EP1432706A2 - 3-pyridyl or 4-isoquinolinyl thiazoles as c17,20 lyase inhibitors - Google Patents

3-pyridyl or 4-isoquinolinyl thiazoles as c17,20 lyase inhibitors

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Publication number
EP1432706A2
EP1432706A2 EP02799636A EP02799636A EP1432706A2 EP 1432706 A2 EP1432706 A2 EP 1432706A2 EP 02799636 A EP02799636 A EP 02799636A EP 02799636 A EP02799636 A EP 02799636A EP 1432706 A2 EP1432706 A2 EP 1432706A2
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EP
European Patent Office
Prior art keywords
pyridyl
alkyl
halogen
thiazole
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02799636A
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German (de)
English (en)
French (fr)
Inventor
Donald Bierer
Andrea Mcclure
Wenlang Fu
Furahi Achebe
Gaetan H. Ladouceur
Michael J. Burke
Cheng Bi
Barry Hart
Jacques Dumas
Robert Sibley
William J. Scott
Jeffrey Johnson
Davoud Asgari
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Bayer Pharmaceuticals Corp
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Bayer Pharmaceuticals Corp
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Publication date
Application filed by Bayer Pharmaceuticals Corp filed Critical Bayer Pharmaceuticals Corp
Publication of EP1432706A2 publication Critical patent/EP1432706A2/en
Withdrawn legal-status Critical Current

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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 ofthe 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 hormone 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).
  • CYP 17, P 50 17 Another critical set of enzymatic conversions in steroid metabolism is facilitated by 17-alpha- hydroxylase-17,20-lyase (CYP 17, P 50 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. l'Allemand et al. (2000) Eur. J. Clin. Invest. 30: 28-33).
  • the 07,20-lyase activity of CYP 17 catalyzes the conversion of 17 ⁇ -hydroxy- pregnenolone-and-l-7 ⁇ -hydroxy-progesterone-to-dehydroepiandrosterone-(-DHEA-)-and- delta4-androstenedione (androstenedione) respectively.
  • DHEA and androstenedione lyase products 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.
  • the C17-hydroxylase activity of CYP 17 catalyzes the conversion ofthe common intermediate progesterone to 17- hydroxyprogesterone, a precursor of cortisol. Therefore the first activity of CYP 17, the C17-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 ofthe most frequently diagnosed forms of cancer in men in the U.S. and Europe.
  • Prostate cancer is typically andro gen-dependent and, accordingly, the reduction in androgen production via surgical or pharmacological castration remains the major treatment option for this indication.
  • 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).
  • Pharmacological inhibition of CYP 17 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 ( ⁇ jar V, et al, J. Med. Chem., 1998, 41, 902).
  • CYP17 inhibitor the fungicide ketoconazole
  • 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).
  • ketoconazole 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 ofthe 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.
  • total androgen blockade as first line therapy may be more effective than conventional androgen deprivation by achieving maximum suppression of androgen concentrations which may also prevent AR amplification. It is presently unclear whether sequential treatment with different agents can prolong the benefits ofthe initial therapy. This strategy has been found effective in breast cancer treatment. New agents which act by different mechanisms could produce second responses in a portion of relapsed patients. Although the percentage of patients who respond to second-line hormonal therapy may be relatively low, a substantial number of patients may benefit because ofthe high incidence of prostate cancer. Furthermore, there is the potential for developing more potent agents than current therapies, none of which are completely effective in blocking androgen effects.
  • the invention provides substituted 3-pyridyl heterocyclic compounds which inhibit the lyase activity of enzymes, e.g., 17 ⁇ -hydroxylase-C 17,20 lyase.
  • the compounds ofthe invention have the formula (I)
  • L 1 represents a chemical bond; a carbonyl group
  • R 1 represents H or Ci . 4 alkyl
  • L 2 represents a chemical bond; -(CH 2 ) a - ; -CH 2 O- ; -NCTL 1 )- ; or
  • J represents H; C ⁇ _ 4 alkyl; or halogen.
  • R is selected from
  • R 3 represents H, C 1- alkyl, C -6 cycloalkyl, or phenyl optionally substituted by halogen;
  • R 4 represents -(CH ⁇ OR 1 or -(CH 2 ) a N(R 1 ) 2 ;
  • R 5 represents j-N
  • A may also be
  • G is other than a pyridyl or an N-oxide-
  • A may also be
  • d is O, l, or 2 ; and R 6 is selected from ⁇ 5 ⁇ " C TalkylT
  • R 7 represents H, C 1-4 alkyl, C 1- haloalkyl, phenyl, benzyl, or pyridyl optionally substituted 20 by C 1-3 haloalkyl; halogen; NO 2 ; CN; CO 2 R 1 ; 25 C 1- acyl ; phenyl optionally substituted by halogen ; benzyl ; N(R 2 ;
  • R represents C 1-4 alkyl or phenyl optionally substituted by halogen.
  • A may also be
  • R 9 represents C 1-4 alkyl or phenyl optionally substituted by halogen
  • N ⁇ ® N ⁇ ® , provided that A is other than a pyridyl or an N-oxide- containing group
  • A is other than a pyridyl or an N-oxide- containing group
  • R 11 represents H, C 1-4 alkyl, or phenyl optionally substituted by halogen
  • N ⁇ • ⁇ * ;
  • one of A and G is a 3-pyridyl moiety of formula (II) or (IIA), or a 4-isoquinolyl moiety of formula (IIB) or (IIC)
  • a and G is other than a pyridyl or an N-oxide-containing group
  • R 2 of formulae (II) and (IIA) is selected from the group consisting of
  • Z represents CH 2 , S, or N(R J )
  • R3' represents H, C 3-4 alkyl, C 4-6 cycloalkyl, or phenyl optionally substituted with halogen; l ⁇ / ⁇ 4 ⁇
  • A-L 1 and J may be joined and together with the carbon atoms to which they are connected form a ring moiety selected from the group consisting of
  • h is O, l, or 2; and R 12 represents C 1-4 alkyl or C 1-4 alkoxy;
  • k is 0 or 1 ;
  • R 13 represents C 1-4 alkyl or phenyl; said ring moiety being joined to the thiazole at the positions indicated by the truncated valences shown in the partial structures above to form a fused ring thiazole; and for these fused ring thiazoles, L 2 is a bond and G is a 3-pyridyl moiety of formula (III) or (IIIA)
  • R 2" is C M alkyl
  • the invention also provides pharmaceutical compositions for inhibiting lyase activity, comprising a compound ofthe invention plus a pharmaceutically acceptable carrier.
  • the invention also provides methods for inhibiting lyases, comprising contacting the lyase with a compound of the invention.
  • 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 ofthe 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 heterocyclic compounds inhibit the enzyme 17 ⁇ -hydroxylase-C 17,20 lyase.
  • the compounds ofthe invention have the formula (I) in which the several substituent moieties are as described in claim 1 and in the above summary ofthe invention.
  • L 1 preferebly represents a chemical bond; a carbonyl group;
  • L 2 preferably represents a chemical bond; -(CH 2 ) a - ; or -NCR 1 )- in which R 1 represents H or Ci . 4 alkyl;
  • J preferably represents H; or C 1 - 4 alkyl.
  • R 5 represents
  • Y represents N(R J ) , O, S, or
  • A may also be
  • G is other than a pyridyl or an N-oxide- containing group.
  • L 1 is a bond
  • A may also be
  • R 7 represents C 1-4 alkyl or C 1-4 haloalkyl; halogen; NO 2 ;
  • A may also be
  • R 9 represents C 1-4 alkyl or phenyl optionally substituted by halogen
  • R 10 represents CN, NO 2 , or halogen.
  • G preferably represents
  • R 2 is selected from C 1-6 alkyl; C 1-4 haloalkyl;
  • Y represents NCR 1 ) , O, S, or
  • A is other than a pyridyl or an N-oxide- containing group
  • R 6 is selected from C 1-6 alkyl ; C 1-4 haloalkyl ;
  • R 7 represents C 1-4 alkyl or C 1- haloalkyl; halogen;
  • A is other than a pyridyl or an N-oxide- containing group
  • one of A and G is a 3-pyridyl moiety of formula (II) or (IIA), or a 4-isoquinolyl moiety of formula (IIB) or (IIC)
  • a and G is other than a pyridyl or an N-oxide-containing group
  • a and G is other than a pyridyl or an N-oxide-containing group
  • R 2 of formulae (II) and (IIA) is R 2 ; but when each of A and G is joined to the thiazole ring via a chemical bond L 1 and L 2 respectively, then R 2 of formulae (II) and (IIA) is selected from the group consisting of
  • A-L 1 and J may be joined and together with the carbon atoms to which they are connected form a ring moiety selected from the group consisting of
  • R 12 represents C 1-4 alkyl or C 1-4 alkoxy
  • R 13 represents C 1-4 alkyl or phenyl; said ring moiety being joined to the thiazole at the positions indicated by the truncated valences shown in the partial structures above to form a fused ring thiazole; and for these fused ring thiazoles, L 2 is a bond and G is a 3-pyridyl moiety of formula (III) or (IIIA)
  • R 2" is C 1-4 alkyl
  • L 2 more preferably represents a chemical bond; -(CH 2 ) a - ; or -NCR 1 )- in which R 1 represents H or Ci . . 4 alkyl; and
  • J more preferably represents H. Furthermore, in this more preferred embodiment 1) when L 1 is a chemical bond, A represents
  • R is selected from C 1-6 alkyl; C 1-4 haloalkyl; C 3-6 cycloalkyl; and phenyl optionally substituted by halogen.
  • L 1 is a bond
  • A may also be
  • A may also be
  • R 7 represents C 1- alkyl or C 1-4 haloalkyl; halogen;
  • A may also be
  • g is 0, 1, or 2; and R 10 represents CN, NO 2 , or halogen.
  • G more preferably represents
  • R 2 is selected from C 1-6 alkyl
  • A is other than a pyridyl or an N-oxide- containing group
  • R 6 is selected from C ⁇ -6 alkyl ; C M haloalkyl ; OR 7 ; in which
  • R 7 represents C 1-4 alkyl or C 1-4 haloalkyl; halogen; NO 2 ; CN; CO 2 R J ; and
  • one of A and G is a 3-pyridyl moiety of formula (II) or (IIA), or a 4-isoquinolyl moiety of formula (IIB) or (IIC) R 2'
  • a and G is other than a pyridyl or an N-oxide-containing group
  • a and G is other than a pyridyl or an N-oxide-containing group
  • R 2 of formulae (II) and (IIA) is R 2 ; but when each of A and G is joined to the thiazole ring via a chemical bond L 1 and L 2 respectively, then R 2 of formulae (II) and (IIA) is selected from the group consisting of
  • L 1 most preferebly represents a chemical bond
  • L 2 most preferably represents a chemical bond
  • J most preferably represents H.
  • A may also be
  • R 7 represents C 1-4 alkyl or C 1-4 haloalkyl; halogen; NO 2 ; and CN; or
  • R 10 represents CN, NO 2 , or halogen.
  • G most preferably represents
  • R 2 is selected from C 1-6 alkyl
  • A is other than a pyridyl or an N-oxide- containing group
  • R 6 is selected from C 1-6 alkyl ; C 1-4 haloalkyl ;
  • R 7 represents C 1-4 alkyl or C 1-4 haloalkyl; halogen; NO 2 ;
  • one of A and G is a 3-pyridyl moiety of formula (II) or (IIA), or a 4-isoquinolyl moiety of formula (IIB) or (IIC)
  • a and G is other than a pyridyl or an N-oxide-containing group
  • R 2 is R 2 ; but when each of A and G is joined to the thiazole ring via a chemical bond L and L respectively, then R of formulae (II) and (IIA) is selected from the group consisting of
  • agonist of an enzyme refers to a compound that binds to the enzyme and stimulates the action ofthe naturally occurring enzyme, or a compound which mimics the activity ofthe naturally occurring enzyme.
  • an enzyme refers to a compound that binds to the enzyme and inhibits the action ofthe naturally occurring enzyme.
  • analog of a compound refers to a compound having a some structural similarityi:o-a-particular-compound-and-having-essentialTy-the-same-type-of-biol ⁇ gieal activity as the compound.
  • CYP 17 substrate includes any ofthe various steroid hormones acted upon by a CYP 17 or a CYP17-like P 450 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 C 17,20- lyase activity.
  • Progesterone is converted to delta 4- androstenedione via a CYP 17 C 17,20- 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 ofthe steroid ho ⁇ nones that are synthesized from a cholesterol precursor via a CYP17-mediated reaction, such as a C17- hydroxylase reaction or a C 17,20-lyase reaction.
  • Examples of 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 CYP 17 CI 7,20-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.
  • 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 CYP17-mediated reaction.
  • the glucocorticoids among other functions, promote gluconeogenesis and the formation 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 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 ofthe level of one or more CYP 17 metabolites. Examples include a hormone dependent cancer, such as an androgen-dependent prostate cancer, which may be treated by inhibiting CYP17-mediated androgen synthesis, and an estrogen-dependent breast cancer or ovarian cancer, wliich may be treated by inhibiting CYP17-mediated estrogen synthesis. Other examples of "CYP 17 metabolite-associated diseases or disorders” are Cushing's disease, hypertension, prostatic hyperplasia, and glucocorticoid deficiency.
  • derivative of a compound refers to another compound which can be derived, e.g., by chemical synthesis, from the original compound.
  • a derivative of a compound has certain structural similarities with the original compound.
  • 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 ofthe 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 ofthe 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 ofthe 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% ofthe activity ofthe 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 ofthe 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, tefrazole, 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 ofthe 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, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, j9-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, -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, j3-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list ofthe abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry;(i.e., J. Org. Chem. 2002, 67(1), 24A.
  • the abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
  • the definition of 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 ofthe 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 ofthe 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- 07,20-lyase.
  • Exemplary compounds ofthe invention are set forth in Table 1 below.
  • the exemplary 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 Examples.
  • the compounds are grouped in the Tables according to the method used for their synthesis, as described in the Examples.
  • J.3_ 2 (4jnethyl(3:pvridy ⁇ -4rr(4-methvlphenvl methyll- 3-thiazole
  • Certain compounds ofthe present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope ofthe 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 ofthe 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.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution ofthe diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery ofthe 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 ofthe present invention. These salts can be prepared in situ during the final isolation and purification of
  • 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,
  • compositions ofthe subject compounds include the conventional nontoxic salts or quaternary ammonium salts ofthe compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived ?.s fr ⁇ m 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 ofthe 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 ofthe 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.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative 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 ofthe compounds described above include compounds which otherwise conespond thereto, and wliich 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 ofthe compound in binding to 17 ⁇ -hydroxylase-Cl 7,20-lyase receptors.
  • the compounds ofthe present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, 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- C17,20 lyase, comprising contacting a lyase with a compound ofthe 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 ofthe invention, such that the activity ofthe lyase is inhibited.
  • the cell may further be contacted with a composition stimulating the uptake ofthe 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 ofthe present invention, such that the lyase is inhibited in a cell ofthe 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.
  • Prefened 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 ofthe 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 ofthe 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 CYP17-mediated androgen synthesis, and estrogen-dependent breast cancer or ovarian cancer, which maybe treated by inhibiting CYP17-mediated estrogen synthesis.
  • adenocarcinoma ofthe 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.
  • breast cancer particularly breast cancer in postmenopausal women
  • breast cancer can be treated by administration of a CI 7,20-lyase inhibitor ofthe invention because adrenal-and-ovarian-androgens-are-the-main-preeursors-of-the-estrogens-whieh-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.
  • compositions ofthe 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 ofthe 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.
  • CYP 17 metabolite- associated diseases or disorders 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 ofthe invention may function as antifungal compounds.
  • the therapeutic methods ofthe 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 ofthe 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 ofthe 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% ofthe population) and the ED 50 (the dose therapeutically effective in 50% ofthe 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 50 .
  • Compounds which exhibit large therapeutic indices are prefened. 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 formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration ofthe 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 ofthe invention have an IC 50 less than 10 ⁇ M as determined by the biochemical or cellular assay described herein. Some compounds ofthe 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 biotransfbrmation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The
  • 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 fransdermal administration.
  • Parenteral administration includes intravenous, intraarticular, intramuscular, intraperitoneal, and subcutaneous injections, as well as use of infusion techniques.
  • One or more compounds ofthe 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 Dmg Delivery Systems (Sixth Edition), edited by Ansel et al, publ. by Williams & Wilkins, (1995).
  • compositions containing a compound ofthe 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-pynolidone 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 ofthe 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.
  • 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-pynolidone, 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.
  • dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin
  • 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.
  • 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 ofthe 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.
  • an anti-oxidant such as ascorbic acid.
  • compositions ofthe 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 ofthe 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 may be 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 ofthe 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. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration ofthe 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.
  • 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 ofthe 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 ofthe 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 fransdermal routes, using those forms of fransdermal 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 ofthe 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 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 ofthe 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 ofthe 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 ofthe 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 ofthe individual patient, as well as the severity ofthe patient's symptoms.
  • a compound ofthe invention materials and/or reagents required for administering the compounds ofthe invention may be assembled together in a kit.
  • the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being particularly prefened.
  • 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-su ⁇ h4ike-appara1 ⁇ s fr ⁇ m-wh ⁇ the body, such as the lungs, or injected into an animal, or even applied to and mixed with the other components ofthe kit.
  • kits 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 may be provided in another container means.
  • the kits ofthe invention may also include an instruction sheet defining administration ofthe agent. Kits may also comprise a compound ofthe invention, labeled for detecting lyases.
  • the kits ofthe 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 wliich the desired vials are retained.
  • kits ofthe invention also may comprise, or be packaged with a separate instrument for assisting with the injection/administration or placement ofthe ultimate complex composition within the body of an animal.
  • a separate instrument for assisting with the injection/administration or placement ofthe 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.
  • compounds of Formula I can be prepared according to Methods G, H, I, J, K, L, P, Q, R, S, and W.
  • Halo ketones III are commercially available or may be prepared using an electophilic halogen reagent such as bromine, N-chlorosuccinimide, N- bromosuccinimide, or phenyltrimethylammonium tribromide using the general methods or specific examples described below or other methods commonly employed in the art.
  • the conesponding alphahydroxy ketone can be converted into III using standard conditions employed in the art to convert an alcohol functionality into a halogen or other leaving group commonly employed in the art.
  • Ketones II are commercially available, are prepared prepared according to methods specifically described below, or are prepared according methods described in the following references: Comins, D. L., Smith, R., Stroud, E., Heterocycles, Vol. 22, No. 2, 1984, 339; Leete, E.; Leete, S. A. S., J. Org. Chem. Vol. 43, No. 11, 1978, 2122; Kim, J. G.; Yu, D. S.; Moon, S. H.; Park, J.; Park, W. W. J. Korean Chem. Soc. Vol. 37, No. 9, 1993, 826.
  • ketones II can be prepared from the conesponding carboxylic acids using standard conditions employed in the art to convert a carboxylic acid functionality into a ketone.
  • Thioamide VI can be prepared from nitrile V upon treatment with hydrogen sulphide using procedures described below.
  • VI can be prepared from amide IV upon treatment with Lawessons reagent or P 4 S 10 .
  • Nitriles V are commercially available or can be prepared according to the methods described below for Intermediates A-H, or they can be prepared according the methods described in the following references: Comins, D. L., Smith, R., Stroud, E., Heterocycles, Vol. 22, No. 2, 1984, 339; Leete, E.; Leete, S. A.
  • a or G is 4-methyl pyridyl
  • such compounds can be treated with H 2 O or MCPBA, as shown in Scheme 2, to yield 4-methyl pyridine N-oxides, wliich can be optionally converted to chloro derivatives XII and XVI as shown in Scheme 3.
  • the N-oxide XI or XV is converted to chloride XII or XVI by freatment with tosyl chloride at elevated temperature.
  • Treatment of chlorides XII or XVI with amines ofthe formula XIII results in the formation of 4-aminopyridines ofthe formulae XIV and XVII.
  • XVII Compounds of Formula I, when A or G is a 4-methyl pyridyl, can be alkylated using a base, such as LDA, followed by treatment with an elecfrophilic reagent, such as an alkyl iodide, as shown in Scheme 4.
  • a base such as LDA
  • an elecfrophilic reagent such as an alkyl iodide
  • Other bases commonly employed in the art such as n-butyl lithium or tert-butyl lithium, and other elecfrophilic reagents commonly employed in the art, such as alkyl bromides, alkyl chlorides, akyl tosylates, or alkyl triflates, may also be utilized. Separation by chromatography (column chromatography, flash chromatography, preparative TLC, or HPLC) affords the alkylated thiazoles of Formulae XIX and XII.
  • LCMS 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, 120A), and a Finnigan LCQ ion trap mass spectrometer with elecfrospray 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 min at a flowrate of 1.0 mL/min was used with an initial hold of 0.5 min and a final hold at 95% B of 0.5 min. Total run time was 6.5 min.
  • Step 1 2,6-Dihydroxy-4-methyl-3-pyridinecarbonitrile (150 g, 1 mol) and phosphorus oxychloride (600 mL, 6.4 mol) were stined under an Ar atmosphere and triethylamine (300 mL, 2.1 mol) was added. After refluxing for 16 h, the mixture was concentrated in vacuo, and the residue partitioned between ice water (6 L) and dichloromethane (2 L). The organic and then filtered through a pad of silica gel (465 g) on a sintered glass funnel.
  • Step 1 mono-Ethyl malonate (35.0 g, 265 mmol) and THF (300 mL) were placed into a 500 mL round-bottomed flask and cooled to -70 °C under Ar. To this solution was added 330 mlTc ⁇ fTT ⁇ vl «-Bu ⁇ ⁇ (27 ⁇ equiv., 53O mmolTslowly and " tl ⁇ e oluTi ⁇ nrallo d-tc stir-fo ' - ' lO- min at -70 °C.
  • the acid chloride was added to the solution slowly, stined for one more h at -70 °C, and then the reaction temperature was allowed to go to rt overnight.
  • the solution was concentrated in vacuo and the residue was partitioned between IN HCI, (200 mL) and Et 2 O (2 x 300 mL).
  • the organic layer was washed sequentially with saturated NaHCO 3 solution (200 mL) and H 2 O (200 mL), then dried over Na 2 SO 4 .
  • the filtrate was concenfrated and the crude product was purified by chromatography using hexanes-EtOAc (95:5). The average yields ofthe beta-ketoesters were 30-50%.
  • Step 2 The beta-ketoester (347 mmol) and 2-cyanoacetamide (347 mmol) were placed into a 500 mL round-bottomed flask and dissolved in 100 mL of THF under Ar. To this solution was slowly added a solution of KOH (1.1 equiv., 25.2 g, 382 mmol) in 150 mL MeOH. The solution allowed to stir at 70 °C for 8 h, during which time a solid slowly formed. The reaction mixture was cooled the solution to rt and the solid was filtered. The solid was dissolved in warm water (250 mL) and concentrated. HCI was added slowly until the pH was 1 - 2.
  • KOH 1.1 equiv., 25.2 g, 382 mmol
  • the resulting solid was filtered and dried to afford the 4-substituted-2,6-dihydroxy-3- cyanopyridine.
  • the average yields ofthe 4-substituted-2,6-dihydroxy-3-cyanopyridines were 30-90%.
  • Step 3 In a 500 mL round-bottomed flask were placed the 4-substituted-2,6-dihydroxy-3- cyanopyridine (314 mmol) and POCl 3 (3.3 equiv, 1035 mmol, 95.3 mL) under Ar. Triethylamine (471 mmol, 65.5mL) was added very slowly using an ice bath for cooling. The reaction mixture was heated to 130 °C for 8 h under Ar after the addition was finished. After cooling to rt, the reaction mixture was concentrated in vacuo and poured into ice (150 g). The residue was partitioned between CH 2 C1 2 (3 x 200 mL) and ice water.
  • the separated organic layer was washed sequentially with NaHCO 3 (saturated 200 mL) and H 2 O (200 mL), then dried over Na 2 SO .
  • the filtrate was concentrated and purified by column chromatography using hexanes-EtOAc (80:20) as eluant. The average yields ofthe 4- substituted-2,6-dichloro-3-cyanopyridines were 35-50%.
  • Step 4 Into a 500 mL round-bottomed flask were placed the 4-substituted-2,6-dicbloro-3- cyanopyridines (232 mmol), 10% Pd/C (2.0 g), Et 3 N (927 mmol, 130 mL) and EtOH (300 mL). The mixture was hydrogenated at atmospheric pressure for 24 to 48 h at rt. The catalyst was removed by filtration and the filtrate was concentrated. The residue was partitioned between CH 2 C1 2 (3 x 200 mL) and H 2 O (200 mL), and then the separated organic layer was dried over Na 2 SO 4 . Concentration and purification by column chromatography usin he aire ⁇ tO ⁇ c ⁇ (95 ⁇ 5 ⁇ — of 85-95%.
  • Step 1 Ethyl 3-oxohexanoate (50 g, 0.32 mol) and 2-cyanoacetamide (26.6 g, 0.32 mol) were dissolved in methanol (100 mL). A solution of KOH (20.7 g, 0.37 mol) in methanol (150 mL) was added slowly using an additional funnel. The resulting mixture was refluxed at 70 °C overnight. After the reaction, the white precipitate that formed was filtered and collected. The crude product was dissolved in warm water (250 mL, 50-60 °C). Concentrated HCI was added dropwise with stirring until the pH was 1 -2.
  • Step 2 Under Ar, POCl 3 (56.5 mL, 0.614 mol) was added dropwise into an ice-bath cooled, three-neck round-bottomed flask containing 2,6-dihydroxy-4-propyl-3-pyridinecarbonitrile (33.1 g, 0.186 mol). Then Et 3 N (38.86 mL, 0.279 mol) was added into the mixture very slowly with cooling. After the addition was complete, the mixture was warmed to rt, then heated under reflux at 140 °C overnight. After cooling to rt, the excess POCl 3 was evaporated. The brown residue that remained was added slowly into 500 g of crushed ice with stirring. Then concentrated NaOH solution was added dropwise with stirring until the pH reached 8.
  • reaction mixture was degassed, filled with Ar, and then degassed again. After this step was repeated 3 more times, H 2 was filled into the flask using a hydrogen balloon. Connected with the hydrogen balloon, the reaction mixture was stined overnight. After the reaction, the mixture was degassed again.
  • the Pd/C was filtered andlT ⁇ eT ⁇ lTfate was evaporat TS ⁇ til-a " light-ydl ⁇ w-pre2ipitate-formed-inside:
  • Step 1 Ethyl 3-oxo-3-phenylpropanoate (51.9 mL, 0.300 mol) and 2-cyanoacetamide (25.2 g, 0.300 mol) were dissolved in ethanol (100 mL). The mixture was heated to 50 °C under Ar. To this reaction mixture was added a solution of KOH (21.8 g, 0.330 mol) in ethanol (100 mL) via an additional funnel. The reaction was refluxed for approximately 17 h. After cooling to rt, the reaction mixture was filtered. The solid product was washed with ethanol and dried in vacuo overnight at 45 °C, providing
  • Step 3 Into a dry round-bottomed flask was charged 5% palladium on carbon (0.38 g) and anhydrous ethanol (5 mL). Into another flask was charged 2,6-dichloro-4-phenyl-3- cyanopyridine (3.83 g, 15.4 mmol), triethylamine (8.57 mL, 61.5 mmol) and anhydrous ethanol (80 mL). This solution was fransfened to the reaction flask and this flask was then purged with Ar. The flask was evacuated and then purged with Ar; this process was repeated twice more. A balloon of H 2 was attached to the flask and the reaction was then purged with hydrogen, then evacuated.
  • Step 1 To a mixture of Cul (1.37, 0.0072 mol), dimethyl sulphide (33.5 mL, 0.46 mol) and 3-cyanopyridine (15.0g, 0.144 mol) in anhydrous THF (390 mL) at -25 to -20 °C was added phenyl chloroformate (23.9 mL, 0.19 mol) and the mixture was stined at this temperature for 15-20 min. To this suspension at -25 to -20°C was added cyclopropyl magnesium bromide
  • Step 2 A mixture ofthe crude dihydropyridine and sulphur (3.9g, 0.144 mol) was heated in decalin (250 mL) for a period of 3 h.
  • Step 1 In a 2000 mL, three-necked flask equipped with an overhead stiner were placed 3- cyanopyridine (20.8 g, 0.2 mol), Cul (1.9 g, 0.01 mol), methyl sulfide (48 mL), and 600 mL of THF under Ar. The solution was cooled to -40 °C and phenylchloroformate (25.1 L, 0.2 mol) was added via an additional funnel with stirring. After 25 min, 0.1 M solution o ⁇ tert- butylmagnesium chloride in THF (200 mL, 0.2 mol) was added dropwise over lh. The mixture was stined at -40 °C for 2 h, then at rt overnight.
  • Step 2 The intermediate dihydropyridine (10.0 g) was dissolved in dry toluene (100 mL). A solution of o-chloranil (12.3 g, 0.5 mol) in 70 mL of acetic acid was added dropwise. The mixture was stined at rt for 8 h and then concenfrated. Toluene (100 mL), ether (100 mL), celite (10 g), and 10% NaOH solution (200 mL) were then added. The mixture was stined for 15 min and filtered through celite.
  • Step 1 A stined mixture of (l-ethoxylidene)malononitrile (50 g, 0.36 mol), dimethylformamide dimethyl acetal (84.9 mL, 0.6 mol) and anhydrous methanol (110 mL) was refluxed under Ar for 1 h, then left to cool and stand at rt overnight.
  • Step 2 Hydrogen chloride gas was vigorously bubbled into a stined suspension of 1,1 - dicyano-2-methoxy-4-dimethylamino-l,3-butadiene (8.29 g, 46.8 mmol) in anhydrous methanol (178 mL) for 5 min periods twice during the day, then left to stir at rt over the weekend.
  • the yellow solution was concentrated in vacuo, and the resulting solid stined in methanol while sodium bicarbonate was cautiously added until gas evolution ceased, and the pinkish-red liquid was basic to pH paper.
  • the reaction mixture was concentrated to a solid, triturated with dichloromethane, and then filtered.
  • Step 3 A solution of 2-chloro-3-cyano-4-methoxypyridine (3.4 g, 20.0 mmol) in anhydrous ethanol (75 mL) was hydrogenated over 5% Pd/C (340 mg) at 10 psi. Upon completion of the reaction, catalyst was removed by filtration. The filtrate was in vacuo to afford 2.54 g (94.7%) of 4-methoxy-3 -cyanopyridine as a colorless solid.
  • Hydrogen sulfide gas was bubbled into a solution of 6.0 g (51 mmol) of 3-pyridylacetonitrile in 100 mL anhydrous DMF under Ar at rt at a moderate rate for 20 min.
  • the reaction was warmed to 60 °C, then a solution of diethylamine (7.88 mL, 76.5 mmol) in 10 mL DMF was added in one portion. After 1.5 h, the reaction mixture was cooled and Ar was bubbled through the reaction for 1 h. The DMF was evaporated. The residue was dissolved in EtOAc and purified by flash chromatography using EtOAc as eluant. 1H NMR and MS data were consistent with the product.
  • Isoquinoline-4-thiocarboxamide was prepared according to General Method B:
  • 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 stined at rt under Ar. Phenyl chloroformate (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 ofthe intermediate dihydropyridine (134.3 g, 0.52 mol) in dichloromethane (100 mL) was added to a stined suspension of sulfur (16.67 g, 0.52 mol) in decalin and slowly heated to reflux under an Ar sweep. After refluxing 1 h, the reaction mixture was allowed to cool to rt, then filtered through a pad of silica gel.
  • Step 1 To a mixture of Cul (78.5g, 0.412 mol), dimethyl sulphide (203 mL, 2.76 mol) and 3-acetyl pyridine (50.0g, 0.412 mol) in anhydrous THF (1100 L) at rt was added phenyl chloroformate (55.2 mL, 0.44 mol) and the mixture was stined 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 stined at this temperature for 30 min, then warmed slowly to rt over 1.0-1.5 h.
  • Step 1 Cyclopropyl bromide (50.0 g, 413 mmol) was dissolved in 500 mL of anhydrous THF. Dry magnesium (10.0 g, 411 mmol) was charged to a round-bottomed flask containing a catalytic amount of iodine. 20% ofthe solution ofthe cyclopropyl bromide solution was then charged into the flask. After observing bubble formation, the remaining cyclopropyl bromide solution was added over 15 min, thereby causing the reaction mixture to reflux. After 30 min, a 5.0 mL aliquot ofthe reaction mixture was taken to determine the concentration ofthe Grignard reagent.
  • the reaction mixture was allowed to warm to rt and then quenched with 400 mL of 20% aqueous ammonium chloride. Ethyl acetate (200 mL) was added. The organic layer was collected and the aqeuous layer was washed with 400 mL of ethyl acetate. The organic layers were combined, washed with brine, and then concentrated in vacuo. The residue was dissolved in dichloromethane and chromatographed on silica gel using a Biotage Flas ⁇ TTbL column, first el ⁇ tlng with ⁇ -E7o ' flO%-EtOAc :: hcxan"e7and-then with 4 L of 15% EtOAc-hexane.
  • the oragnic layer was then washed with 250 mL of brine, dried with sodium sulfate, filtered, and concentrated to obtain 2.13 g of an oil.
  • the acidic aqueous layers were extracted again with 500 mL of dichloromethane.
  • the reaction mixture was cooled to rt, during which time crystals precipitated out ofthe reaction solution.
  • the crystals were filtered and rinsed with 24% aqueous HBr.
  • the crude yield was 7.19 g (77%).
  • the material was recrystallized from 24% aqueous HBr, providing 5.18 g (56%) ofthe title compound.
  • 2-(2-Bromoacetyl)pyridine hydrobromide was prepared from 2-acetylpyridine according to the method used for 3-(2-bromoacetyl)pyridine hydrobromide, 23% yield.
  • 4-(2-Bromoacetyl)pyridine hydrobromide was prepared from 4-acetylpyridine according to the method used for 3-(2-bromoacetyI)pyridine hydrobromide, 44% yield.
  • 3-Acetylpyridine (5 g, 4.3 mL, 41.3 mmol) was dissolved in ether and the solution was cooled to 0 °C under Ar. A solution of 2N HCl/ether (1.2 eq, 25 mL) was added, and a white solid precipitated. The solid was rinsed with ether and dried, yielding 5.98 (92%) ofthe HCI salt.
  • the 3-acetyl pyridinium hydrochloride was then dissolved in 1 eq of IN HCI. An equivalent of N-chlorosuccinimide was added and the reaction was refluxed overnight. Ether was added to the reaction mixture; a solid precipitated. The solid was washed with ether and dried under vacuum, providing 6.52 g (83% > ) ofthe title compound. The product was used without further purification.
  • 4-(2-Ethyl)-3-(2-chloroacetyl)pyridine was prepared from 4-(2-ethyl)-3-acetylpyridine according to the method used to prepare 4-methyl-3-(2-chloroacetyl)pyridine. MS and NMR data were consistent with the structure and the product was used without further purification.
  • 4-(l-Propyl)-3-(2-chloroacetyl)pyridine was prepared from 4-(l-propyl)-3-acetylpyridine according to the method used to prepare 4-methyl-3-(2-chloroacetyl)pyridine. MS and NMR data were consistent with the structure and the product was used without further purification.
  • 4-(tert-Butyl)-3-(2-chloroacetyl)pyridine was prepared from 4-(tert-butyl)-3-acetylpyridine according to the method used to prepare 4-methyl-3-(2-chloroacetyl)pyridine. MS and NMR data were consistent with the structure and the product was used without further purification.

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AU2002362603A1 (en) 2003-04-07
WO2003027085A3 (en) 2003-12-04
JP2005528325A (ja) 2005-09-22
WO2003027096A1 (en) 2003-04-03
CA2461363A1 (en) 2003-04-03
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WO2003027107A1 (en) 2003-04-03
WO2003027095A1 (en) 2003-04-03
WO2003027094A3 (en) 2003-10-23
WO2003027094A2 (en) 2003-04-03
JP2005532983A (ja) 2005-11-04
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WO2003027085A2 (en) 2003-04-03

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