount of a compound of the invention, such that the breast cancer in the subject is treated.
  • the invention is based at least in part on the discovery that substituted 3-pyridyl oxazole compounds inhibit the enzyme 17 ⁇ -hydroxylase-C 17,20 lyase.
  • compounds of the invention have the formula in which R 1 represents
  • R 4 is selected from G -6 alkyl, C3-5 cycloalkyl, CF3 ; and m is 0, 1, or 2; or
  • R 3 is other than a pyridyl or an N-oxide-containing group
  • R ⁇ n i n which R 6 is selected from C 1-4 alkyl, CF 3 , OCHF 2 , and halogen; and n is 0, 1, or 2.
  • R 2 represents H, C 1-6 alkyl, halogen, or tolyl.
  • R 3 represent
  • R 7 is selected from the group consisting of C 1-4 alkyl
  • R 9 is C 1-4 alkyl or C 3-5 cycloalkyl, and s is 0, 1, or 2; or
  • R 1 is other than a pyridyl or an N-oxide-containing group.
  • R 1 and R 3 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • R 4 is selected from C ⁇ -6 alkyl and C3-5 cycloalkyl; and m is 0, 1, or 2; or
  • R 2 represents H.
  • R 3 represents
  • R 7 is selected from the group consisting of
  • R 1 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • compounds of the invention have the formula in which R 1 represents r ? ⁇ " — (R ⁇ n in which R 6 is selected from CF 3 , OCHF2, and halogen; and n is 0, 1, or 2.
  • R 2 represents H.
  • R 3 represents
  • R is C 1-4 alkyl or C 3-5 cycloalkyl, and s is O, l, or 2; or
  • R 3 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • agonist of an enzyme refers to a compound that binds to the enzyme and stimulates the action of the naturally occurring enzyme, or a compound which mimics the activity of the naturally occurring enzyme.
  • antagonist of an enzyme refers to a compound that binds to the enzyme and inhibits the action of the naturally occurring enzyme.
  • CYP 17 substrate includes any of the various steroid honnones acted upon by a CYP 17 or a CYP17-like P 50 enzyme. Examples include pregnenolone, progesterone and their 17 ⁇ -hydroxylated forms. Pregnenolone is converted to DHEA via a CYP 17 C 17,20-lyase reaction, but is also subj ect to C 17 ⁇ -hydroxylation via the C 17,20- lyase activity.
  • Progesterone is converted to delta 4- androstenedione via a CYP 17 Cl 7,20- lyase reaction, but is also subject to C17 alpha-hydroxylation via the Cl 7-hydroxylase activity to form 17-hydroxyl-progesterone, a precursor to hydrocortisone (i.e. cortisol).
  • CYP 17 metabolite refers to any of the steroid hormones that are synthesized from a cholesterol precursor via a CYP17-mediated reaction, such as a C17- hydroxylase reaction or a Cl 7,20-lyase reaction.
  • CYP 17 metabolites include the androgens, such as testosterone, which are synthesized via a CYP 17 Cl 7,20-lyase reaction from CYP 17 substrate precursors such as pregnenolone (converted to DHEA by the CYP 17 Cl 7,20-lyase activity), and progesterone (converted to delta 4- androstenedione by the CYP17 C17,20-lyase activity).
  • Progestagens such as progesterone are primarily synthesized in the co ⁇ us luteum.
  • the androgens are responsible for, among other things, development of male secondary sex characteristics and are primarily synthesized in the testis.
  • Other examples include the estrogens, which are also synthesized from a cholesterol precursor via a CYP17-mediated reaction.
  • the estrogens are responsible for, among other things, the development of female secondary sex characteristics and they also participate in the ovarian cycle and are primarily synthesized in the ovary.
  • Another group of CYP 17 metabolites are the glucocorticoids, such as hydrocortisone (i.e. cortisol), which is synthesized from progesterone via a CYP 17- mediated reaction.
  • the glucocorticoids among other functions, promote gluconeogenesis and the fomiation of glycogen and also enhance the degradation of fat.
  • the glucocorticoids are primarily synthesized in the adrenal cortex.
  • CYP 17 metabolite is further meant to include other steroid hormones which, although not necessarily synthesized by a CYP17-mediated reaction, may nonetheless be understood by the skilled artisan to be readily affected by an alteration in a CYP17-mediated activity.
  • the mineralocorticoids such as aldosterone
  • progesterone is also converted to the glucocorticoids and sex steroids via CYP17-mediated reactions
  • an alteration of a CYP 17 activity can alter the amount of progesterone available for conversion to aldosterone.
  • inhibition of CYP 17 activity can increase the amount of progesterone available for conversion into aldosterone.
  • the mineralocorticoids function, among other things, to increase reabso ⁇ tion of sodium ions, chloride ions, and bicarbonate ions by the kidney, which leads to an increase in blood volume and blood pressure.
  • the mineralocorticoids are primarily synthesized in the adrenal cortex.
  • CYP 17 metabolite-associated disease or disorder refers to a disease or disorder which maybe treated by alteration of the level of one or more CYP 17 metabolites.
  • examples include a hormone dependent cancer, such as an androgen- dependent prostate cancer, which maybe treated by inhibiting CYP17-mediated androgen synthesis, and an estrogen-dependent breast cancer or ovarian cancer, which may be treated by inhibiting CYP 17-mediated estrogen synthesis.
  • hormone dependent cancer such as an androgen- dependent prostate cancer, which maybe treated by inhibiting CYP17-mediated androgen synthesis
  • an estrogen-dependent breast cancer or ovarian cancer which may be treated by inhibiting CYP 17-mediated estrogen synthesis.
  • Other examples of "CYP 17 metabolite-associated diseases or disorders” are Gushing' s disease, hypertension, prostatic hype ⁇ lasia, and glucocorticoid deficiency.
  • Disease associated with an abnormal activity or level of a lyase refers to diseases in which an abnormal activity or protein level of a lyase is present in certain cells, and in which the abnormal activity or protein level of the lyase is at least partly responsible for the disease.
  • a "disease associated with a lyase” refers to a disease that can be treated with a lyase inhibitor, such as the compounds disclosed herein.
  • a “lyase” refers to an enzyme having a lyase activity.
  • Lyase activity refers to the activity of an enzyme to catalyze the cleavage of the bond C17-C20 in 17 ⁇ -hydroxy-pregnenolone and 17 ⁇ -hydroxy-progesterone to form dehydroepiandrosterone (DHEA) and delta4-androstenedione, respectively. Lyase activity also refers to the cleavage of a similar bond in related compounds.
  • a “lyase inhibitor” is a compound which inhibits at least part of the activity of a lyase in a cell.
  • the inhibition can be at least about 20%, preferably at least about 40%, even more preferably at least about 50%, 70%, 80%, 90%, 95%, and most preferably at least about 98% of the activity of the lyase.
  • a "patient” or “subject” to be treated by the subject method can mean either a human or non-human animal.
  • Treating refers to preventing, curing or improving at least one symptom of a disease.
  • the following definitions pertain to the chemical structure of compounds:
  • heteroatom as used herein means an atom of nitrogen, oxygen, or sulfur.
  • alkyl refers to the radicals of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups.
  • cycloalkyl (alicyclic) refers to radicals of cycloalkyl compounds, examples being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups that contain at least one double or triple bond respectively.
  • lower alkyl as used herein means an alkyl group but having from one to six carbons, preferably from one to four carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls.
  • aryl as used herein means an aromatic group of 6 to 14 carbon atoms in the ring(s), for example, phenyl and naphthyl. As indicated, the term “aryl” includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic.
  • heteroaryl as used herein means an aromatic group which contains at least one heteroatom in at least one ring. Typical examples include 5-, 6- and 7-membered single-ring aromatic groups that may include from one to four heteroatoms. Examples include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups may also be referred to as "aryl heterocycles” or “heteroaromatics.”
  • ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively.
  • 1,2-dimethylbenzene and ort/zo-dimethylbenzene are synonymous.
  • alkoxyl or "alkoxy” as used herein refer to moiety in which an alkyl group is bonded to an oxygen atom, which is in turn bonded to the rest of the molecule. Examples are methoxy, ethoxy, propyloxy, tert-butoxy, etc.
  • nitro means -NO2; the tenn "halogen” designates -F,
  • sulfhydryl means -SH
  • hydroxyl means -OH
  • sulfonyl means -SO2-.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, / -toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p- toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, ⁇ -toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; see for example, 2002, 67(1), 24A. The abbreviations contained in said list are hereby inco ⁇ orated by reference.
  • each expression e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 rd ed.; Wiley: New York, 1999).
  • the present invention is directed to compounds which inhibit 17 ⁇ -hydroxylase- C17,20-lyase.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and tra/w-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivatizaton with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • compositions of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra).
  • Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., functioning as 17 ⁇ -hydroxylase-Cl 7,20-lyase inhibitors), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding to 17 ⁇ -hydroxylase-Cl 7,20-lyase receptors.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes given below, by the Examples, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • the present invention provides a method of inhibiting a lyase, e.g., 17 ⁇ - hydroxylase-C 17,20 lyase, comprising contacting a lyase with a compound of the invention.
  • the activity can be inhibited by at least 20%, preferably at least about 50%, more preferably at least about 60%, 70%, 80%, 90%, 95%, and most preferably at least about 98%.
  • the invention provides a method for inhibiting a lyase in vitro.
  • the lyase is in vivo or ex vivo.
  • the invention provides methods for inhibiting a lyase in a cell, comprising contacting the cell with a compound of the invention, such that the activity of the lyase is inhibited.
  • the cell may further be contacted with a composition stimulating the uptake of the compound into the cell, e.g., liposomes.
  • the invention provides a method for inhibiting a lyase in a cell of a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a formulation comprising a compound of the present invention, such that the lyase is inhibited in a cell of the subject.
  • the subject can be one having a disease associated with a lyase, e.g., cancer.
  • Types of cancer that can be treated according to the invention preferably include prostate cancer and breast cancer.
  • Other diseases that can be treated include diseases in which it is desired to prevent or inhibit the formation of a hormone selected from the group consisting of the androgens testosterone and dihydrotestosterone (DHT) and the estrogens 17 ⁇ -estradiol and estrone.
  • DHT dihydrotestosterone
  • any disease that can be treated by inhibiting the activity of a lyase e.g., 17 ⁇ -hydroxylase-C 17,20-lyase, can be treated with the compounds of the invention.
  • the invention provides methods and compositions for the treatment of CYP 17 metabolite-associated diseases and disorders.
  • CYP 17 metabolite-associated diseases and disorders include particularly sex steroid hormone dependent cancers, such as androgen-dependent prostate cancer, which may be treated by inhibiting CYP 17-mediated androgen synthesis, and estrogen-dependent breast cancer or ovarian cancer, which may be treated by inhibiting CYP 17-mediated estrogen synthesis.
  • adeno carcinoma of the prostate is a common disease that causes significant morbidity and mortality in the adult male population (see Han and Nelson (2000) Expert Opin. Pharmacother. 1 : 443-9).
  • Hormonal therapy for prostate cancer is considered when a patient fails with initial curative therapy, such as radical prostatectomy or definitive radiation therapy, or if he is found with an advanced disease.
  • Hormonal agents have been developed to exploit the fact that prostate cancer growth is dependent on androgen.
  • Non-steroidal anti-androgens (NSAAs) block androgen at the cellular level. Castration is another, albeit drastic means of decreasing androgens levels in order to treat or prevent prostate cancer.
  • the methods and compositions of the invention are useful in inhibiting the Cl 7,20-lyase activity of CYP 17 and thereby decreasing levels of androgen production and the associated growth of androgen-dependent cancers such as prostate cancer.
  • breast cancer in postmenopausal women, can be treated by administration of a Cl 7,20-lyase inhibitor of the invention because adrenal and ovarian androgens are the main precursors of the estrogens which stimulate the growth of hormone dependent breast cancer.
  • breast cancer can be treated with inhibitors of aromatase that prevent interconversion of estrogens and adrenal and ovarian androgens (see Harris et al. (1983) Eur. J. Cancer Clin. Oncol. 19: 11). Patients failing to respond to aromatase inhibitors show elevated levels of androgens in response to aromatase inhibitor treatment (see Harris et al. (1988) Br. J. Cancer 58: 493- 6).
  • the inhibitors of the invention may be used alone or in combination with other drugs to treat or prevent hormone-dependent cancers such as breast and prostate cancer.
  • susceptibility to prostate cancer and breast cancer has been associated with particular polymo ⁇ hic alleles of the CYP 17 gene (see e.g. McKean-Cowdin (2001) Cancer Res. 61: 848-9; Haiman et al. (2001) Cancer Epidmeiol. Biomarkers 10: 743-8; Huang et al. (2001) Cancer Res. 59: 4870-5).
  • the compositions of the invention are particularly suited to treating or preventing hormone-dependent cancers in individuals genetically predisposed to such cancers, particularly those predisposed due to an alteration in the CYP 17 gene.
  • CYP 17 metabolite-associated diseases or disorders amenable to treatment with the compositions and methods of the invention include those associated with mineralocorticoid excess such as hypertension caused by sodium retention at renal tubules. Such a mechanism operates in hypertension such as primary hyperaldosteronism and some forms of congenital adrenal hype ⁇ lasia. Recently, deficient cortisol metabolism in the aldosterone target organ has been recognized as a novel form of hypertension known as apparent mineralocorticoid excess.
  • Disorders associated with mineralocorticoid synthesis include abnormalities of mineralocorticoid synthesis and/or metabolism which profoundly affect the regulation of electrolyte and water balance and of blood pressure (see e.g. Cormell et al.
  • Mineralocorticoid excess may be caused by aldosterone or 11 -deoxycorticosterone by inadequate conversion of cortisol to cortisone by 11 ⁇ - hydroxysteroid dehydrogenase type 2 in target tissues, by glucocorticoid receptor deficiency or by constitutive activation of renal sodium channels. Changes in electrolyte balance and renin as well as the abnormal pattern of corticosteroid metabolism are usually diagnostic. Where these abnonnalities are inherited (e.g.
  • glucocorticoid remediable hyperaldosteronism (GRA), receptor defects, Liddle's syndrome), the molecular basis is again usually known and, in some cases, may provide the simplest diagnostic tests.
  • GAA glucocorticoid remediable hyperaldosteronism
  • Primary aldosteronism although readily identifiable, presents problems of differential diagnosis, important because optimal treatment is different for each variant.
  • a significant proportion of patients with essential hypertension show characteristics of mild mineralocorticoid excess, for example low renin levels.
  • a decrease in CYP 17 activity can result in an alteration in mineralorticoid (e.g. aldosterone) biosynthesis.
  • CYP 17 metabolite-associated diseases or disorders would include those associated with altered levels of aldosterone production (e.g. hypertension, primary adrenal hype ⁇ lasia). Still other examples of CYP 17 metabolite-associated diseases or disorders" are
  • Gushing' s disease Gushing' s disease, prostatic hype ⁇ lasia, glucocorticoid deficiency, and endometrial cancer.
  • the subject that can be treated according to the invention can be a mammal, e.g., a primate, equine, canine, bovine, ovine, porcine, or feline.
  • the mammal is a human
  • the invention provides methods for inhibiting the lyase activity of enzymes that are present in organisms other than mammals, e.g., yeast and fungus, e.g., mildew.
  • Certain compounds of the invention may function as antifungal compounds.
  • the therapeutic methods of the invention generally comprise administering to a subject in need thereof, a pharmaceutically effective amount of a compound of the invention, or a salt, prodrug or composition thereof.
  • the compounds of the invention can be administered in an amount effective to inhibit the activity of a 17 ⁇ -hydroxylase- Cl 7,20-lyase.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, mtraperitoneal, subcutaneous, rectal and topical routes of administration.
  • Toxicity and therapeutic efficacy of the compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 5 o.
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such reagents to the site of affected tissue in order to minimize potential damage to normal cells and, thereby, reduce side effects.
  • Data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be fonnulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of activity) as determined in cell culture.
  • IC 50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of activity
  • the compounds of the invention have an IC 50 less than 10 ⁇ M as determined by the biochemical or cellular assay described herein. Some compounds of the invention are effective at concentrations of 10 nM, 100 nM, or 1 ⁇ M. Based on these numbers, it is possible to derive an appropriate dosage for administration to subjects.
  • prodrugs are well known in the art in order to enhance the properties of the parent compound. Such properties include solubility, abso ⁇ tion, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al, publ. by Williams & Wilkins, pgs. 27-29, (1995)).
  • prodrugs of the disclosed compounds can be designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention.
  • compositions can be prepared so that they may be administered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally.
  • Dermal administration includes topical application or transdermal administration.
  • Parenteral administration includes intravenous, intraarticular, intramuscular, mtraperitoneal, and subcutaneous injections, as well as use of infusion techniques.
  • One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition.
  • These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition), Managing Editor, John E. Hoover, Mack Publishing Co., (1970) or Pharmaceutical Dosage Form and Drug Delivery Systems (Sixth Edition), edited by Ansel et al, publ. by Williams & Wilkins, (1995).
  • compositions containing a compound of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically acceptable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherem the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin; or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate; or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol; or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compound of the invention in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Pharmaceutical compositions of the invention may also be in the form of an oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • phrases maybe in the form of a sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • Sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the compound of the invention is dissolved in the oily phase.
  • the active ingredient maybe first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the active compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this pu ⁇ ose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions of the invention may also be administered in the form of a suppository for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the invention can be employed.
  • topical application shall include mouth washes and gargles.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will preferably be continuous rather than intermittent throughout the dosage regimen.
  • the compounds of the invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the compounds may be administered simultaneously or sequentially.
  • the active compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • the active compounds may be useful in combination with agents that are effective in the treatment and prevention of osteoporosis, inflammation, neurofibromatosis, restinosis, and viral infections.
  • the active compounds may also be useful in combination with inhibitors of other components of signaling pathways of cell surface growth factor receptors.
  • Drugs that can be co-administered to a subject being treated with a compound of the invention include antineoplastic agents selected from vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, or amsacrine.
  • antineoplastic agents selected from vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, or amsacrine.
  • Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described
  • Radiation therapy including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with a compound of the invention to treat a disease, e.g., cancer.
  • a disease e.g., cancer.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • Kits of the invention In one embodiment, a compound of the invention, materials and/or reagents required for administering the compounds of the invention may be assembled together in a kit.
  • the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being particularly preferred.
  • the kit may further comprise one or more other drugs, e.g., a chemo- or radiotherapeutic agent.
  • drugs e.g., a chemo- or radiotherapeutic agent.
  • the container means may itself be geared for administration, such as an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the formulation may be applied to an infected area of the body, such as the lungs, or injected into an animal, or even applied to and mixed with the other components of the kit.
  • kits also maybe provided in dried or lyophilized forms.
  • reagents or components are provided as a dried form, reconstitution generally is by the addition of a suitable solvent. It is envisioned that the solvent also may be provided in another container means.
  • the kits of the invention may also include an instruction sheet defining administration of the agent. Kits may also comprise a compound of the invention, labeled for detecting lyases.
  • kits of the present invention also will typically include a means for containing the vials in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.
  • a means for containing the vials in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.
  • the kits of the invention also may comprise, or be packaged with a separate instrument for assisting with the injection/administration or placement of the ultimate complex composition within the body of an animal.
  • a separate instrument for assisting with the injection/administration or placement of the ultimate complex composition within the body of an animal.
  • Such an instrument may be an inhalant, syringe, pipette, forceps, measured spoon, eye dropper or any such medically approved delivery vehicle.
  • Other instrumentation includes devices that permit the reading or monitoring of reactions or amounts of compounds or polypeptides.
  • C 17,20 Lyase inhibitory activity of compounds can be determined using, e.g., the biochemical or the cellular assays set forth in the Examples. A person of skill in the art will recognize that variants of these assays can also be used.
  • the compounds of the invention can also be tested in animal models, e.g., animal models of prostate or breast cancer.
  • Each of the compounds of the invention was subjected to a biochemical assay and a cellular assay for determining its C 17,20 lyase inhibitory activity.
  • Recombinant human Cl 7,20-lyase (hLyase) was expressed in baculovirus-infected Sf9 cells and hLyase enriched microsomes were prepared from cultures as described (Barnes H. J.; Jenkins, C. M.; Waterman, M. R. Archives of Biochemistry and Biophysics 1994, 315(2), 489-494).
  • Recombinant murine Cl 7,20-lyase (mLyase) was prepared in a similar manner.
  • hLyase and mLyase preparations were titrated using assay conditions to determine protein concentrations to be used for assays. Both mLyase and hLyase assays were run in an identical manner except that cytochrome b5 was omitted in the murine assay.
  • Test compound solutions (20 mM in DMSO) were diluted 1 :4 with DMSO and put into the top well of a 96-well mother plate. These solutions were then diluted serially in six steps (1:4 each step) with DMSO to obtain 800 ⁇ M to 51.2 nM concentrations on a mother plate (columns 3-12) for subsequent use in the assay. These compound solutions were further diluted twenty- fold in water to obtain a daughter plate containing compound concentrations ranging from 40 ⁇ M to 2.56 nM in 5% DMSO. The first 2 columns (of wells) on each 96-well mother plate were used for the DHEA (dehydroepiandrosterone) standard curve. DHEA standards were serially diluted (in half-logs) in DMSO to obtain
  • reaction mixture clear-bottomed opaque 96-well assay plates were loaded with 50 ⁇ L of assay buffer (50 mM Na PO 4 , pH 7.5), 5 ⁇ L of the diluted compounds (or standards), and 30 ⁇ L of substrate solutions (7 mM NADPH, 3.35 ⁇ M 17- OH-pregnenolone, 3.35 ⁇ g/mL human cytochrome b 5 in 50 mM Na PO 4 ). Reactions were initiated with the addition of hLyase or mLyase in assay buffer (10 ⁇ L). Enzymatic reactions were incubated at room temperature for 2 hours with gentle agitation.
  • YM116 a potent Cl 7,20-lyase inhibitor.
  • concentration of DHEA generated by hLyase (or mLyase) was determined by radioimmunoassay (RIA).
  • RIA utilized a 3 H-DHEA (0.08 ⁇ Ci) tracer in 50 ⁇ L of scintillation proximity assay (SPA) buffer (100 mM Tris-HCl, pH 7.5, 50 mM NaCl, 0.5% BSA, 0.2% Tween 20) which was added to each well.
  • SPA scintillation proximity assay
  • DHEA antiserum from rabbit (50 ⁇ L) with anti-rabbit SPA beads in SPA buffer was added to all wells. Mixtures were allowed to equilibrate with gentle agitation for 1 hour followed by overnight equilibration with no agitation. 3 H-DHEA bound to the SPA beads was determined by scintillation counting with a Wallac microbeta counter. The concentration of DHEA generated was calculated from raw data (CPM) and the standard curve. The concentration of DHEA formed in the presence of test compounds was expressed as a percent inhibition compared to the DHEA concentration in the absence of test compounds: [1 - (nM DHEA formed in the presence of test compound/nM DHEA formed in the absence of test compounds)] x 100. Determination of IC 50 for each compound was performed using the Analyze 5 program.
  • Human 07,20-lyase cellular assay Human HEK 293-lyase stable transfectant cells were seeded in a 96-well plate at
  • Test compounds (columns 3-12), DMSO vehicle (column 2), or DHEA standards (column 1) of 5 ⁇ L each were added to the cell plate and incubated for 10 min. at room temperature. The final concentrations of DHEA standards were 750, 250, 83.3, 27.7, 9.2, 3, 1, and 0.3 nM.
  • the reaction was initiated with 10 ⁇ L of 5 ⁇ M 17-OH-pregnenolone being added to all the wells of the cell plate, then incubated for 1 hour at 37°C. Following the incubation, 90 ⁇ L of media (containing DHEA product) was removed from the cell plate and transferred to the SPA assay plate. The subsequent SPA procedure for the detection of DHEA product was performed in the same manner as described for the enzyme assay (see above). The mother plate of test compounds was also prepared in the same manner as the enzyme assay. However, the highest concentration of compounds on the daughter plate was 200 ⁇ M rather than 40 ⁇ M, such that the highest dose of compound tested was 10 ⁇ M in final concentration (cellular assay) rather than 2 ⁇ M (biochemical assay).
  • Reagents for the SPA assay were obtained from the following sources: 3 H-DHEA: NEN (NET814), Anti-DHEA: Endocrine Sciences (D7-421), Anti- Rabbit SPA Beads: Amersham (RPNQ 0016), 17-OH- ⁇ regnenolone: Steraloids (Q4710), NADPH: Sigma (N1630), Cytochrome b5: Panvera (P2252), DHEA (500 ⁇ M stock in 100% EtOH), BSA: Sigma (A9647).
  • test compound was considered to be active if the IC 50 in the human C 17,20 biochemical assay or in the human C 17,20 cellular assay was less than 10 ⁇ M. All the compounds tested have IC 50 in the human C 17,20 biochemical assay or the human C 17,20 cellular assay of less than 10 ⁇ M.
  • the eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonirile with 0.02% TFA. Gradient elution from 10% B to 95% B over 3.5 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
  • Pyridine-3,4-dicarboxylic acid 4-methyl ester is obtained by conditions described in Moore, B., McLaughlin, R.; Urban, F., Young, G. Organic Preparations and Procedures, International, Vol. 28, No. 3, 1996, 360.
  • Method B The syntheses of compounds of the formula Nil are exemplified by the synthesis of 3-[4-(3-Bromo-phenyl)-oxazole-2-yl]-4-methyl-pyridine, example 1.
  • 3-Bromophenacyl bromide (5.0 g, 18 mmol) was added to a stirred suspension 4-methyl nicotinic acid hydrochloride, C (3.1 g, 18 mmol) and potassium carbonate (5.0 g, 36 mmol) in ⁇ , ⁇ -dimethylforamide (30 mL). The resulting mixture was heated at 55°C for 1 hour. After cooling to ambient temperature, water was added. The aqueous layer was extracted with Ethyl Acetate (3x). The combined organic layers were dried (MgSO 4 ), and concentrated.
  • Analytical HPLC were obtained using a Gilson HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (50 x 4.6 mm, 12 ⁇ m).
  • the eluents were A: acetonitrile w/0.1% TFA and B: H 2 O w/0.1% TFA.
  • Gradient elution from 10% B to 90% over 4 min at a flowrate of 4.0 mL/min was used with an initial hold of 0.5 min and a final hold at 90% B of 0.5 minutes. Total run time was 5 min.
  • nictinic acid chlorides of formula IX are prepared by treating nictinic acids of formula NIII with oxalyl chloride and DMF.
  • Step 1 A suspension of NaN 3 (0.234 g, 3.6 mmol), 4-chlorophenacyl bromide, G (0.700 g, 3.0 mmol, commercially available) in DMSO (10 ml) was stirred at ambient temperature for 1 hour. The mixture was poured into ice water (100 ml) and was extracted with Et 2 O (2 x 60 ml). The combined organic layers were dried (MgSO 4 ), and evaporated to crude intermediate, 2-azido-l-(4-chloro-phenyl)-ethanone (0.501 g).
  • Step 2 Nicotinoyl chloride hydrochloride (0.141 g, 0.79 mmol) was added to a solution of crude intermediate, 2-azido-l-(4-chloro-phenyl)-ethanone (0.155 g, 0.79 mmol), triphenylphosphine (0.355 g, 1.35 mmol) in toluene (20 ml). The resulting suspension was stirred at ambient temperature for 12 hours. The mixture was filtered and the solid was washed with toluene.
  • the oxazoles of formula XIN were prepared by the reaction described in general method E.
  • a 3-[4-phenyl)-oxazol-2-yl]-4-methyl-pyridine, XIII (prepared by General Method B) is reacted with a base (e.g. LDA) and an alkyl iodide (generally commercially available) to afford oxazoles of the fonnula XIV.
  • a base e.g. LDA
  • an alkyl iodide generally commercially available
  • Method E The synthesis of oxazole derivatives of the formula XIN are exemplified by the synthesis of 4-butyl-3-[4-(4-fluorophenyl)-l,3-oxazol-2-yl]pyridine, example 50, 3-[4- (4-fluorophenyl)-5-propyl-l,3-oxazol-2-yl]-4-methylpyridine, example 51, and 3-[4-(4- fluorophenyl)-5-iodo-l,3-oxazol-2-yl]-4-methylpyridine, example 52.
  • Analytical HPLC were obtained using a Gilson HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (50 x 4.6 mm, 12 ⁇ m).
  • the eluents were A: acetonitrile w/0.1% TFA and B: H 2 O w/0.1% TFA.
  • Gradient elution from 10% B to 90% over 4 min at a flowrate of 4.0 mL/min was used with an initial hold of 0.5 min and a final hold at 90% B of 0.5 minutes. Total run time was 5 min.
  • the exemplary compounds 50 - 52 are named as shown in Table 6.
  • the alpha-halo ketones of the formula XVII are prepared by converting ketones, generally commercially available, of the formula XV to the hydrochloride salt of the formula XVI.
  • the hydrochloride salt of the formula XVI is treated with N-halo succinamide to afford the alpha-halo ketones of the formula XVII.
  • Method F The syntheses of alpha-halo ketones of the formula XVII are exemplified by the synthesis 2-chloro-l-(3-pyridyl)ethan-l-one, hydrochloride, L.
  • Method G The syntheses of oxazoles of the formula XXI are exemplified by the synthesis of 3-[2-(4-Chloro-phenyl)-oxazol-4-yl]-4-methyl-pyridine, example 53.
  • Example 53 Preparation of 3-[2-(4-Chloro-phenyl)-oxazol-4-yl]-4-methyl- pyridine.
  • Step 2 To a mixture of 4-chloro-benzoic acid 2-(4-methyl-pyridin-3-yl)-2-oxo-ethyl ester (0.5 g, 1.54 mmol) and acetamide (0.46 g, 7.8 mmol) in ⁇ -xylene (20 mL), BF 3 etherate (0.44 mL, 3.1 mmol) was added. The mixture was heated to reflux for 18 hours. After cooling to ambient temperature, NaHCO 3 aqueous was added. The aqueous layer was extracted with EtOAc (3x), and combined organic layers were dried with magnesium sulfate and concentrated.
  • the exemplary compounds 54 -61 are named as shown in Table 8.

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Abstract

L'invention porte sur des 3-pyridyl oxazoles substitués inhibiteurs de la C17, 20 lyase, sur des préparations pharmaceutiques les contenant, et sur leur méthodes d'utilisation pour le traitement du cancer.
PCT/US2002/030834 2001-09-26 2002-09-26 3-pyridyl oxazoles substitues, inhibiteurs de la c17,20 lyase Ceased WO2003027107A1 (fr)

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PCT/US2002/030979 Ceased WO2003027101A1 (fr) 2001-09-26 2002-09-26 3-pyridyl pyrroles et 3-pyridyl pyrazoles substitues en tant qu'inhibiteurs de la lyase c17,20
PCT/US2002/030981 Ceased WO2003027105A1 (fr) 2001-09-26 2002-09-26 3-pyridyl thiophenes substitues en tant qu'inhibiteurs de la lyase c17,20
PCT/US2002/030482 Ceased WO2003027094A2 (fr) 2001-09-26 2002-09-26 3-pyridyl indoles et indazoles substitues servant d'inhibiteurs de c17,20 lyase
PCT/US2002/030983 Ceased WO2003027096A1 (fr) 2001-09-26 2002-09-26 3-pyridyl imidazoles substitues en tant qu'inhibiteurs de la lyase c17,20
PCT/US2002/030483 Ceased WO2003027085A2 (fr) 2001-09-26 2002-09-26 Thiazoles 3-pyridyle ou 4-isoquinolinyle utilises comme inhibiteurs de lyase c17,20
PCT/US2002/030834 Ceased WO2003027107A1 (fr) 2001-09-26 2002-09-26 3-pyridyl oxazoles substitues, inhibiteurs de la c17,20 lyase
PCT/US2002/030982 Ceased WO2003027095A1 (fr) 2001-09-26 2002-09-26 3-pyridyl tetrazoles substitues en tant qu'inhibiteurs de la lyase c17,20 de la steroide
PCT/US2002/030924 Ceased WO2003027100A1 (fr) 2001-09-26 2002-09-26 Inhibiteurs de lyase c17,20 a base de 3-pyridyle-pyrimidine substituee

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PCT/US2002/030981 Ceased WO2003027105A1 (fr) 2001-09-26 2002-09-26 3-pyridyl thiophenes substitues en tant qu'inhibiteurs de la lyase c17,20
PCT/US2002/030482 Ceased WO2003027094A2 (fr) 2001-09-26 2002-09-26 3-pyridyl indoles et indazoles substitues servant d'inhibiteurs de c17,20 lyase
PCT/US2002/030983 Ceased WO2003027096A1 (fr) 2001-09-26 2002-09-26 3-pyridyl imidazoles substitues en tant qu'inhibiteurs de la lyase c17,20
PCT/US2002/030483 Ceased WO2003027085A2 (fr) 2001-09-26 2002-09-26 Thiazoles 3-pyridyle ou 4-isoquinolinyle utilises comme inhibiteurs de lyase c17,20

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Cited By (11)

* Cited by examiner, † Cited by third party
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Families Citing this family (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE440096T1 (de) * 2000-12-08 2009-09-15 Takeda Pharmaceutical Substituierte thiazolderivate mit 3- pyridylgruppen, verfahren zu deren herstellung und deren verwendung
JP4160295B2 (ja) * 2000-12-08 2008-10-01 武田薬品工業株式会社 ３−ピリジル基を有する置換チアゾール誘導体、その製造法および用途
US20040147561A1 (en) * 2002-12-27 2004-07-29 Wenge Zhong Pyrid-2-one derivatives and methods of use
CA2525547C (fr) * 2003-05-14 2012-07-03 Torreypines Therapeutics, Inc. Composes et leurs utilisations pour la modulation de l'amyloide-beta
ES2222827B1 (es) * 2003-07-30 2006-03-01 Laboratorios Del Dr. Esteve, S.A. Derivados de 5-indolilsulfonamidas, su preparacion y su aplicacion como medicamentos.
CA2545719A1 (fr) * 2003-11-14 2005-06-02 Vertex Pharmaceuticals Incorporated Thiazoles et oxazoles utiles en tant que modulateurs de transporteurs de type cassette de liaison a l'atp
AU2005232745A1 (en) 2004-04-13 2005-10-27 Astellas Pharma Inc. Polycyclic pyrimidines as potassium ion channel modulators
JP4602686B2 (ja) * 2004-04-15 2010-12-22 広栄化学工業株式会社 ２，６−ジハロゲノ−４−アリールピリジン類の製造法
EP2363129A1 (fr) 2004-10-13 2011-09-07 PTC Therapeutics, Inc. Composes de suppression de non-sens et procedes de leur utilisation
JP5214971B2 (ja) * 2004-10-20 2013-06-19 メルク セローノ ソシエテ アノニム ３−アリルアミノピペリジン誘導体
WO2006051723A1 (fr) * 2004-11-09 2006-05-18 Kaneka Corporation Méthode de synthèse de 1-halogéno-3-aryl-2-propanone
GB0428514D0 (en) * 2004-12-31 2005-02-09 Prosidion Ltd Compounds
BRPI0519774A2 (pt) * 2005-01-19 2009-02-10 Biolipox Ab composto ou um sal farmaceuticamente aceitÁvel do mesmo, formulaÇço farmacÊutica, uso de um composto ou um sal farmaceuticamente aceitÁvel do mesmo, mÉtodo de tratamento de uma doenÇa em que inibiÇço da atividade de um membro da famÍlia mapeg É desejada e/ou necessÁria, produto combinado, e, processo para a preparaÇço de um composto
AP2358A (en) 2005-05-09 2012-01-30 Achillion Pharmaceuticals Inc Thiazole compounds and methods of use.
NZ565470A (en) * 2005-07-29 2010-11-26 4Sc Ag Novel heterocyclic NF-kB inhibitors
FR2889526B1 (fr) * 2005-08-04 2012-02-17 Aventis Pharma Sa 7-aza-indazoles substitues, compositions les contenant, procede de fabrication et utilisation
EP1932833B1 (fr) * 2005-10-07 2012-08-01 Kissei Pharmaceutical Co., Ltd. Compose heterocyclique azote et composition pharmaceutique le contenant
TWI385169B (zh) 2005-10-31 2013-02-11 Eisai R&D Man Co Ltd 經雜環取代之吡啶衍生物及含有彼之抗真菌劑
AR056893A1 (es) * 2005-12-28 2007-10-31 Takeda Pharmaceutical Compuestos heterociclicos fusionados y no fusionados, antagonistas de receptores mineralocorticoides
KR101081293B1 (ko) 2006-01-18 2011-11-08 에프. 호프만-라 로슈 아게 11 베타-에이치에스디1 억제제로서 티아졸
EP1979314B1 (fr) * 2006-01-24 2013-01-09 Eli Lilly & Company Sulfamide d'indole modulateur de récepteurs de la progestérone
KR20120034772A (ko) * 2006-03-29 2012-04-12 에프. 호프만-라 로슈 아게 Ｍｇｌｕｒ2 길항물질로서의 피리딘 및 피리미딘 유도체
US7649007B2 (en) 2006-08-15 2010-01-19 Wyeth Llc Oxazolidine derivatives as PR modulators
WO2008021309A1 (fr) 2006-08-15 2008-02-21 Wyeth Dérivés d'imidazolidin-2-one utiles en tant que modulateurs pr
WO2008021338A2 (fr) 2006-08-15 2008-02-21 Wyeth Dérivés d'oxazolidone tricycliques utiles en tant que modulateurs du récepteur de la progestérone
US7538107B2 (en) 2006-08-15 2009-05-26 Wyeth Oxazinan-2-one derivatives useful as PR modulators
US8183264B2 (en) 2006-09-21 2012-05-22 Eisai R&D Managment Co., Ltd. Pyridine derivative substituted by heteroaryl ring, and antifungal agent comprising the same
JP5284788B2 (ja) * 2006-09-21 2013-09-11 エーザイ・アール・アンド・ディー・マネジメント株式会社 ヘテロアリール環置換ピリジン誘導体およびそれらを含有する抗真菌剤
NZ576569A (en) 2006-10-02 2012-05-25 Cortendo Ab Publ Ketoconazole enantiomer in humans
WO2008070350A2 (fr) 2006-10-27 2008-06-12 The Board Of Regents Of The University Of Texas System Procédés et compositions liés aux enveloppements de déshydrons
US9187485B2 (en) 2007-02-02 2015-11-17 Baylor College Of Medicine Methods and compositions for the treatment of cancer and related hyperproliferative disorders
BRPI0811939A2 (pt) 2007-05-22 2014-11-25 Achillion Pharmaceuticals Inc Tiazóis substituídos por heteroarila
EP2786993B1 (fr) 2007-08-13 2017-11-15 Monsanto Technology LLC Procédé et compositions pour le contrôle de nématodes
HRP20120948T1 (hr) 2007-10-09 2012-12-31 Merck Patent Gmbh Derivati piridina koji su korisni kao aktivatori glukokinaze
US8513287B2 (en) 2007-12-27 2013-08-20 Eisai R&D Management Co., Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
KR20100113557A (ko) * 2008-01-11 2010-10-21 노파르티스 아게 키나제 억제제로서의 피리미딘
WO2009099194A1 (fr) 2008-02-08 2009-08-13 Shiseido Company Ltd. Agent blanchissant pour la peau et préparation externe pour la peau
US9447049B2 (en) 2010-03-01 2016-09-20 University Of Tennessee Research Foundation Compounds for treatment of cancer
US8822513B2 (en) 2010-03-01 2014-09-02 Gtx, Inc. Compounds for treatment of cancer
US9029408B2 (en) 2008-06-16 2015-05-12 Gtx, Inc. Compounds for treatment of cancer
PL2303021T3 (pl) * 2008-06-16 2019-10-31 Univ Tennessee Res Found Związki do leczenia nowotworu
US8697694B2 (en) * 2008-08-20 2014-04-15 Merck Sharp & Dohme Corp. Substituted pyridine and pyrimidine derivatives and their use in treating viral infections
WO2010033977A2 (fr) 2008-09-22 2010-03-25 Cayman Chemical Company Composes multiheteroaryles servant d'inhibiteurs de la h-pgds, ainsi que leur utilisation dans le traitement des maladies induites par la prostaglandine d2
US20120010241A1 (en) * 2009-03-19 2012-01-12 Sanofi Hsp90 inhibiting indazole derivatives, compositions containing same and use thereof
EP2493866A1 (fr) * 2009-10-29 2012-09-05 Bristol-Myers Squibb Company Composés hétérocycliques tricycliques
WO2011051198A2 (fr) * 2009-10-30 2011-05-05 Bayer Cropscience Ag Dérivés de pyridine en tant qu'agents phytoprotecteurs
DE102009058280A1 (de) * 2009-12-14 2011-06-16 Merck Patent Gmbh Thiazolderivate
RU2581367C2 (ru) 2010-03-01 2016-04-20 Джи Ти Икс, ИНК. Соединения для лечения рака
CN103140490A (zh) 2010-07-15 2013-06-05 百时美施贵宝公司 氮杂吲唑化合物
KR101823275B1 (ko) 2010-08-04 2018-03-08 펠피큐어 파마슈티걸즈 아이엔씨 전립선 암종의 치료를 위한 병용 요법
AU2011320565A1 (en) * 2010-10-28 2013-05-23 Innocrin Pharmaceuticals, Inc. Metalloenzyme inhibitor compounds
EP2638041B1 (fr) 2010-11-12 2015-07-22 Bristol-Myers Squibb Company Dérivés azaindole substitués
GB2485404A (en) * 2010-11-15 2012-05-16 Nat Univ Ireland Metal-complexed pyridyl-substituted tetrazole compounds and their use in treating cancer
CN102675286B (zh) * 2011-03-07 2015-08-19 中国科学院上海药物研究所 一类吲唑类化合物及其制备方法、用途和药物组合物
WO2012162468A1 (fr) * 2011-05-25 2012-11-29 Janssen Pharmaceutica Nv Dérivés de thiazole en tant qu'inhibiteurs de pro-métalloprotéinases de matrice
WO2013049263A1 (fr) 2011-09-27 2013-04-04 Bristol-Myers Squibb Company Composés d'hétéroaryle bicycliques substitués
EP2903615B1 (fr) * 2012-10-05 2021-04-07 Merck Sharp & Dohme Corp. Dérivés de 5-pyridin-3-yl-2,3-dihydro-1h-indole en tant qu'inhibiteurs de aldostérone synthase (cyp11b2) pour le traitement de l'hypertension artérielle
US9522141B2 (en) 2012-12-20 2016-12-20 Merck Sharp & Dohme Corp. Indazole compounds as aldosterone synthase inhibitors
CN105163584B (zh) 2013-03-05 2019-06-04 田纳西大学研究基金会 用于治疗癌症的化合物
CA2902335C (fr) 2013-03-14 2021-09-14 Pellficure Pharmaceuticals, Inc. Nouvelle therapie pour le carcinome de la prostate
AU2015314772B2 (en) 2014-09-12 2020-02-27 Pellficure Pharmaceuticals, Inc. Compositions and methods for treatment of prostate carcinoma
EP3528799A1 (fr) 2016-10-24 2019-08-28 Pellficure Pharmaceuticals, Inc. Compositions pharmaceutiques de 5-hydroxy-2-méthylnaphtalène-1, 4-dione
JP7193071B2 (ja) * 2017-02-08 2022-12-20 国立大学法人東海国立大学機構 蛍光発光材料および紫外線吸収剤
US20210246109A1 (en) * 2020-02-11 2021-08-12 University Of Kentucky Research Foundation Potent and selective inhibitors of cytochrome p450
WO2023049199A1 (fr) * 2021-09-24 2023-03-30 Zeno Management, Inc. Composés azole
CN117551029A (zh) * 2023-11-22 2024-02-13 河南大学 一种4-溴-3-氰基吡啶的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006556A1 (fr) * 1998-07-27 2000-02-10 Abbott Laboratories Antiproliferants a base d'oxazolines substituees

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK150068C (da) * 1978-06-02 1987-06-29 Pfizer Analogifremgangsmaade til fremstilling af aminothiazoler
JPS55133366A (en) * 1979-04-05 1980-10-17 Otsuka Pharmaceut Factory Inc Thiazole derivative
US4536505A (en) * 1983-05-17 1985-08-20 Ciba-Geigy Corporation Certain N-(pyridyl) indoles
DE3940476A1 (de) * 1989-12-07 1991-06-13 Bayer Ag Pyridinylpyrimidin-derivate
DE3940477A1 (de) * 1989-12-07 1991-06-13 Bayer Ag Hetaryl-substituierte pyridinylpyrimidin-derivate
JPH04154773A (ja) * 1990-10-15 1992-05-27 Green Cross Corp:The チアゾール誘導体
DE4117560A1 (de) * 1991-05-29 1992-12-03 Bayer Ag Verwendung von pyridinylpyrimidin-derivaten zum schutz technischer materialien
TW223004B (fr) * 1991-11-25 1994-05-01 Sumitomo Chemical Co
US5395817A (en) * 1992-01-22 1995-03-07 Imperial Chemical Industries Plc N-arylindoles and their use as herbicides
US5599774A (en) * 1992-01-22 1997-02-04 Imperial Chemical Industries Plc N-arylindoles and their use as herbicides
US5444038A (en) * 1992-03-09 1995-08-22 Zeneca Limited Arylindazoles and their use as herbicides
PT630367E (pt) * 1992-03-09 2000-10-31 Zeneca Ltd Novos arilindazoles e sua utilizacao como herbicidas
KR980700077A (ko) * 1994-11-29 1998-03-30 나까토미 히로타카 2-아미노티아졸유도체 및 그 염류로 이루어진 항균제 또는 살균제(Antibacterial Prepartion or Bactericide comprising 2-Aminothiazole Derivative or Salt Thereof
US6046136A (en) * 1997-06-24 2000-04-04 Zeneca Limited Herbicidal heterocyclic N-oxides compounds
US5840721A (en) * 1997-07-09 1998-11-24 Ontogen Corporation Imidazole derivatives as MDR modulators
AU732406B2 (en) * 1997-10-03 2001-04-26 Merck Frosst Canada & Co. Aryl thiophene derivatives as PDE IV inhibitors
EP1077958A1 (fr) * 1998-05-12 2001-02-28 American Home Products Corporation Acides oxazol-aryl-carboxyliques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie
WO2001064674A1 (fr) * 2000-03-01 2001-09-07 Janssen Pharmaceutica N.V. Derives de thiazolyle 2,4-disubstitue

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006556A1 (fr) * 1998-07-27 2000-02-10 Abbott Laboratories Antiproliferants a base d'oxazolines substituees

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DN GRIGORYEV, BJ LONG, IP NANE,VCO NJAR, Y LIU AND AMH BRODIE: "Effects of new 17alpha-hydroxylase/C17,20-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo", BRITISH JOURNAL OF CANCER, vol. 81, no. 4, 1999, pages 622 - 630, XP009001303 *
NORTON P PEET ET AL: "Synthesis of a 2,5-diaryloxazoline as a potentieal platelet-activating factor antagonust", JOURNAL OF HETEROCYCLIC CHEMISTRY, HETERO CORP., TAMPA, FL, US, vol. 31, March 1994 (1994-03-01), pages 419 - 423, XP002121432, ISSN: 0022-152X *
YAN ZHUANG AND ROLF W. HARTMANN: "Synthesis and Evaluation of Azole-substituted 2-Aryl-6-methoxy-3,4-dihydronaphthalenes and -naphthalenes as Inhibitors of 17 alpha-Hydroxylase-C17,20-Lyase (P450 17)", ARCH. PHARM. PHARM. MED. CHEM., vol. 332, 1999, pages 25 - 30, XP002222972 *

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US8796314B2 (en) 2009-01-30 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9139589B2 (en) 2009-01-30 2015-09-22 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9090601B2 (en) 2009-01-30 2015-07-28 Millennium Pharmaceuticals, Inc. Thiazole derivatives
US8796271B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
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US8859768B2 (en) 2010-08-11 2014-10-14 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9062038B2 (en) 2010-08-11 2015-06-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8765746B2 (en) 2010-10-13 2014-07-01 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
JP2013544792A (ja) * 2010-10-22 2013-12-19 バイエル・インテレクチユアル・プロパテイー・ゲー・エム・ベー・ハー 殺害虫剤としての新規ヘテロ環式化合物
US9173396B2 (en) 2010-10-22 2015-11-03 Bayer Intellectual Property Gmbh Heterocyclic compounds as pesticides
JP2014512411A (ja) * 2011-04-28 2014-05-22 ノバルティス アーゲー １７α−ヒドロキシラーゼ／Ｃ１７，２０−リアーゼ阻害剤
US9339501B2 (en) 2011-04-28 2016-05-17 Novartis Ag 17a-hydroxylase/C17,20-lyase inhibitors
CN115087657A (zh) * 2019-12-18 2022-09-20 加利福尼亚大学董事会 Lin28抑制剂和其使用方法
CN115087657B (zh) * 2019-12-18 2025-01-21 加利福尼亚大学董事会 Lin28抑制剂和其使用方法

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AU2002362603A1 (en) 2003-04-07
CA2461363A1 (fr) 2003-04-03
WO2003027101A1 (fr) 2003-04-03
WO2003027085A2 (fr) 2003-04-03
AU2002340010A1 (en) 2003-04-07
WO2003027096A1 (fr) 2003-04-03
JP2005528325A (ja) 2005-09-22
WO2003027094A3 (fr) 2003-10-23
WO2003027085A3 (fr) 2003-12-04
CA2461360A1 (fr) 2003-04-03
EP1432698A2 (fr) 2004-06-30
WO2003027095A1 (fr) 2003-04-03
EP1432706A2 (fr) 2004-06-30
WO2003027094A2 (fr) 2003-04-03
WO2003027100A1 (fr) 2003-04-03
JP2005532983A (ja) 2005-11-04

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