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WO1994005276A1 - Composes cytotoxiques - Google Patents

Composes cytotoxiques Download PDF

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Publication number
WO1994005276A1
WO1994005276A1 PCT/US1993/008427 US9308427W WO9405276A1 WO 1994005276 A1 WO1994005276 A1 WO 1994005276A1 US 9308427 W US9308427 W US 9308427W WO 9405276 A1 WO9405276 A1 WO 9405276A1
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substituted
hydrazone
group
hydroxy
halogen
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Lee Roy Morgan
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • C07D335/14—Thioxanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D335/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/88—Nitrogen atoms

Definitions

  • tamoxifen which is especially useful in the palliative treatment of advanced carcinoma of the breast in post-menopausal women.
  • tamoxifen is usually ineffective against non-estrogen-dependent tumors and is generally less effective in pre-menopausal women.
  • tamoxifen undergoes an isomerization under physiological conditions from a therapeutically useful antiestrogenic compound to an estrogenic isomer which can stimulate the growth of estrogen-dependent tumor cells.
  • U.S. Patent No. 4,732,904 which is incorporated herein by reference, discloses a number of hydrazone compounds that have antiestrogenic activity. These antiestrogenic hydrazone compounds do not undergo isomerization to estrogenic compounds under physiological conditions and the estrogenic side effects observed for tamoxifen are therefore absent. These hydrazone compounds have been proposed as alternative treatments for estrogen-dependent breast cancers.
  • the substituted benzophenone nitrophenyl hydrazones such as 4,4'-dihydroxybenzophenone-2,4- dinitrophenylhydrazone (A-007) are superior anti-cancer agents when compared to the acetophenone and propriophenone nitrophenyl hydrazones.
  • Antiestrogens such as tamoxifen and the hydrazone-based compounds are thought to bind to estrogen or antiestrogen receptors.
  • the complex of the receptor and the antiestrogen may then bind to nuclear chromatin in an atypical manner and for a longer time than the normal hormone receptor complex.
  • antiestrogens may deplete the cytoplasm of free receptor. Either or both of these effects could severely impair the continued growth of an estrogen- dependent tumor.
  • Estrogen-dependent cancer cells have often been observed to eventually lose their ability to produce estrogen- binding protein receptors and degenerate into much more aggressive estrogen-independent life-threatening cancers.
  • a few estrogen-dependent cells originally present in the tumor mass may outgrow the estrogen-independent cells and become predominant. Indeed, the use of antiestrogens to treat estrogen- dependent tumors may lead to the clonal selection of estrogen-independent tumor cells and therefore may promote the conversion of an estrogen-dependent breast cancer to a non-estrogen-dependent breast cancer.
  • cytotoxic compounds are cytotoxic, and differ from antiestrogens in not requiring interaction with an estrogen receptor to exert their therapeutic action.
  • An exaimle of such a cytotoxic compound is the anthracycline antibiotic doxorubicin, also known as ADRIAMYCIN. This compound exerts its antineoplastic activity by preferentially affecting rapidly dividing tumor cells.
  • the underlying principle of chemotherapy using general cytotoxic agents is based upon the observation that malignant tumor cells replicate at a higher rate than normal body cells and are therefore correspondingly more susceptible to these compounds. Because clonogenic malignant cells can give rise to sufficient progeny to kill the host, it is necessary to destroy every such malignant cell in order to achieve a cure.
  • the cell-kill caused by antineoplastic agents follows first order kinetics; that is, a constant percentage, rather than a constant number, of cells is killed by a given therapeutic application.
  • This finding has had a profound impact on clinical cancer chemotherapy.
  • a patient with advanced acute ly phocytic leukemia might harbor 10 12 or about 1 kg of malignant cells.
  • a drug capable of killing 99.99% of these cells would reduce the tumor mass to about 100 mg, and this would be apparent as a complete clinical remission.
  • 10 8 malignant cells would remain, any of which could cause a relapse in the disease.
  • the logical outgrowth of these concepts has been the attempt to achieve total cell-kill by the use of several chemotherapeutic agents concurrently or in rational sequences.
  • cytotoxic agents Many of the most potent cytotoxic agents have activity only against cells that are in the process of division. Accordingly, human malignancies that are currently most susceptible to chemotherapeutic agents are those with a large growth fraction, that is, a high percentage of cells in the process of division. Similarly, normal tissues that proliferate rapidly (for example, bone marrow and intestinal epithelium) are subject to damage by some of these potent cytotoxic drugs, and such toxicity often limits utility. On the other hand, slow growing tumors with a small growth fraction, for example carcinomas of the colon or lung, are often unresponsive to cytotoxic drugs.
  • anthracycline antibiotic doxorubicin is one of the most effective agents described to date for the treatment of estrogen-independent breast tumors. A number of important biochemical effects have been described for doxorubicin and related anthracycline antibiotics, any one or all of which could play a role in the therapeutic and toxic effects of such drugs.
  • doxorubicin is relatively effective against a number of solid tissue tumors, including breast carcinoma, some tumors may be resistant or may develop resistance to this compound.
  • Pleiotropic drug resistance to the anthracycline antibiotics appears to result from acceleration of the efflux of anthracyclines and other agents from the cell.
  • a membrane associated glycoprotein, synthesized in high quantity as a result of gene amplification, has been implicated (Myers et al. Antitumor Antibiotics I:
  • doxorubicin can result in serious toxic manifestations.
  • Total dosage of doxorubicin as low as 250 mg/m 2 can cause myocardial toxicity.
  • Such chronic, cumulative dose- related toxicity is manifested by congestive heart failure that issunresponsive to digitalis and a mortality rater,in excess of 50%.
  • the risk of myocardial toxicity is greater than 20% of patients at total doses higher than 550 mg/m 2 .
  • the selection of a particular drug for antineoplastic chemotherapy-is therefore based on a nuir'jer of considerations including estrogen receptor status of the tumor, the potential for drug resistance and the side effects of administering the drug. If a treatment regime includes multi-drug therapy, the potential for complex side effects is greatly increased.
  • the current drug of choice for treating estrogen- dependent breast cancer is tamoxifen; this drug can present problems caused by the isomerization of the drug to a tumor-promoting estrogenic form.
  • the antiestrogenic hydrazones disclosed in U.S. Patent No. 4,732,904 offers an alternative to tamoxifen.
  • neither these hydrazones nor tamoxifen are known to be effective against estrogen-independent tumors.
  • the need for new and improved cancer chemotherapeutic is demonstrated by the intense research anc? development activity in this area.
  • Another object of the present invention is to provide an improved method for the treatment of estrogen-independent tumors, which compounds are not associated with doxorubicin induced cardiotoxicity.
  • Yet another object is to provide improved compounds that have an anti-viral activity. Finally, it is also an object of the present invention to provide such compounds having minimal toxic effects.
  • DHBDNP 2,4-dinitrophenylhydrazone
  • neoplastic cells which are not necessarily estrogen dependent cells
  • exposing the neoplastic cells to an effective amount of a compound sufficient to inhibit growth of the neoplastic cells.
  • the compound has the formula X - R 1 wherein X is phenyl substituted with one or more substituents selected from the group consisting of nitro, lower alkyl (preferably methyl) , and trihalomethyl; and R 1 is selected from the group consisting of (a) a benzophenone hydrazone, with one or more substituents on the benzophenone selected from the group consisting of halogen, hydroxy, acetoxy and lower alkoxy, wherein a benzophenone substituted with only lower alkoxy or only hydroxy has at least one of the alkoxy or hydroxy substituents in an ortho position on the benzophenone; (b) a substituted or unsubstituted xanthone hydrazone, wherein the substituted xanthone hydrazone is substituted on the xanthone with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, acetoxy and halogen; (c) a substituted or unsubsti
  • the present invention includes any one of these groups (a) through (j), or any combination of (a) through (j), for R 1 .
  • the lower alkoxy substitution on R 1 may be methoxy or ethoxy, but is preferably ethoxy.
  • the lower alkyl substituent on X is methyl or ethyl.
  • the present invention provides a method of impairing growth of neoplastic cells by exposing the neoplastic cells to an effective amount of a compound sufficient to inhibit growth of the neoplastic cells.
  • the compound has the formula X - R 1 wherein X is phenyl substituted with one or more substituents selected from the group consisting of methyl and trihalomethyl, and R 1 is benzophenone hydrazone, substituted on the benzophenone with one or more substituents selected from the group consisting of halogen, hydroxy and lower alkoxy, such as methoxy.
  • the method of impairing growth of neoplastic cells comprises exposing the neoplastic cells to an effective amount of a compound sufficient to inhibit growth of the neoplastic cells.
  • the compound is selected from the group consisting of 4-fluoro-4'-hydroxybenzophenone-2,4- dinitrophenylhydrazone; 2,6-dihydroxyanthraquinone-bis- 2,4-dinitrophenylhydrazone; 1,8-dihydroxyanthraquinone- 10-(2,4-dinitrophenylhydrazone) ; 1,2- dihydroxyanthroquinone-10-2-(2,4- dinitrophenylhydrazone) ; 6,9-diacetoxyanthraquinone-10- (2,4-dinitrophenylhydrazone) ; 2,4-dihydroxybenzophenone-
  • 2,4-dinitrophenylhydrazone 4,4-dimethoxy-2,2' - dihydroxybenzophenone-2,4-dinitrophenylhydrazone; 4,4 ' - dihydroxybenzophenone-2,4-dimethylphenylhydrazone; 2- hydroxyfluoren-9-one-2,4-dinitrophenylhydrazone; xanthone-2,4-dinitrophenylhydrazone; 2,7- difluoroxanthone-2,4-dinitrophenylhydrazone; 2,4,4'- trihydroxybenzophenone-2,4-dinitrophenylhydrazone; 4,4'- dihydroxybenzophenone-2-nitrophenylhydrazone; 2, 2 ' ,4,4'- tetrahydroxybenzophenone-2,4-dinitrophenylhydrazone;
  • hydrazones which are suitable for use in the method of treatment or in compositions that include a pharmaceutically inert carrier, the hydrazones may be represented by the formula
  • R 1 H, 0C0CH3 or OH
  • R 2 H, halogen, OCOCH 3 , or OH
  • R 3 H, OH, halogen, OCOCH 3 , or lower alkoxy
  • R 4 H, OCOCH 3 or OH
  • R 7 H, OH, or OCOCH 3
  • R 8 H, OH, halogen, OCOCH 3 , or lower alkoxy
  • R 9 H, halogen, OCO Ha, or OH
  • R 10 H or OH
  • each of R ⁇ R 4 and R 7 -R 10 is independently selected from the group consisting of hydrogen, hydroxy, acetoxy, lower alkoxy and halogen, and R 11 is hydrogen, and R 5 and R 6 together form i) a single bond of a five membered ring, or ii) an oxygen in a six membered ring, or iii) a carbonyl in a six membered ring, or iv) a carbon in a six membered ring; or v) a nitrogen with or without substitution in a six membered ring; or vi) a sulfur in a six membered ring; or vii) two carbons connected by a double bond in a seven membered ring; or
  • each of R 1 -R 4 and R 7 -R 9 is independently selected from the group consisting of hydrogen, hydroxy, acetoxy, lower alkoxy and halogen, and R 10 and R 11 together form a carbonyl of a six membered ring, and R 5 and R 6 together form i) a single bond of a five membered ring, or ii) an oxygen in a six membered ring, or i ⁇ ) a carbonyl in a six membered ring, or iv) a carbon in a six membered ring; or v) a nitrogen with or without substitution in a six membered ring; or vi) a sulfur in a six membered ring; or vii) two carbons connected by a double bond in a seven membered ring; or
  • each of R ⁇ R* and R 7 -R 10 is independently selected from the group consisting of hydrogen, hydroxy, acetoxy, lower alkoxy and halogen, R 11 is hydrogen and R 5 and R 6 together form a carbon in a six membered ring linked to phenylhydrazone substituted with one or more substituents selected from the group consisting of nitro, methyl and trihalomethyl; or
  • R 11 is H and each of R 1 -R 10 is independently selected from the group consisting of hydrogen, hydroxy, acetoxy, lower alkoxy and a halogen and wherein at least one of R 1 -R 10 is a halogen and wherein at least one of R 1 -
  • R 10 is a hydroxy
  • the halogen substitutions in (a) - (e) are preferably chlorine or fluorine.
  • the lower alkoxy is methoxy or ethoxy.
  • the present invention also includes the substitution patterns of any one of (a) through (e) , or any combination of these groups.
  • a subset of the hydrazones of the present invention comprises: 4-fluoro-4'-hydroxybenzophenone-
  • 2,4-dinitrophenylhydrazone 2, 6-dihydroxyanthraquinone- bis-2,4-dinitrophenylhydrazone; 1,8- dihydroxyanthraquinone-10-(2,4-dinitrophenylhydrazone) ; 2,4-dihydroxybenzophenone-2,4-dinitrophenylhydrazone; 2 ,4-dihydroxyfluoren-9-one-2,4-dinitrophenylhydrazone; 4,4'-dimethoxy-2,2'-dihydroxybenzophenone-2,4- dinitrophenylhydrazone; 2-hydroxyfluoren-9-one-2,4- din trophenylhydrazone; xanthone-2,4- dinitrophenylhydrazone; 2,4,4'-trihydroxybenzophenone- 2,4-dinitrophenylhydrazone; 2,2', 4,4'- tetrahydroxybenzophenone-2,4-dinitrophenylhydrazone; 2,
  • a therapeutically effective amount of the compound is suspended in a pharmaceutically inert carrier such as peanut oil.
  • a pharmaceutically inert carrier such as peanut oil.
  • the compounds can be made into a pill for oral administration.
  • the compound could also be combined with an aqueous vehicle for injection for systemic use.
  • the compound can be placed in suitable pharmaceutical solvents, such as propylene glycol, dimethylsulfoxide (DMSO) , inert materials or mixtures thereof, and applied topically to tumor recurrences, of the kind that occur on the chest wall after breast tumors are surgically removed.
  • suitable pharmaceutical solvents such as propylene glycol, dimethylsulfoxide (DMSO) , inert materials or mixtures thereof, and applied topically to tumor recurrences, of the kind that occur on the chest wall after breast tumors are surgically removed.
  • the present invention also includes compounds of the formula
  • each of R x -R 4 and R 7 -R 10 is independently selected from the group consisting of hydrogen, hydroxy, acetoxy, lower alkoxy and halogen and R 11 is hydrogen, and R 5 and R 6 together form i) a carbonyl in a six membered ring; or ii) a carbon in a six membered ring; or iii) a nitrogen with or without substitution in a six membered ring; or iv) a sulfur in a six membered ring; or v) two carbons connected by a double bond in a seven membered ring; or (c) each of R ⁇ R* and R 7 -R 9 is independently selected from the group consisting of hydrogen, hydroxy, acetoxy, lower alkoxy and halogen and R 10 and R together form a carbonyl of a six membered ring, and R 5 and R 6 together form i) a single bond of a five membered ring; or ii
  • FIG. 1 shows the x-ray crystallographic structure of A-007 and a schematic diagram of this coir.pound, showing hydrogen bonding as a dotted line.
  • FIG. 2 is a graph showing the percentage of growth inhibition of two cell lines, FDCP-1 (a bone marrow cell line) and MDA-435 (a human breast cancer cell line) with exposure to increasing concentrations of A-007.
  • FIG. 3 is a graph showing the percentage of growth inhibition of two cell lines, FDCP-1 (a bone marrow cell line) and MDA-435 (a human breast cancer cell line) with exposure to increasing concentrations of doxorubicin.
  • FIG. 4 is a graph showing serum levels of A-007 in a 507 g male Sprague Dawley rat dosed once orally with A-007 ( 1 g/kg) .
  • the curve 1 used acrylonitrile:water 85:15 as an eluant
  • curve 3 used acrylonitrile:water 70:30 as an eluant
  • curve 2 is an average curve of 1 and 2.
  • This unexpected cytotoxic activity is apparently a result of the increased molecular planarity.
  • This increased planarity is produced by planar ring structures, enhanced intramolecular hydrogen bonding and/or the inclusion of polar groups that promote hydrogen bonding.
  • the described compounds share aryl-based structures that have been made more or less polar through substitutions or the aryl structures, or have been made more co-planar through intramolecular hydrogen bonding or fusion of the rings. Additional changes have been introduced into the hydrazone moiety to influence electrostatic distributions and/or polarity.
  • Samples (1 cm) of sterile fresh human cancer ti ⁇ sues with histologies of malignant cancers were obtained from surgical biopsies or resections. Such tissue can be stored in 20-50 cc RPMI-1640 tissue culture medium (Gibco Laboratories) at 5-10°C for up to five days. Tissue samples were transferred under sterile conditions to a laboratory where, under sterile conditions, the tissue was removed from the holding solution and minced by scalpel and scissors.
  • Cellular suspensions were made by cutting the specimen into 0.1 mm fragments in petri dishes with 60 ml of RPMI-1640 tissue culture medium (Gibco Laboratories) containing 10% fetal bovine serum (FBS) (Gibco Laboratories) , 100 units/ml streptomycin (Sigma Chemical Co.) and 100 units/ml penicillin (Sigma Chemical Co.).
  • RPMI-1640 tissue culture medium Gibco Laboratories
  • FBS fetal bovine serum
  • streptomycin Sigma Chemical Co.
  • penicillin Sigma Chemical Co.
  • NUNC SlideFlasks which are available from Nunc, Inc. (Catalog No. 170920 or Flask style 177453). These flasks are described more fully in United States Patent No. 3,726,764.
  • the bottom edge of the flask is sealed to a baseplate slide by a thermoplastic or adhesive seal which is substantially fluid impervious.
  • the seal between the bottom edge of the housing and the baseplate can be selectively broken by prying the baseplate away from housing. This may be achieved by inserting the supplied SlideFlask opener below the flange and prying the housing away from the base by exerting pressure as described by the manufacturer's instructions.
  • the baseplate slide acts as a conventional microscope slide that can be examined under a microscope.
  • the SlideFlask is used as an ordinary small-size culture flask with a culture area of 9 cm 2 . After culturing, the contents are poured out, the bottom of the flask (the slide) is removed by using the SlideFlask opener, air dried, sprayed with Pro-FixxTM (fixation, staining, etc.). The bottom of the flask has standard slide microscopy d ' tensions and is handled exactly as a standard microscopy slide. Employing light microscopy, the cell growth on each slide is counted. Determination of Cytotoxicity
  • Flasks No Test Compound. Flasks were diluted to 6 ml with RPMI-1640 medium containing 10% FBS, 100 ⁇ g/ml streptomycin and 100 units/ml penicillin. Test Flasks Flasks were diluted as in the control flasks to 6 ml with RPMI-1640 medium plus FBS, penicillin and streptomycin and test compounds were added to a final concentration of 0.005-20 ⁇ g/ml.
  • the flasks were incubated for seven (7) to twenty-one (21) days in a 5% C0 2 incubator at 37°C. In some instances, incubation time was extended to obtain sufficient cell numbers to count. Sufficient cell growth was arbitrarily determined to be present when at least 10 cells per high power field (cells/HPF) or ten clumps of cells/HPF were present in the control culture. A minimum of 5 HPFs were counted per flask. After sufficient cell growth in the flasks, the medium and contents were poured out and the slide bottom peeled off using the SlideFlask opener.
  • the slid s which were previously labelled, were air dried for a few minutes and sprayed with a cytofixative (Pro-FixxTM, Lerner Labs) . They were then examined under a conventional light microscope as any cytological or histological slides would ordinarily be examined. If the laboratory has an inverted field microscope, the above slide preparation can be eliminated and the flasks containing cells and liquid content can be counted directly, without preparing and staining the slides. High power fields were scanned, counted and compared in all tissue culture systems. Ten (10) cells/HPF in 5 HPF were considered 100% growth, because sufficient cell growth in the control culture was set at 10 cells/HPF.
  • U.S. Patent No. 4,732,904 discloses that 4,4'- dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A- 007) , the structure of which is shown below, has antiestrogenic activity.
  • A-007 has antiestrogenic activity means that the growth of estrogen-dependent tumor cells is inhibited by this compound.
  • the determination of estrogen-dependent status for tumors, and therefore of potential sensitivity to antiestrogen therapy, may be made by determining the concentration of both estrogen and progesterone receptors on the surface of tumor cells. Tumors are classified as estrogen receptor plus or estrogen receptor minus (ER+/ER-) and progesterone receptor plus or progesterone receptor minus (PgR+/PgR- ) depending on the concentration of receptors present.
  • An ER+ cell is generally considered to be estrogen dependent, but the presence of PgR and ER together appears to be a better indicator of susceptibility to antiestrogen treatment than ER status alone.
  • PgR is detected in approximately two-thirds of ER+ tumors, and is only occasionally found in ER- tumors.
  • Quantitative methods including ligand binding assays, monoclonal antibody assays, and enzyme immunochemical analyses have been used to detect and quantitate the ER and PgR, as disclosed in ACTA Oncologica, 27:1-19 (1988). Using such techniques it has been determined that breast cancer tissue containing ER concentrations greater than 5 fentomoles/ng and PgR concentrations greater than 3 fentomoles/ng is considered sensitive to antiestrogen therapy (J. Clin. Oncol., 1:227-241 (1985)). Generally speaking, the higher the ER/PgR concentrations, the more sensitive the tissue should be to the antiestrogen therapy.
  • Table I The data shown in Table I was generated in a continuing study of the activity of A-007.
  • Cells from human breast tumors were cultured and assayed for sensitivity to A-007 as described above.
  • the estrogen and progesterone receptor concentrations of these cell lines were quantified by conventional methods.
  • Table I it was found that those breast cancer cells with higher ER/PgR values had a lower IC 50 for A-007 and were therefore more sensitive. This finding is in agreement with previous observations.
  • breast cancer cells which had ER/PgR values below those considered to be the threshold level for antiestrogen sensitivity also showed sensitivity to A-007, albeit at a reduced level.
  • the IC 50 for A-007 was 10 ⁇ g/ml for breast cancer cells and tissue which had less than 5 fmol/ ⁇ g protein of ER and less than 3 fmol/ ⁇ g protein of PgR. These ER/PgR levels would therefore classify the tissue as being derived from non-estrogen-dependent tumors, yet A-007 had some activity against it. This suggests that A-007 has cytotoxic activity against non-estrogen- dependent tumor cells and that therefore A-007 may have an additional anti-tumor modality in addition to its antiestrogenic mode of action. Cytotoxic activity as used in this context refers to antineoplastic activity that is not mediated by interaction with estrogen receptors or interference with interaction between estrogen and cellular components such as DNA.
  • ER & PgR estrogen and progesterone receptor values are in fmol/ ⁇ g protein. Tumors with ER and PgR values ⁇ 3 and ⁇ 5 respectively are considered negative for these receptors.
  • EXAMPLE II X-Ray Crystallographic structure of A-007
  • X-ray crystallography data for A-007 shows that the gre-n-diphenyl rings are perpendicular to each other, resulting in a non-planar ring system through the aryl moieties of the molecule.
  • This x-ray crystallographic structure, and the hydrogen bonds are illustrated in FIG. 1.
  • Empirical Formula C 19 H 1 N A 0 5
  • Solubility ethanol, acetone, acetic acid Physical Description: red crystals
  • Solubility acetic acid, acetone, ethanol
  • 2,2'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (1-29) wherein the benzophenone is substituted on each ring of the benzophenone with a hydroxy in the ortho position.
  • Empirical Formula C 19 H 1 N0 6 Molecular Weight: 394 Melting Point: 270 - 271° Solubility: ethanol, acetone, methanol Physical Description: red needles Anal, calc: C, 57.86; H, 3.55; N, 14.21 Found: C, 57,8i; H, 3.54; N, 14.34
  • Empirical Formula C- ⁇ H ⁇ OgN,
  • Solubility acetic acid, ethanol, dimethylsulfoxide
  • Empirical Formula C 19 H 15 N 3 0 ⁇ ,
  • Solubility acetic acid, acetone, ethanol
  • Empirical Formula C 19 H 14 N ⁇ 0 7
  • Solubility acetic acid, acetone, ethanol
  • Xanthone-2,4-dinitrophenylhydrazone (1-75) wherein the aryl structure is an unsubstituted xanthone.
  • Empirical Formula C 19 H 12 N 0 5
  • Empirical Formula C 19 H 12 N,,0 5 Molecular Weight: 376 Melting Point: >270° Solubility: dimethylsulfoxide
  • Empirical Formula C 21 H 2 oN 2 ⁇ 2
  • Solubility acetic acid, dimethylsulfoxide, ethanol
  • Empirical Formula C 21 H 18 Ni,0 8 Molecular Weight: 454 Melting Point: 218 - 219°
  • Solubility acetic acid, acetone, ethanol Physical Description: red crystals
  • 2,4-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (1-131) wherein the benzophenone is substituted with more than one hydroxy on only one of the six membered rings of the benzophenone.
  • Empirical Formula C 19 H 14 N0 6 Molecular Weight: 394 Melting Point: 304 - 304° Solubility: acetone, ethanol, methanol Physical Description: red crystals Anal, calc: C, 57.86; H, 3.55; N, 14.21 Found: C, 57.73; H, 3.51; N, 14.19
  • Empirical Formula C 19 H li( N0 6 Molecular Weight: 394 Melting Point: 304 - 304° Solubility: acetone, ethanol, methanol Physical Description: red crystals Anal, calc: C, 57.86; H, 3.55; N, 14.21 Found: C, 57.7°.; H, 3.51: N, 14.19
  • 1,9-Dihydroxyanthraquinone-10-(2,4-dinitrophenylhydrazo ne) (KT-II-27) wherein the anthraquinone is substituted with more than one hydroxy, in this example on different rings of the anthraquinone.
  • Empirical Formula C 20 H 12 N 4 O 7 Molecular Weight: 420 Melting Point: >280°
  • Solubility dimethylsulfoxide Physical Description: reddish-brown Anal calc: C, 57.86; N, 3.55; N, 14.21 Found: C, 57.78; H, 3.51; N, 14.19
  • Empirical Formula C 26 H 16 N 8 O 10 Molecular Weight: 600 Melting Point: 348°C (dec) Solubility: dimethylsulfoxide, dimethylformamide Physical Description: red crystals
  • Empirical Formula C 19 H 13 N ⁇ ,F0 5
  • Solubility ethanol, acetonitrile, acetone
  • Difluorodibenzosuberenone-2,4-dinitrophenylhydrazone (B-198) wherein the dibenzosuberenone is substituted with at least two halogens, in this instance fluorine,
  • th -anthraquinone is substituted with at least one acetoxy, in this example two acetoxys on the same ring of the anthraquinone.
  • Procedure 1 4-Nitro- or 2,4-dinitrophenyl hydrazine (0.0016 moles) was suspended in 5 ml of methanol. The 4-nitrophenyl hydrazine was used if the 4-nitrophenylhydrazone product was being prepared while the 2,4-dinitrophenylhydrazine was used if a 2,4 dinitrophenylhydrazone was being prepared. Dropwise, 0.4-0.5 ml of concentrated sulfuric acid was cautiously added with stirring and the warm solution filtered. A solution of the carbonyl compound (0.0016 moles) in 5-20 ml of methanol or ethanol was added dropwise to twice the above phenylhydrazine solution.
  • Procedure 2 4-Nitro- or 2,4-dinitrophenyl hydrazine 2.5 g (0.016 moles) was dissolved in 30 ml of 85% phosphoric acid. The solution was diluted with 20 ml of 95% ethanol, allowed to stand and then filtered. The carbonyl compound (0.008 moles) was dissolved in 10-40 ml of ethanol and the calculated volume of the above reagent added, to produce a 2:1 ratio of the 4-nitro- or 2,4-dinitrophenyl hydrazine and ketone, respectively. If a precipitate did not form immediately, it was diluted with a little water. The derivative was collected and recrystallized.
  • 2,4-Dinitrophenylhydrazine (4.8 g, 0.024 mol) was dissolved in 85% phosphoric acid (60 ml) .
  • the solution was diluted with ethanol (40 ml) and heated at 80°C.
  • the solution of 2,2'- dihydroxy-4,4'-dimethoxybenzophenone (5.5 g, 0.02 mol) in ethanol (40 ml) was added for 10 minutes and the heating was continued at 80°C for an additional 4 hours then cooled.
  • the solvent was evaporated and the slurry was diluted with water (200 ml) .
  • EXAMPLE IV Cytotoxicity of Compounds
  • the cytotoxic activity of many of the compounds of the present invention was tested against tumor cells derived from a variety of human cancers by the test assay described in Example I above. As described in Example I, the IC 50 for A-007 against non- estrogen-dependent tumors derived from human breast cancers was determined to be 10 ⁇ g/ml. The data shown in Table III indicates that some of the compounds disclosed herein exhibited even more potent cytotoxic activity than A-007 itself.
  • the specific compounds disclosed above are effective in inhibiting the growth of estrogen- independant tumor cells.
  • Table III show that the IC 50 values for the compounds against cultured tumor cells derived from various human cancers were in the range of 0.05-20 ⁇ g/ml.
  • the most potent compounds included KT-II-27, I-lll and B-193.
  • the amount of KT-II-27 required to produce 50% inhibition of the lung tumor cells tested was 0.05 ⁇ g/ml. Because these compounds are cytotoxic, it will be apparent to one skilled in the art that any amount of one of these compounds will be an effective amount sufficient to inhibit growth of tumor cells. Increasing the dosage of the compound will produce a greater inhibition of growth.
  • the therapeutic index for a particular hydrazone may be determined as described in Example V.
  • Example VI the topical application of an ointment containing 0.25% of A-007 was effective in inhibiting growth of human tumors.
  • the compounds of the present invention have their unexpected cytotoxic effect against tumor cells because of their structural similarities.
  • the mechanism(s) of action of these compounds is presently unknown, however it is believed that the compounds may exert their cytotoxic effect by directly intercalating into DNA.
  • Antiestrogenic compounds including A-007 are thought to disrupt estrogen utilization and to interact with the DNA of the cell, disrupting normal cell function.
  • the hydrazones described herein are effective against tumor cells (such as those derived from human kidney, stomach and lung cancers) which do not have estrogen receptors, and so the formation of an ER/hydrazone complex is not required for cytotoxicity.
  • the compounds of the present invention comprise three primary moieties: (1) a phenyl ring joined through (2) a hydrazine linkage to (3) an aryl ring structure which comprises at least a bicylic ring structure.
  • the common structure may be represented as
  • the steric bulk of the aryl ring (3) is believed to inhibit free rotation about the N-N bond (2) , which diminishes movement of the phenyl ring (1) relative to the aryl ring.
  • this spatial stabilization appears to enhance the cytotoxic activity of these compounds.
  • the present invention also encompasses a number of variations on the basic structure shown above.
  • the variant compounds include those with modified aryl ring structures which may include heterocyclic ring structures, modified hydrazine linkages and substitutions on both the phenyl and aryl- based moieties.
  • the compounds of the present invention may thus be represented as:
  • X is the phenyl ring and R 1 is selected from the following groups:
  • the phenyl ring may be substituted with one or more of the following groups: nitro, lower alkyl and trihalomethyl, preferably nitro and trihalomethyl, most preferably nitro. Suitable combinations also include lower alkyl and trihalomethyl, lower alkyl alone, or triahlomethyl alone. At least some of these groups are believed to have a polarizing effect on the molecule and to influence the resonance of the phenyl ring structure.
  • the compounds of the present invention may include nitrophenyl rings (for example in 1-41) , dinitrophenyl rings (for example in KT-II-27) and dimethylphenyl rings (for example in 1-87) .
  • the aryl ring structure (R 1 ) is substituted with one or more hydroxy, lower alkoxy, acetoxy or halogen groups.
  • the aryl ring structure is substituted with one or more substituents selected from the following groups: hydroxy alone; hydroxy and lower alkoxy; hydroxy, lower alkoxy, and acetoxy; lower alkoxy alone; lower alkoxy and acetoxy; lower alkoxy, acetoxy and halogen; acetoxy alone; acetoxy and halogen; and halogen alone.
  • the lower alkoxy is methoxy or ethoxy
  • the halogen is preferably F or Cl.
  • the hydrazone or phthalazinone structure may be substituted with a single hydroxy group (1-23) , two hydroxy groups (1-29) or four hydroxy groups (1-37) .
  • the aryl moiety may be substituted with one or two alkoxy groups (such as methoxy, which may further be combined with one or more hydroxy groups as in I-lll) one or more halogens (for example, two halogens in 1-26, B-192, B-197, and B-198) , or a single halogen and a single hydroxy (11-61) .
  • the aryl moiety may be substituted with a substituted or unsubstituted phenylhydrazone (B-193) .
  • the aryl group is substituted with one or more acetoxy groups (for example, two acetoxy groups as in KT-II- 95) .
  • the co-planarity between at least part of the aryl-based moiety (for example, the ring structures which form part of the hydrazone or phthalazinone moiety) and the phenyl ring contributes to the cytotoxicity of the claimed compounds.
  • the component rings of the aryl moiety may be non-planar.
  • the aryl-based moiety comprises a tricyclic ring structure, such as in B-181 and KT-II-27, the aryl ring groups are co-planar.
  • Substitution of a hydrogen bonding group, such as hydroxy or acetoxy, in the 2 or 2' position on benzophenone (as in 1-29, I-lll or 1-131) or in the 6 position on anthraquinone (KT-II-95) is also believed to increase molecular planarity by optimizing a hydrogen bonding interaction with the NH of the hydrazine linkage. This is a substitution ortho to the ring carbon that is bonded to the carbon that forms a double bond with the hydrazine nitrogen.
  • the aryl ring is substituted at the 2 position on the benzophenone, which is the position ortho to the 1 position, which is bonded to the carbon (formerly of a carbonyl) that forms the hydrazone linkage.
  • the planarity of the aryl structure is even more evident when the aryl group is an indano phthalazinone (B-187) .
  • Particularly preferred embodiments of this invention which show enhanced cytotoxic activity possess substitutions on both the phenyl and aryl-based ring structures, leading to especially enhanced co-planarity between these moieties.
  • cytotoxicities of the compounds of the present invention were evaluated in granulocyte macrocyte colony forming cells (FDCP-1) , and in MDA-MB- 435 human estrogen-independent breast cancer cells.
  • FDCP-1 cell line was provided by Dr. Joel S. Greenberger, University of Massachusetts Medical Center.
  • Interleukin 3 necessary for the growth of this cell line, was obtained from conditioned medium of murine myelomonocytic leukemia cell lines. Briefly, murine FDCP-1 cells were grown in RPMI 1640 medium without glutamine, with 10% FBS at 37°C for ten (10) to fourteen (14) days.
  • A-007 was tested against the MDA-MD-435 and FDCP-1 cell lines.
  • Cells tested were maintained on plastic in complete Eagle's minimal essential medium supplemented with 5% FBS, sodium pyruvate, nonessential amino acids, L-glutamine, and vitamins. Cells that had been cultured for long periods were discarded, renewing the cultures from frozen stocks after every ten in vitro passages. Unless otherwise specified, all tissue culture reagents were obtained from GIBCO Laboratories (Grand Island, NY) .
  • MDA-MB-435 cells were suspended in medium and seeded at 2,000 to 3,000 cells/well in 96-well tissue culture plates. After an attachment period of eighteen (18) hours for the anchoring dependent lines, the cells were fed with fresh medium (controls) or with medium cont-lining different concentrations of A-007. After an additional 96 hours, the antiproliferative activity was determined by monitoring the number of viable cells. This was accomplished by the tetrazolium (MTT, N2128) assay (Alley et al., Cancer Research 4_8:589-601, 1988.) The MTT procedure has been shown to correlate with cellular protein, dye exclusion, and clonogenic assays under a variety of culture and assay conditions.
  • MTT tetrazolium
  • Assay for In Vitro Myelotoxicity The FDCP-1 cells were harvested during exponential growth.
  • Cell counts were performed using a hemocytometer. The MTT assay was performed as previously described above. Briefly, 2,000 cells were plated in each well of a 96-well microwell flat bottomed plate. This seeding density was chosen to ensure that the cells would be in an exponential growth phase at the end of the four (4) day incubation period. Cells were inoculated with 0.2 ml of McCoy's Medium 5A, supplemented with 10% FBS and 15% WEHI-3 conditioned medium. A-007 and doxorubicin were tested each at five (5) to ten (10) concentrations, covering a 1- to 2-log concentration range, to determine IC 50 data for A-007 as compared to doxorubicin.
  • 0.2 mg (40 ⁇ l of 5 mg/ml) of MTT was added to each well and incubated at 37°C for an additional two (2) hours. Plates were then centrifuged at 450 x g for five (5) minutes. The medium was then aspirated gently from all plates, taking care not to disturb the cells at the bottom of the wells. Dimethyl sulfoxide (150 ⁇ l) was finally added to each well, and the plates were placed on a shaker for ten (10) minutes to solubilize the formazan product. The plates were read immediately thereafter, at 570 nm on an MR 5,000 Micro titer plate reader. Absorbance levels from drug tested cells were compared with untreated control absorbance values. Each test incorporated a cell dose inoculum, and the true control was determined by an extrapolation.
  • Drug survival Curves Drug dose response data were obtained by adding drugs to the cultures after twenty-four (24) hours of incubation, resulting in a four (4) day exposure. A 6- to 8-fold drug concentration range was used. Drug survival curves (FIG. 2 and 3) were generated by plotting surviving fractions against drug concentrations using a linear scale. Drug sensitivity was measured by determining the dose response curve.
  • results allow pre-clinical therapeutic indexes for A-007 to be determined relative to the IC 50 for the FDCP-1 murine hematopoietic progenitor granulocyte macrophage colony forming cell (GMCFC) line.
  • the IC 50 for A-007 on FDCP-1 cells was determined to be 9.52 ⁇ g/ml.
  • the IC 50 for A-007 on MDA-435 was determined to be 2.52 ⁇ g/ml.
  • the therapeutic index (TI) IC 50 FDCP-1/IC 50 MDA-435) for A-007 on MDA-435 cells was therefore determined to be 3.77 (versus FDCP-1) as shown in FIG. 2.
  • Doxorubicin has a T.I.
  • A-007 has a T.I. of 3.77.
  • A-007's T.I. supports its relatively non- myelotoxic and yet useful therapeutic activities toward breast cancer. Calculated and plotted values for growth inhibition in doxorubicin are expressed as the mean value plus or minus the standard error of the mean in FIG. 3.
  • a response occurred within 2-6 weeks and lasted 2-8 months.
  • a response was a complete response (CR) if the treated lesions disappeared; a partial response (PR) if > 50% ⁇ 100% of the treated lesions disappeared; and no response (NR) if the treated lesion demonstrated ⁇ 50% disappearance. Only the treated lesions were measured. No toxicities (hematological or blood chemistry) or allergies have been noted from topical A-007.
  • eleven treated patients were classified as ER-/PgR- ( ⁇ 3/ ⁇ 5) and therefore as having estrogen-independent breast cancer. Of these patients, three showed a complete response to treatment with A-007, five showed a partial response to the treatment, and three showed no response. This data indicates that A-007 is active in estrogen-independent breast cancers, as well as estrogen-dependent breast cancers.
  • the ointment is preferably made with 0.25-10% active ingredient, in a base such as propylene glycol that allows the active ingredient to be applied topically to the skin.
  • the described compounds may be included in inert preparations such as gelatin capsules, and pressed tablets with sucrose, cellulose or other inert substances for dissolution and absorption.
  • the materials may also be included in inert oils for injection or solubilized as salts for aqueous infusions.
  • A-007 is absorbed orally from a propylene glycol solution (100 mg/ml) to produce a peak serum level of 210 ng/ml after about 20 hours.
  • Plasma levels of A-007 versus time in hours is shown in FIG. 4.
  • a subject such as a patient or a test animal
  • EXAMPLE VIII Antiviral Activity of the Compounds The compounds of the present invention can be shown to exhibit antiviral activity in addition to the cytotoxic activity demonstrated above.
  • a CEM-SS human lymphocytic target cell line was maintained in RPMI- 1640 medium (Gibco, Grand Island, NY) without phenol red and supplemented with 5% fetal bovine serum, 2mM L- glut mine and 50 ⁇ g/ml gentamicin (complete medium) . Exponentially growing cells were pelleted and resuspended at a concentration of 2.0 x 10 5 cells/ml in complete medium.
  • the Hatian variant of HIV, HTLV-III RJ . (3.54 x 10 6 SFU/ml) was used throughout.
  • Frozen virus stock solutions were thawed immediately before use and resuspended in complete medium to yield 1.2 x 10 5 SFU/ml.
  • the appropriate amounts of the pure compounds for anti-HIV evaluations were dissolved in 100% DMSO and then diluted in complete medium to the desired initial concentration (and with final DMSO content not exceeding 1%) . All serial drug dilutions, reagent additions, and plate-to-plate transfers were carried out with an automated Bio ek 1000 Workstation (Beckman Instruments, Palo Alto, CA) .
  • Uninfected CEM-SS cells were plated at a density of 1 x 10* cells in 50 ⁇ l of complete medium. Diluted HIV-1 virus was then added to appropriate wells in a volume of 50 ⁇ l to yield a multiplicity of infection of 0.6. Appropriate cell, virus, and drug controls were incorporated in each experiment; the final volume in each microtiter well was 200 ⁇ l . Quadruplicate wells were used for virus-infected cells, and duplicate wells were used for uninfected cells. Plates were incubated at 37°C in an atmosphere containing 5% C0 2 for six (6) days.
  • Estrogenic activity of the claimed compounds in the uterus was determined by employing the wet uterine weight of the immature (3 week old) Sprague Dawley rat. Rats were sacrificed after three consecutive days of daily intraperitoneal (i.p.) administration of test compounds at the specified doses. The mean control (unstimulated) uterine weight for a 21 day old rat was averaged at 74 mg. Five to ten animals were employed at each dose level. The purr se of this test was to determine the estrogenic activity of each of the test compounds. Estrogenic activity can be determined by comparing the net uterine weight of the test animals to which the compounds were administered with the mean weight of rats not being injected with the drug.
  • the data in Table V also shows antiuterotrophic activity, and demonstrates the inability of the test compounds to inhibit stimulation of uterii, which have been already stimulated by administration of 0.64 ⁇ q of estradiol benzoate to the test animal.
  • a Sprague Dawley rat receiving this dose of estradiol benzoate has a mean wet weight uterus of 145 mg. Percent inhibition of stimulation is measured by comparing the stimulated uterine weight (145 mg) with the uterine weight wherein estradiol benzoate and the test compound are administered concomitantly.

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Abstract

Composés présentant des effets cytotoxiques contre des tumeurs indépendantes de l'÷strogène. Ces composés peuvent être représentés par la formule X-R1 dans laquelle X représente un cycle phényle pouvant être substitué par un ou plusieurs groupes nitro, méthyle ou trihalométhyle, et R1 représente une hydrazone de benzophénone, une hydraxone de xanthone, une hydrazone de thioxanthone, une hydrazone de fluorène, une hydrazone d'anthraquinone, une phénylhydrazone d'anthraquinone, une indano [1,2,3-de]-2H-phtalazinone, une tétraline [1,2,3-de]-2H-phtalazinone, une hydrazone d'acridone, ou une hydrazone de dibenzosubérénone. La fraction R1 peut être substituée par un ou plusieurs groupes hydroxy, méthoxy ou halogène. Ces composés sont utiles en tant qu'agents chimiothérapeutiques antinéoplasiques.
PCT/US1993/008427 1992-09-08 1993-09-08 Composes cytotoxiques Ceased WO1994005276A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006119284A2 (fr) 2005-05-04 2006-11-09 Dekk-Tec, Inc. Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques
EP2298295A1 (fr) * 2005-01-31 2011-03-23 Ception Therapeutics, Inc. Inhibiteurs du facteur de nécrose tumorale
US8618125B2 (en) 2011-01-14 2013-12-31 Heptiva LLC Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance
WO2017059120A1 (fr) * 2015-09-30 2017-04-06 Gilead Sciences, Inc. Composés et combinaisons pour le traitement du vih
KR20200094141A (ko) * 2017-10-27 2020-08-06 트랜스퓨전 헬스, 엘엘씨 플루오렌의 유도체를 이용하여 증대된 조혈 줄기 세포를 제조하는 조성물 및 방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3053678A (en) * 1960-03-23 1962-09-11 Cassella Farbwerke Mainkur Ag Spundyed regenerated cellulose products
US4673692A (en) * 1984-10-19 1987-06-16 Teikoku Hormone Mfg. Co., Ltd. Diphenylmethylimine derivatives, their compositions and pharmaceutical uses
US4732904A (en) * 1984-12-24 1988-03-22 Morgan Lee R Antiestrogenic hydrazones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3053678A (en) * 1960-03-23 1962-09-11 Cassella Farbwerke Mainkur Ag Spundyed regenerated cellulose products
US4673692A (en) * 1984-10-19 1987-06-16 Teikoku Hormone Mfg. Co., Ltd. Diphenylmethylimine derivatives, their compositions and pharmaceutical uses
US4732904A (en) * 1984-12-24 1988-03-22 Morgan Lee R Antiestrogenic hydrazones

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9096607B2 (en) 2005-01-31 2015-08-04 The Trustees Of The University Of Pennsylvania Tumor necrosis factor inhibitors
EP2298295A1 (fr) * 2005-01-31 2011-03-23 Ception Therapeutics, Inc. Inhibiteurs du facteur de nécrose tumorale
US8765810B2 (en) 2005-01-31 2014-07-01 The Trustees Of The University Of Pennsylvania Tumor necrosis factor inhibitors
WO2006119284A2 (fr) 2005-05-04 2006-11-09 Dekk-Tec, Inc. Composes aromatiques conjugues utilise a des fins diagnostiques et therapeutiques
US9498473B2 (en) 2011-01-14 2016-11-22 Heptiva LLC Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance
US9408841B2 (en) 2011-01-14 2016-08-09 Heptiva LLC Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance
US8618125B2 (en) 2011-01-14 2013-12-31 Heptiva LLC Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance
WO2017059120A1 (fr) * 2015-09-30 2017-04-06 Gilead Sciences, Inc. Composés et combinaisons pour le traitement du vih
US10059697B2 (en) 2015-09-30 2018-08-28 Gilead Sciences, Inc. Compounds and combinations for the treatment of HIV
KR20200094141A (ko) * 2017-10-27 2020-08-06 트랜스퓨전 헬스, 엘엘씨 플루오렌의 유도체를 이용하여 증대된 조혈 줄기 세포를 제조하는 조성물 및 방법
JP2021501198A (ja) * 2017-10-27 2021-01-14 トランスフュージョン ヘルス，リミティド ライアビリティ カンパニー フルオレンの誘導体を用いて造血幹細胞を増殖する組成物および方法
KR102770289B1 (ko) * 2017-10-27 2025-02-19 이뮨브리지 인코포레이티드 플루오렌의 유도체를 이용하여 증대된 조혈 줄기 세포를 제조하는 조성물 및 방법
AU2018354418B2 (en) * 2017-10-27 2025-09-11 Immunebridge Inc. Compositions and methods of making expanded hematopoietic stem cells using derivatives of fluorene

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