Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
  • C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
  • C07C321/20—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/02—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms
  • C07C317/10—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
  • C07C323/02—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/07—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings

Definitions

• the invention relates to compositions and methods for the treatment of cancer.
• Extracellular signals received at transmembrane receptors are relayed into the cells by the signal transduction pathways (Pelech et al., Science 257:1335 (1992)) which have been implicated in a wide array of physiological processes such as induction of cell proliferation, differentiation or apoptosis (Davis et al., J. Biol. Chem. 268:14553 (1993)).
• the Mitogen Activated Protein Kinase (MAPK) cascade is a major signaling system by which cells transduce extracellular cues into intracellular responses (Nishida et al., Trends Biochem. Sci. 18:128 (1993); Blumer et al., Trends Biochem. Sci. 19:236 (1994)).
• ERKs Extracellular-Signal-Regulated Kinases
• ERK-1 and ERK-2 are the archetypal and best-studied members of the MAPK family, which all have the unique feature of being activated by phosphorylation on threonine and tyrosine residues by an upstream dual specificity kinase (Posada et al., Science 255:212 (1992); Biggs III et al., Proc. Natl. Acad. Sci. USA 89:6295 (1992); Garner et al., Genes Dev. 6:1280 (1992)).
• JNK-1 and JNK-2 c-Jun NH2-terminal kinases 1 and 2
• SPKs stress-activated protein kinases
• the activated JNK binds to the amino terminus of the c-Jun protein and increases the protein's transcriptional activity by phosphorylating it at ser63 and ser73 (Adler e a/., Proc. Natl. Acad. Sci. USA 89:5341 (1992); Kwok et al., Nature 370:223 (1994)).
• Thr-Pro-Tyr JNK
• Thr-Glu-Tyr ERK
• Phosphorylation of MAPKs and JNKs by an external signal often involves the activation of protein tyrosine kinases (PTKs) (Gille et al., Nature 358:414 (1992)), which constitute a large family of proteins encompassing several growth factor receptors and other signal transducing molecules.
• PTKs protein tyrosine kinases
• Protein tyrosine kinases are enzymes which catalyze a well defined chemical reaction: the phosphorylation of a tyrosine residue (Hunter et al., Annu Rev Biochem 54:897 (1985)). Receptor tyrosine kinases in particular are attractive targets for drug design since blockers for the substrate domain of these kinases is likely to yield an effective and selective antiproliferative agent.
• the potential use of protein tyrosine kinase blockers as antiproliferative agents was recognized as early as 1981 , when quercetin was suggested as a PTK blocker (Graziani et al., Eur. J. Biochem. 135:583-589 (1983)).
• MAPK extracellular signal-regulated kinases which constitute the Ras/Raf/MEK/ERK kinase cascade (Boudewijn etal., Trends Biochem. Sci. 20, 18 (1995)). Once this pathway is activated by different stimuli, MAPK phosphorylates a variety of proteins including several transcription factors which translocate into the nucleus and activate gene transcription. Negative regulation of this pathway could arrest the cascade of these events.
• Oncoproteins in general, and signal transducing proteins in particular, are likely to be more selective targets for chemotherapy because they represent a subclass of proteins whose activities are essential for cell proliferation, and because their activities are greatly amplified in proliferative diseases.
• the biologically active compounds are in the form of (Z)-styryl benzylsulfones. It is a further object of the invention to provide intermediates useful for the preparation of compounds having anticancer activity.
• the intermediates comprise (Z)-styryl benzylsulfides. /57872
• compositions comprising a pharmaceutically acceptable carrier and one or more compounds of the formula I
• R 1 is selected from the group consisting of hydrogen, chloro and nitro
• R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo, iodo and fluoro;
• R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo, iodo and fluoro; provided at least one of R or R 2 is hydrogen.
• R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo and fluoro; and R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo and fluoro. According to another embodiment, at least one of R 2 , R 3 and R 4 is iodo.
• compositions of compounds of formula I are provided wherein R., is hydrogen. More preferably, R 1 and R 3 are hydrogen, and R 2 and R 4 are independently selected from the group consisting of chloro, fluoro, iodo and bromo, most preferably selected from chloro, bromo and fluoro.
• novel compounds of formula I are provided where R 1 ( R 2 , R 3 and R 4 are defined as above, provided:
• R 1 or R 2 are hydrogen;
• Ri and R 2 may not both be hydrogen when:
• R 3 and R 4 are both hydrogen, (ii) R 3 is chloro and R 4 is hydrogen, or (iii) R 4 is chloro and R 3 is hydrogen; and (c) when R 1 is hydrogen and R 2 is methyl: (i) both R 3 and R 4 may not be hydrogen,
• R 3 may not be chloro when R 4 is hydrogen, and (iii) R 4 may not be chlcro when R 3 is hydrogen.
• R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo and fluoro; and R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo and fluoro.
• at least one of R 2 , R 3 and R 4 is iodo.
• R ⁇ is hydrogen in the novel compounds of the invention. More preferably, R 1 and R 3 are hydrogen, and R 2 and R 4 are independently selected from the group consisting of chloro, fluoro, iodo and bromo, most preferably selected from chloro, bromo and fluoro.
• novel (Z)- styryl benzylsulfides are provided which are useful as intermediates in the preparation of the biologically active (Z)-styryl benzylsulfones.
• the (Z)- styryl benzylsulfides have the formula: /57872
• R 1 is selected from the group consisting of hydrogen, chloro and nitro
• R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo, iodo and fluoro, provided that at least one of R or R 2 is hydrogen;
• R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo, iodo and fluoro; provided: (a) at least one of R or R 2 is hydrogen;
• R- and R 2 may not both be hydrogen when: (i) R 3 and R 4 are both hydrogen, (ii) R 3 is chloro and R 4 is hydrogen, or (iii) R 4 is chloro and R 3 is hydrogen; and (c) when R, is hydrogen and R 2 is methyl:
• R 3 and R 4 may not be hydrogen, (ii) R 3 may not be chloro when R 4 is hydrogen, and (iii) R 4 may not be chloro when R 3 is hydrogen.
• R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo and fluoro; and R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo and fluoro.
• at least one of R 2 , R 3 and R 4 is iodo.
• R 1 is hydrogen in the aforementioned intermediates. More preferably, R 1 and R 3 are hydrogen, and R 2 and R 4 are independently selected from the group consisting of chloro, fluoro, iodo and bromo, most preferably selected from chloro, bromo and fluoro.
• R 2 , R 3 and/or R 4 is halogen
• the halogen is preferably selected from the group consisting of chloro, bromo and fluoro.
• lower alkyl is meant straight or branched chain alkyl containing from one to six carbon atoms.
• the preferred alkyl group is methyl.
• lower alkoxy is meant straight or branched chain alkoxy containing from one to six carbon atoms.
• the preferred alkoxy group is methoxy.
• a method of treating an individual for cancer or other proliferative disorder comprising administering to said individual an effective amount of the aforesaid pharmaceutical composition.
• a method of inhibiting growth of tumor cells in an individual afflicted with cancer comprising administering to said individual an effective amount of the aforesaid pharmaceutical composition.
• a method of inducing apoptosis of cancer cells, more preferably tumor cells, in an individual afflicted with cancer comprising administering to said individual an effective amount of the aforesaid pharmaceutical composition.
• certain (Z)- styryl sulfone derivatives selectively kill various tumor cell types without killing normal cells. Without wishing to be bound by any theory, it is believed that the compounds affect the MAPK signal transduction pathway, thereby affecting tumor cell growth and viability. This cell growth inhibition is associated with regulation of the ERK and JNK types of MAPK.
• the compounds of the invention have been shown to inhibit the proliferation of various tumor cells by inducing cell death.
• the compounds are effective against a broad range of tumor types, including but not limited to the following: breast, prostate, ovarian, lung, brain (i.e, glioma) and renal.
• the compounds are also effective against leukemic cells.
• the compounds do not kill normal cells in concentrations at which tumor cells are killed.
• Treatment of this broad range of tumor cells with the styryl sulfone compounds of the invention leads to inhibition of cell proliferation and induction of apoptotic cell death.
• the effect is observed for estrogen receptor (ER) positive as well as estrogen receptor negative cells.
• the compounds are also useful in the treatment of non- cancer proliferative disorders, including but not limited to the following: hemangiomatosis in new born, secondary progressive multiple sclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganlioneuromatosis, keloid formation, Pagets Disease of the bone, fibrocystic disease of the breast, Peronies and Duputren's fibrosis, restenosis and cirrhosis.
• non- cancer proliferative disorders including but not limited to the following: hemangiomatosis in new born, secondary progressive multiple sclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganlioneuromatosis, keloid formation, Pagets Disease of the bone, fibrocystic disease of the breast, Peronies and Duputren's fibrosis, restenosis and cirrhosis.
• Tumor cells treated with the compounds of the invention accumulate in the G2/M phase of the cell cycle. As the cells exit the G2/M phase, they appear to undergo apoptosis. Treatment of normal cells with the styryl sulfones does not result in apoptosis.
• sulfones of the present invention block the phosphorylating capacity of ERK-2.
• the styryl sulfones of the present invention enhance the ability of JNK to phosphorylate c-Jun protein compared to mock-treated cells. Without wishing to be bound by any theory, this result suggests that the styryl sulfones may be acting like pro-inflammatory cytokines or UV light, activating the JNK pathway, which in turn may switch on genes responsible for cell growth inhibition and apoptosis.
• the compounds of the present invention were prepared by synthetic methods yielding pure compounds in the (Z)-isomeric configuration.
• the nucleophilic addition of the appropriate thiols to substituted phenylacetylene with subsequent oxidation of the resulting sulfide by hydrogen peroxide yields the Z- styryl sulfone.
• the procedure is generally described by Reddy et al., Sulfur Letters 13:83 (1991), the entire disclosure of which is incorporated herein as a reference.
• the sodium salt of benzyl mercaptan or the appropriate substituted benzyl mercaptan is allowed to react with phenylacetylene or the appropriate substituted phenylacetylene forming the pureZ- isomer of the corresponding styryl benzylsulfide in good yield.
• the styryl sulfones of the invention may be administered in the form of a pharmaceutical composition, in combination with a pharmaceutically acceptable carrier.
• the active ingredient in such formulations may comprise from 0.1 to 99.99 weight percent.
• pharmaceutically acceptable carrier is meant any carrier, diluent or excipient which is compatible with the other ingredients of the formulation and to deleterious to the recipient.
• the compounds of the invention may be administered to individuals (mammals, including animals and humans) afflicted with breast /57872
• the compounds may be administered by any route, including oral and parenteral administration.
• Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, rectal, or subcutaneous administration.
• the active agent is preferably administered with a pharmaceutically acceptable carrier selected on the basis of the selected route of administration and standard pharmaceutical practice.
• the active agent may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. See Gennaro Alphonso, ed., Remington's Pharmaceutical Sciences, 18th Ed., (1990) Mack Publishing Co., Easton, PA. Suitable dosage forms may comprise, for example, tablets, capsules, solutions, parenteral solutions, troches, suppositories, or suspensions.
• the active agent may be mixed with a suitable carrier or diluent such as water, an oil, saline solution, aqueous dextrose (glucose) and related sugar solutions, or a glycol such as propylene glycol or polyethylene glycol.
• Solutions for parenteral administration preferably contain a water soluble salt of the active agent.
• Stabilizing agents, antioxidizing agents and preservatives may also be added.
• Suitable antioxidizing agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA.
• Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.
• the active agent may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, or other suitable oral dosage forms.
• the active agent may be combined with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and then formed into tablets by conventional tableting methods.
• a daily dosage of from about 0.05 to about 50 mg/kg/day may be utilized. Higher or lower doses are also contemplated.
• A. Cells The effect of the Z-styryl sulfones on normal fibroblasts and on tumor cells of breast, prostate and ovarian origin was examined utilizing the following cell lines: breast tumor cell lines: MCF-7, BT-20 and 435; prostate tumor cell lines LnCaP and DU-145; and ovarian tumor cell lines OVCAR and SKOV3.
• NIH/3T3 and HFL cells which are normal murine and human fibroblasts, respectively, were also tested.
• LnCap is an androgen-dependent prostate tumor cell line.
• MCF-7 is an estrogen- responsive breast tumor cell line
• BT-20 and 435 are estrogen- unresponsive breast tumor cell lines.
• MCF-7, BT-20 and 435 were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum supplemented with penicillin and streptomycin.
• DMEM Dulbecco's modified Eagle's medium
• LnCaP and Du145 were cultured in RPM I with 10% fetal bovine serum containing penicillin and streptomycin.
• NIH3T3 and HFL cells were grown in DMEM containing 10% calf serum supplemented with penicillin and streptomycin. All cell cultures were maintained at 37°C in a humidified atmosphere of 5% C0 2 .
• Examples 8 and 14 Two of the twenty compounds tested (Examples 8 and 14) had kill rates of over 75%; three compounds (Examples 6, 10, and 16) had rates of 60-70%.
• the five compounds exhibiting the highest activity contained halogen in the 4-position in Formula I.
• Normal cells HFL and NIH 3T3 were treated with the same compounds in Table 1 under the same conditions of concentration and time. The normal cells were not killed.
• Example 22 The procedure of Example 22 was followed for certain of the (Z)-benzylsulfones, substituting the following cancer cell lines: lung, N417 and H157; renal, CAKI-1 and CAKI-2; glioma, U87 and SW1088. The results are set forth in Table 2.

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• 1999
  • 1999-03-31 US US09/282,855 patent/US6201154B1/en not_active Expired - Lifetime
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