WO2003027100A1 - Inhibiteurs de lyase c17,20 a base de 3-pyridyle-pyrimidine substituee - Google Patents

Inhibiteurs de lyase c17,20 a base de 3-pyridyle-pyrimidine substituee Download PDF

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WO2003027100A1
WO2003027100A1 PCT/US2002/030924 US0230924W WO03027100A1 WO 2003027100 A1 WO2003027100 A1 WO 2003027100A1 US 0230924 W US0230924 W US 0230924W WO 03027100 A1 WO03027100 A1 WO 03027100A1
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group
alkyl
compound
lyase
pyridyl
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PCT/US2002/030924
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William J. Scott
Wenlang Fu
Mary-Katherine Monahan
Donald Bierer
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Bayer Pharmaceuticals Corporation
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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 45 o -mediated hydroxylation steps.
  • the cholesterol side-chain cleavage activity that represents the first step in steroid hormone biosynthesis is a P 45 n -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).
  • CYP 17, P 45 n 17 Another critical set of enzymatic conversions in steroid metabolism is facilitated by 17-alpha- hydroxylase-17,20-lyase (CYP 17, P 45 n 17).
  • CYP 17 is a bifunctional enzyme which possesses both a C17,20-lyase activity and a C17-hydroxylase activity.
  • these two alternative enzymatic activities of CYP 17 result in the formation of critically different intermediates in steroid biosynthesis and each activity appear to be differentially and developmentally regulated (see e.g. PAllernand 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 C17-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 C 17- hydroxylase activity, promotes the formation of glucocorticoids while the second activity of CYP 17, the 07,20-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 maybe 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).
  • CYP 17 Pharmacological inhibition of CYP 17 maybe 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. et al., Br. Med. J., 1987, 294, 419).
  • CYP cytochrome P450
  • CYP 17 inhibitors In addition to the use of CYP 17 inhibitors in the treatment of prostate cancer, a second potential indication would be for estrogen-dependent breast cancer. In postmenopausal patients with advanced breast cancer, treatment with high doses of ketoconazole resulted in suppression of both testosterone and estradiol levels, implicating CYP 17 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 hormone (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 heterocyclic compounds which inhibit the lyase activity of enzymes, e.g., 17 ⁇ -hydroxylase-C 17,20 lyase.
  • enzymes e.g., 17 ⁇ -hydroxylase-C 17,20 lyase.
  • Compounds of the invention have the formula
  • R 1 represents
  • R 3 is selected from the group consisting of C 1-4 alkyl; C 3-5 cycloalkyl; N(R 4 ) 2 wherein R 4 is H or C 1-4 alkyl; halogen;
  • R is selected from the group consisting of C 1-4 alkyl, halogen, NO 2 , C 1-4 alkoxy, CN, CF 3 , and OCF 3 ; and p is 0, 1, or 2; or
  • R is selected from the group consisting of C 1-4 alkyl, C 3-5 cycloalkyl, and N(R 4 ) ⁇ 2 ; and q is 0, 1, or 2; or
  • R 1 is other than a pyridyl or an N-oxide- containing group.
  • R 1 or R 2 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • the following provisos apply: a) if both R 1 and R 2 are unsubstituted pyridyl groups, one is a 3- pyridyl group and the other is a 3- or 4- pyridyl group; b) when R 1 is a dichloro-substituted 4-pyridyl group, the chlorine substituents are located on the 2 and 3 positions or the 2 and 5 positions.
  • Pharmaceutically acceptable salt of these materials also are 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. Exemplary 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. Accordingly, 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. Similarly, 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 pyrimidine compounds inhibit the enzyme 17 ⁇ -hydroxylase-C 17,20 lyase.
  • R 1 represents
  • R 3 is selected from the group consisting of C 1-4 alkyl; C 3-5 cycloalkyl; halogen; and C ⁇ alkoxy; and m is 0, 1, or 2; is selected from the group consisting of halogen,
  • R 2 represents
  • R is selected from the group consisting of C 1-4 alkyl; C 3-5 cycloalkyl; and N(R 4 ) 2 wherein R 4 is H or C 1-4 alkyl; and q is 0, 1, or 2; or
  • R 1 is other than a pyridyl or an N-oxide- containing group.
  • R 1 or R 2 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions. Furthermore, the following provisos apply: a) if both R and R are unsubstituted pyridyl groups, one is a 3- pyridyl group and the other is a 3- or 4- pyridyl group; b) when R 1 is a dichloro-substituted 4-pyridyl group, the chlorine substituents are located on the 2 and 3 positions or the 2 and 5 positions. Pharmaceutically acceptable salt of these materials also are within the scope of the invention.
  • R 1 represents in which R is selected from the group consisting of Ci- 4 alkyl; C 3-5 cycloalkyl; and halogen; and m is 0, 1, or 2;
  • R 2 represents
  • R 1 is other than a pyridyl or an N-oxide- containing group.
  • R or R is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • the following provisos apply: a) if both R 1 and R 2 are unsubstituted pyridyl groups, one is a 3- pyridyl group and the other is a 3- or 4- pyridyl group; b) when R 1 is a dichloro-substituted 4-pyridyl group, the chlorine substituents are located on the 2 and 3 positions or the 2 and 5 positions.
  • R 2 represents
  • R is selected from the group consisting of C 1-4 alkyl and C 3-5 cycloalkyl; and q is 0, 1, or 2.
  • R 1 or R 2 is a 3-pyridyl group which is unsubstituted at the 2- and 6- positions.
  • both R 1 and R 2 are unsubstituted pyridyl groups, one is a 3- pyridyl group and the other is a 3- or 4- pyridyl group; b) when R 1 is a dichloro-substituted 4-pyridyl group, the chlorine substituents are located on the 2 and 3 positions or the 2 and 5 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.
  • analog of a compound refers to a compound having a some structural similarity to a particular compound and having essentially the same type of biological activity as the compound.
  • CYP 17 substrate includes any of the various steroid hormones acted upon by a CYP 17 or a CYP17-like P 45 n enzyme. Examples include pregnenolone, progesterone and their 17 ⁇ -hydroxylated forms. Pregnenolone is converted to DHEA via a CYP 17 C17,20-lyase reaction, but is also subject to C17 ⁇ -hydroxylation via the 07,20-lyase activity.
  • Progesterone is converted to delta 4- androstenedione via a CYP 17 C17,20-lyase reaction, but is also subject to C17 alpha-hydroxylation via the C17-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 CYP 17-mediated reaction, such as a C 17- hydroxylase reaction or a C 17,20-lyase reaction.
  • CYP 17 metabolites include the androgens, such as testosterone, which are synthesized via a CYP 17 CI 7,20-lyase reaction from CYP 17 substrate precursors such as pregnenolone (converted to DHEA by the CYP 17 CI 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 corpus 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 CYP 17-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 foraiation 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 CYP 17-mediated reaction, may nonetheless be understood by the skilled artisan to be readily affected by an alteration in a CYP 17- mediated activity.
  • the mineralocorticoids such as aldosterone
  • progesterone is also converted to the glucocorticoids and sex steroids via CYP 17-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 reabsorption 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 may be treated by alteration of the level of one or more CYP17 metabolites. Examples include a hormone dependent cancer, such as an androgen-dependent prostate cancer, which maybe treated by inhibiting CYP 17-mediated androgen synthesis, and 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 Cushing's disease, hypertension, prostatic hyperplasia, 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” a disease refers to preventing, curing or improving at least one symptom of a disease.
  • 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 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. These aryl groups may also be referred to as “aryl heterocycles" or "heteroaromatics.”
  • 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 term “halogen” designates -F, -CI, - Br or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO2-.
  • triflyl, tosyl, esyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, j7-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, 7-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • 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.
  • the term "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-
  • Exemplary compounds of the invention are set forth in Table 1 below.
  • the compounds of Table 1 are producible from known compounds (or from starting materials which, in turn, are producible from known compounds), through the general preparative methods described in the General Methods or Examples.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and tr ⁇ /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.
  • the term "phannaceutically acceptable salts" in this respect 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 fonnation 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 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.
  • a disease associated with a lyase e.g., cancer.
  • Preferred types of cancer that can be treated according to the invention 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-Cl 7,20-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 maybe treated by inhibiting CYP 17-mediated estrogen synthesis.
  • adenocarcinoma 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 CI 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 CI 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).
  • 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.
  • 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 hyperplasia. 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. Connell et al.
  • Mineralocorticoid excess may be caused by aldosterone or 11-deoxycorticosterone by inadequate conversion of cortisol to cortisone by 1 l ⁇ -hydroxy steroid 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 abnormalities are inherited (e.g.
  • glucocorticoid remediable hyperaldosteronism GAA
  • receptor defects LMA
  • Liddle's syndrome the molecular basis is again usually known and, in some cases, may provide the simplest diagnostic tests.
  • 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.
  • the "CYP 17 metabolite- associated diseases or disorders" of the invention would include those associated with altered levels of aldosterone production (e.g. hypertension, primary adrenal hyperplasia).
  • CYP 17 metabolite-associated diseases or disorders are Cushing's disease, prostatic hyperplasia, 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, intraperitoneal, 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 5 o (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 5 o/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 5 o 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 formulated in animal models to achieve a circulating plasma concentration range that includes the IC 5 n (i.e., the concentration of the test compound which achieves a half- maximal inhibition of activity) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • the compounds of the invention have an IC 5 n 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, absorption, 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)). Commonly used 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.
  • Major drug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuromdation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al, publ. by McGraw-Hill, pages 11-13, (1996)).
  • 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, intraperitoneal, 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 fonn 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 maybe 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 absorption 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 wherein 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, hydroxypropylmethylcellulose, 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.
  • preservatives for example ethyl or n-propyl p- hydroxybenzoate
  • coloring agents for example ethyl or n-propyl p- hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • 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.
  • compositions 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 may be 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.
  • 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 maybe 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.
  • 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.
  • Radioactive agents For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference” (PDR), 1996 edition (Medical Economics Company, Montvale, NJ. 07645-1742, USA).
  • 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.
  • 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.
  • 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. These normally will be a separate fonnulation, but may be formulated into a single pharmaceutically acceptable composition.
  • 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.
  • the compositions of these kits also may be provided in dried or lyophilized forms. When 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 maybe 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 pennit the reading or monitoring of reactions or amounts of compounds or polypeptides.
  • Formula I are commercially available, are prepared according to methods described below to prepare Intermediates A-F or are prepared according the method described in the following reference: Comins, D. L., Smith, R., Stroud, E., Heterocycles, Vol. 22, No. 2, 1984, 339. Other methods commonly employed in the art may also be used to prepare 3-acetylpyridines II. Treatment of II with an alkoxybis(dialkylamino)methane, preferably methoxybis(dimethylamino)methane at a temperature between 80 - 180 °C affords the intermediate enamine III. Preferably the reaction is run neat and the temperature is between 100-140 °C.
  • aryl enamines from aryl acetyl may be employed.
  • Enamines III are then treated with benzamidines IN using General Methods A, B, or C to prepare 3-(pyridyl)pyrimidines of Formula I.
  • the benzamidines IN are commercially available or are prepared according to methods commonly employed in the art to prepare aryl benzamidines from aryl nitriles.
  • Pyridyl nitriles used to make pyridyl benzamidines IV commercially available are prepared using the procedue described by Comins (Comins, D. L., Smith, R., Stroud, E., Heterocycles, Vol. 22, No. 2, 1984, 339) or by using methods commonly employed in the art.
  • LC/MS mass spectral data were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120 A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source.
  • the eluents were A: 2%> acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% 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.
  • Step 1 A solution of 3-acetylpyridine (100 g, 0.82 mol), dimethyl sulfide (400 mL, 5.4 mol) and copper (I) iodide (7.94 g, 0.041 mol) in anhydrous THF (2 L) was stirred at rt under an Ar atmosphere. Phenyl chloro formate (0.4 mL, 0.82 mol) was then added, producing a dark brown precipitate. After 30 min, the mixture was cooled below -21 °C and methyl magnesium bromide (1.4 M in 3:1 toluene-THF, 586 mL, 0.82 mol) was added over 50 min, keeping the reaction temperature below -15 °C.
  • Step 2 A solution of the intermediate dihydropyridine (134.3 g, 0.52 mol) in dichloromethane (100 mL) was added to a stirred suspension of sulfur (16.67 g, 0.52 mol) in decalin and slowly heated to reflux under an argon sweep. After refluxing 1 h, the mixture was allowed to cool to rt, then filtered through a pad of silica gel.
  • Step 1 To a mixture of Cul (78.5 g, 0.412 mol), dimethyl sulphide (203 mL, 2.76 mol) and 3-acetyl pyridine (50.0 g, 0.412 mol) in anhydrous THF (1100 mL) at rt was added phenyl chloroformate (55.2 mL, 0.44 mol) and the mixture was stirred for 40-50 min. To this suspension at -25 to -20°C was added isopropyl magnesium chloride (220 mL, 0.44 mol, 2.0 M solution in THF) over 30-40 min. The mixture was stirred at this temperature for 30 min, then warmed slowly to rt over 1.0-1.5 h.
  • Step 1 50.0 g (413 mmol) of cyclopropyl bromide was dissolved in 500 mL of anhydrous THF. 10.0 g (411 mmol) of dry magnesium was charged to a round-bottomed flask containing a catalytic amount of iodine. About 20% of the bromide solution was then charged into the flask. After observing bubble formation, the remaining solution was added over 15 min, thereby causing the reaction mixture to reflux. After 30 min, a 5.0 mL aliquot of the reaction mixture was removed to determine the concentration of the Grignard reagent.
  • Step 2 Cul (780 mg, 4.10 mmol) was added to a round-bottomed flask under inert conditions. A suspension was then formed by the addition of 100 mL of THF. Dimethyl sulfide (40 mL) was added, yielding a clear yellow solution. 3-Acetylpyridine (10.0 g, 82.7 mmol) was then dissolved in 70 mL of THF and added to the solution. Finally, 13.6 g (86.8 mmol) of phenyl chloroformate was dissolved in 50 mL of THF and added slowly, resulting in the fonnation of a precipitate. The mixture was then cooled to -20 °C by packing in dry ice.
  • Step 3 12.2 g (43.0 mmol) of the dihydropyridine was transferred into a round-bottomed flask containing 143 mL of decahydronaphthalene. Sulfur 1.38 g (43.0 mmol) was added and the flask was heated in an oil bath at 180 °C. Over a 4 h period, an additional 1.38 g of sulfur was added. The heat was then turned off and the reaction was diluted with 500 mL of methyl t-batyl ether. The organic layer was extracted twice with 250 mL portions of 1.0 N HCl. Dichloromethane (500 mL) was added to the aqueous layer, which was then made basic with 1.0 N NaOH.
  • N,N-Dimethylformamide dimethyl acetal (17 mmol) is added dropwise to a solution of a 3-acetyl pyridine or phenyl methyl ketone(8.2 mmol) in 10 mL anhydrous toluene. The reaction is heated to reflux overnight. The reaction mixture is cooled to rt and concentrated in vacuo. The residue is dissolved in chloroform (2 x 10 mL) and concentrated in vacuo until dry. The intermediate enamine is taken on to the next reaction and quantitative yield was presumed. Step 2.
  • the amidine hydrochloride (8.2 mmol) is dissolved in a solution of sodium methoxide (25 wt % in methanol, 1.78 mL) in 100 mL of anhydrous methanol. The resultant solution is stirred at rt for 20 min. To the reaction, a solution of the intermediate enamine (8.2 mmol) in 10 mL methanol is added. The reaction mixture is heated to reflux overnight. The reaction is cooled to rt and the mixture is concentrated in vacuo. The residue is adhered onto silica gel and purified via flash chromatography (EtOAc), yielding 1.39 g (72%) of the target pyrimidine derivative.
  • EtOAc flash chromatography
  • X N or CH Step 1.
  • a mixture of the ketone (1 eq) and bis(dimethylamino)methoxymethane (2 eq) is heated at 110 °C for 2 h under the protection of Ar.
  • the reaction mixture is evaporated and the dark brown oily residue is used in the succeeding reaction without further purification.
  • Step 2 A solution of 300 mg intermediate enamine (1 eq) in 10 mL absolute ethanol is transferred into a solution of the amidine (2 eq) in 4 mL absolute ethanol prepared from sodium (2 eq) and the amidine hydrochloride (2 eq).
  • an amidine dihydrochloride 8 mL of ethanolic amidine solution prepared from sodium (4 eq) and the amidine dihydrochloride (2 eq) is used in the reaction. After shaking and heating under reflux for 24 h, the reaction mixture is evaporated. The resulting residue is taken up in dichloromethane washed with water, dried, and then concentrated. The crude product is purified using a Gilson HPLC.
  • Step 2 A solution of 300 mg intermediate enamine (1 eq) in 10 mL absolute ethanol is transferred into a solution of the amidine (2 eq) in 4 mL absolute ethanol prepared from sodium (2 eq) and the amidine hydrochloride (2 eq).
  • an amidine dihydrochloride 8 mL of ethanolic amidine solution prepared from sodium (4 eq) and the amidine dihydrochloride (2 eq) is used in the reaction. After shaking and heating under reflux for 24 h, the reaction mixture is evaporated. The resulting residue is taken up in dichloromethane washed with water, dried, and then concentrated.
  • the crude product is purified by HPLC using a Polaris C- 18 column and gradient elution from 10% to 90% CH 3 CN in water with 1% TFA in both the water and CH 3 CN.
  • HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120- 1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018%) TFA.
  • C17,20 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.
  • Human and murine C17,20 lyase biochemical assays Recombinant human C 17,20 lyase (hLyase) was expressed in (Sf9) cells, and hLyase enriched microsomes were prepared from cultures as described in the following reference: Baculovirus Expression of Bovine P 45 o in Sf9 Cells and Comparison with Expression in Yeast, Mammalian Cells, and E. Coli. Barnes H. J.; Jenkins, C. M.; Waterman, M. R., Archives of Biochemistry and Biophysics (1994) 315(2) 489-494. Recombinant murine C 17,20 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 assays.
  • Test compounds were diluted 1:4, serially in six steps, with 100% DMSO starting from 800 ⁇ M going to 51.2 nM reserving the first 2 columns for the generation of a standard curve. Each of these compound solutions in 100% DMSO was further diluted twenty fold in H 2 O to obtain compound concentrations ranging from 40 ⁇ M to 2.56 nM in 5% DMSO.
  • Dehydroepiandrosterone (DHEA) standards were serially diluted in 100% DMSO from 400 ⁇ M down to 120 nM in half-log dilutions. Each dilution was further diluted twenty fold in H 2 O to obtain 20 ⁇ M to 6 nM solutions in 5% DMSO using the first 2 columns. Five ⁇ l of these 5% DMSO dilutions were used in the assay.
  • Enzymatic reactions were allowed to run for 2 hours at room temperature with gentle agitation. Reactions were terminated with the addition of 50 ⁇ M (final concentration) YMl 16, a potent C17,20 lyase inhibitor.
  • concentration of DHEA generated by hLyase was determined by radioimmunoassay (RIA) as described below.
  • the concentration of DHEA generated in each reaction was calculated from raw data (CPM) and the standard curve.
  • the lyase inhibitory activity of each compound was determined as the concentration of DHEA generated in the presence of test compounds, expressed as a percent inhibition compared to the DHEA concentration generated in the absence of test compounds (l-(nM DHEA formed in the presence of test compound/nM DHEA formed in the absence of test compounds) x 100).
  • DMEM Dulbecco's Modified Eagle's Medium
  • DHEA standard was diluted with RPMI (4.5 ⁇ L of 500 ⁇ M into 3 mL RPMI, then 1:3 serial dilutions). The media from columns 2-12 of the cell plate was removed and replaced with 100 ⁇ L RPMI without phenol red. Diluted DHEA standards (100 ⁇ L) at a concentration of 750, 250, 83.3, 27.7, 9.2, 3, 1 and 0.3 nM were added to column 1 of the cell plate. 50 ⁇ L of 100% DMSO was added to columns 1 and 2 of the mother plate.
  • the amount of DHEA produced was determined as follows. 90 ⁇ L media was removed from each well of the cell plate and placed into an SPA assay plate (Wallac Isoplate #1450). 50 ⁇ L of 3 H-DHEA (1.6 ⁇ Ci/mL, New England Nuclear (Catalog # NET814)) was added to each well of the SPA assay plate. 50 ⁇ L of anti-DHEA/anti-rabbit SPA beads (20 ⁇ L/mL AB with 10 mg/mL SPA beads) were then added to each well of the plate. The plate was incubated overnight, and the radioactivity counted as described above. The first two columns of the plate were reserved for a standard curve of DHEA and the no compound controls.
  • the raw data was converted to a concentration of DHEA formed (nM) by use of the standard curve.
  • the lyase inhibitory activity of the compounds was determined as the amount of DHEA formed in the presence of compound compared to the amount formed in the absence of compound in the form of a percent inhibition (1- (nM DHEA formed with compound/nM DHEA formed without compound) x 100).
  • 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 5 o in the human C 17,20 biochemical assay or the human C 17,20 cellular assay of less than 10 ⁇ M.

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Abstract

La présente invention concerne des 3-pyridyle-pyrimidines substituées et des compositions à base de ces pyrimidines. L'invention concerne également l'utilisation de 3-pyridyle-pyrimidine substituées et les compositions pharmaceutiques correspondantes comme inhibiteurs de lyases, et notamment de l'enzyme qu'est la 17a-hydroxylase-C17,20. L'invention concerne aussi des traitements anticancéreux applicables à un patient et impliquant l'administration de 3-pyridyle-pyrimidine substituée ou d'une composition en comprenant. Les cancers concernés sont essentiellement celui de la prostate et celui du sein.
PCT/US2002/030924 2001-09-26 2002-09-26 Inhibiteurs de lyase c17,20 a base de 3-pyridyle-pyrimidine substituee WO2003027100A1 (fr)

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

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PCT/US2002/030979 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/US2002/030483 WO2003027085A2 (fr) 2001-09-26 2002-09-26 Thiazoles 3-pyridyle ou 4-isoquinolinyle utilises comme inhibiteurs de lyase c17,20
PCT/US2002/030983 WO2003027096A1 (fr) 2001-09-26 2002-09-26 3-pyridyl imidazoles substitues en tant qu'inhibiteurs de la lyase c17,20
PCT/US2002/030834 WO2003027107A1 (fr) 2001-09-26 2002-09-26 3-pyridyl oxazoles substitues, inhibiteurs de la c17,20 lyase
PCT/US2002/030982 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/US2002/030981 WO2003027105A1 (fr) 2001-09-26 2002-09-26 3-pyridyl thiophenes substitues en tant qu'inhibiteurs de la lyase c17,20

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US8431578B2 (en) 2008-01-11 2013-04-30 Novartis Ag Organic compounds
AU2009203693B2 (en) * 2008-01-11 2012-06-07 Novartis Ag Pyrimidines as kinase inhibitors
JP2011509278A (ja) * 2008-01-11 2011-03-24 ノバルティス アーゲー キナーゼ阻害剤としてのピリミジン類
WO2009087224A1 (fr) * 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
JP2014500864A (ja) * 2010-10-28 2014-01-16 ヴィアメット ファーマスーティカルズ，インコーポレイテッド 金属酵素阻害化合物

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EP1432706A2 (fr) 2004-06-30
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WO2003027095A1 (fr) 2003-04-03
CA2461363A1 (fr) 2003-04-03
JP2005532983A (ja) 2005-11-04
AU2002340010A1 (en) 2003-04-07
WO2003027094A2 (fr) 2003-04-03
CA2461360A1 (fr) 2003-04-03
EP1432698A2 (fr) 2004-06-30
WO2003027105A1 (fr) 2003-04-03
WO2003027094A3 (fr) 2003-10-23
WO2003027085A3 (fr) 2003-12-04
WO2003027101A1 (fr) 2003-04-03
WO2003027107A1 (fr) 2003-04-03
WO2003027085A2 (fr) 2003-04-03
AU2002362603A1 (en) 2003-04-07

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