AU2001283224B2 - Indole compounds useful for the treatment of cancer - Google Patents
Indole compounds useful for the treatment of cancer Download PDFInfo
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- AU2001283224B2 AU2001283224B2 AU2001283224A AU2001283224A AU2001283224B2 AU 2001283224 B2 AU2001283224 B2 AU 2001283224B2 AU 2001283224 A AU2001283224 A AU 2001283224A AU 2001283224 A AU2001283224 A AU 2001283224A AU 2001283224 B2 AU2001283224 B2 AU 2001283224B2
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- cancer
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
WO 02/12188 PCT/US01/24978 INDOLE COMPOUNDS USEFUL FOR THE TREATMENT OF CANCER Cross-Reference to Related Applications This application is a continuation-in-part of U.S. patent application Serial No. 09/360,020 filed July 23, 1999, and claims priority of U.S. provisional patent application Serial No. 60/189,976, filed March 16, 2000, both of which are incorporated by reference herein.
Background of the Invention The invention was made with Government support under Grant No. 5ROI GM23200-24 awarded by the National Institute of Health. The Government has certain rights in the invention.
Prostate cancer is the second leading cause of cancer death among males in the United States. In 1998, an estimated 185,000 men were diagnosed with prostate cancer, and more than 39,000 men died of the disease. See, S. H.
Landis et al., Cancer Statistics, CA Cancer J. Clin., 48, 6 (1998). Although survival rates are good for prostate cancer that is diagnosed early, the treatments for advanced disease are limited to hormone ablation techniques and palliative care. Hormone ablation techniques (orchiectomy and anti-androgen treatments) generally allow only temporary remission of the disease. It usually recurs within 1-3 years of treatment, with the recurrent tumors no longer requiring androgens for growth and survival. D. G. Tang et al., Prostate, 32, 284 (1997). Therapy with conventional chemotherapeutic agents, such as progesterone, estramustine and vinblastine, has also not been demonstrated to be effective to halt progression of the disease.
The number of nonsteroidal anti-inflammatory drugs (NSAIDs) has increased to the point where they warrant separate classification. In addition to aspirin, the NSAIDs available in the U.S. include meclofenamate sodium, oxyphenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac and WO 02/12188 PCT/US01/24978 tolmetin for the treatment of arthritis; mefenamic acid and zomepirac for analgesia; and ibuprofen, fenoprofen and naproxen for both analgesia and arthritis. Ibuprofen, mefenamic acid and naproxen are used also for the management of dysmenorrhea.
The clinical usefulness of NSAIDs is restricted by a number of adverse effects. Phenylbutazone has been implicated in hepatic necrosis and granulomatous hepatitis; and sulindac, indomethacin, ibuprofen and naproxen with hepatitis and cholestatic hepatitis. Transient increases in serum aminotransferases, especially alanine aminotransferase, have been reported. All of these drugs, including aspirin, inhibit cyclooxygenase, that in turn inhibits synthesis ofprostaglandins, which help regulate glomerular filtration and renal sodium and water excretion. Thus, the NSAIDs can cause fluid retention and decrease sodium excretion, followed by hyperkalemia, oliguria and anuria.
Moreover, all of these drugs can cause peptic ulceration. See, Reminaton's Pharmaceutical Sciences, Mack Pub. Co., Easton, PA (18th ed., 1990) at pages 1115-1122.
There is a large amount of literature on the effect of NSAIDs on cancer, particularly colon cancer. For example, see H. A. Weiss et al., Scand J.
Gastroent., 31, 137 (1996) (suppl. 220) and Shiff et al., Exp. Cell Res., 222 179 (1996). More recently, B. Bellosillo et al., Blood, 92, 1406 (1998) reported that aspirin and salicylate reduced the viability ofB-cell CLL cells in vitro, but that indomethacin, ketoralac and NS-398, did not.
C. P. Duffy et al., Eur. J. Cancer, 34, 1250 (1998), reported that the cytotoxicity of certain chemotherapeutic drugs was enhanced when they were combined with certain non-steroidal anti-inflammatory agents. The effects observed against human lung cancer cells and human leukemia cells were highly specific and not predictable; some combinations ofNSAID and agent were effective and some were not. The only conclusion drawn was that the effect was not due to the cyclooxygenase inhibitory activity of the NSAID.
The Duffy group filed a PCT application (W098/18490) on October 24, 1997, directed to a combination of a "substrate for MRP", which can be an anti- 12/06 2007 13:54 FAX 61 3 92438333 GRIFFITH HACK 4IPAUSTRALIA IRIO0 0
O
Cl cancer drug, and a NSAID that increases the potency of the anti-cancer drug.
SNSAIDs recited by the claims are acemetacin, indomethacin, sulindac, sulindac sulfide, c- sulindac sulfone, tolmetin and zomepirac. Naproxen and piroxicam were reported to be C inactive.
Recently, W. J. Wechter et al., Cancer Res., 60, 2203 (2000) reported that the NSAID, R-flurbiprofen, inhibited progression of prostate cancer in the TRAMP mouse, a C( prostate cancer model. The Wechter group filed a PCT application (W098/09603) on September 8, 1997, disclosing that prostate cancer can be treated with R-NSAIDs, 00 including R(-)-etodolac and R-flurbiprofen. In contrast to R(-)-etodolac, the Renantiomer of flurbiprofen and other (R)-2-aryl propionate NSAIDs are converted in Sthe body to the anti-inflammatory S-enantiomers, and hence are pro-drugs of the Cl NSAIDs, while etodolac is not per se an NSAID. Therefore, a continuing need exists for effective methods to employ these preliminary findings to develop new compounds to treat neoplastic disease, including prostate cancer and other cancers.
Summary of the Invention The present invention provides indole compounds of formula
R
5
R
4
SR
3 7 r I y-Z
R
7
R
(I)
wherein R' is lower alkyl, lower alkenyl, lower alkynyl, phenyl, benzyl or 2-thienyl, R 2
R
3
R
4 and R 5 are the same or different and are each hydrogen or lower alkyl; each R is individually hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo, n is 1-3, R 7 is hydrogen, lower alkyl or lower alkenyl, X is oxy and thio, Y is (CH 2 1 or (CH2)t_ 3 SO2 and Z is (ca-(4pyridylXC 2 -C4 alkoxy), 9 amino)(C 2
-C
4 alkoxy), wherein R 8 and R 9 are each H, (Ci-C 3 )alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 3 B:\Mlboune@\Cas\Patef\l\B0D-D-4 ih\P4191 .MiI\SpeciBfL\)atmflB .doc 1Z/4/07 COMS ID No: SBMI-07730632 Received by IP Australia: Time 14:00 Date 2007-06-12 12/06 2007 13:54 FAX 61 3 92438333 GRIFFITH HACK IPAUSTRALIA 007 0 Cl S or nonperoxide 0; an amino acid ester of (w-(HO)(C 2 -C4))alkoxy,
SN(R)CH(R)CO
2 H, l'-D-glucuronyloxy, OH, (C 2 -C)acyloxy, SO 3 H, P0 4
H
2 N(NO)(OH), S02NH2, PO(OH)NH 2
OCH
2
CHN(CH
3 3 amino, lower alkylamino, Cl di(]oweralkyl)amino, phenylamino or tetrazolyl; provided that when n is 1, R 6 is hydrogen, and R' is methyl, then-Y-Z is not -CH 2 CH2- OH, -CH2-OH, -CH 2
CH
2
-OC(O)CH
3 or -CH2-OC(O)CH 3 and provided that when n is 1. R' is 8-ethyl, and R L is ethyl, then-Y-Z is not -CH2CH 2 -OH, or -CH 2 CH2-OC(O)CH 3 c or a pharmaceutically acceptable salt thereof.
00 The present invention also provides a therapeutic method to inhibit the 10 growth of cancer cells and/or to sensitize cancer cells to inhibition by a 0 chemotherapeutic agent. The method comprises contacting cancer cells with an C, effective amount of the compound of formula preferably in combination with a pharmaceutically acceptable carrier. The present compounds can be used to treat a mammal afflicted with cancer, such as a human cancer patient, and are preferably administered in conjunction with a chemotherapeutic agent, such as an alkylating agent or an anti-androgen, radiation and/or other anti-cancer therapy.
The present compounds are effective against hematopoietic cancers, such as leukemias and cancers of the bone marrow, including chronic lymphocytic leukemia (CLL) and multiple myeloma The present compounds were unexpectedly found to be effective against cancer cells that express high levels of the nuclear hormone receptor, peroxisome proliferator activated receptor-y, (PPAR-y), and/or high levels of the anti-apoptotic proteins, Mcl-1 and/or Bag-1. Such cancer cells include at least some types of prostate cancer cells.
Activated PPAR-y binds co-activator protein (CBP), a co-activator of the androgen receptor known to be overexpressed in hormone-resistant prostate cancer.
Thus, compounds of formula that activate PPAR-y production can reduce the level of expression of the androgen receptor known to be over-expressed in hormoneresistant prostate cancer. Therefore, the present compounds can enhance the efficacy of conventional anti-androgen therapy, and can act to inhibit the spread of prostate cancer.
4 Bl\Melbourne\aee\Patent \4BOO-4B s\491.A \Sppeci\AMlEDEITS.dC 12/06/0712/06/07 COMS ID No: SBMI-07730632 Received by IP Australia: Time 14:00 Date 2007-06-12 103.022W01 The present invention is based on the discovery by the inventors that racemic etodolac inhibits the viability of purified CLL or MM cells at concentrations that do not inhibit the viability of normal peripheral blood lymphocytes (PBLs). It was then unexpectedly found that the enantioiner 12/06 2007 13:55 FAX 61 3 92438333 GRIFFITH HACK 4 IPAUSTRALIA R 008 0 0 Cl ofetodolac is as toxic to CLL cells as is the enantiomer_ Tt was then found that Setodolac synergistically interacted with fludarabine and 2-chloroadenosine to kill CLL -s cells at concentration at which the chemotherapeutic agents alone were inactive.
Cl Finally, it was found that both and etodolac inhibited a number of prostate cancer cell lines. Again the enantiomner was at least as effective as the "antiinflammatory" enantiomer- This was unexpected since the enantiomer ofetodolac does not possess significant anti-inflammatory activity and is not converted to the enantiorner to a significant extent in vivo. As noted above, the R-enantiomers of other 00 R-2-arylpropionate NSAIDs are converted to the "active" auti-inflammatory S- 10 enantiomers in vivo, and so function as po-drugs for the NSAID.
o The extent of inhibition was markedly related to the level of expression of PPAR-y by the cell line. Cell lines with an elevated level of PPAR-y expression were inhibited much more effectively than cell lines expressing relatively low levels of PPAR-y, as disclosed in the working examples.
A compound of formula is preferred for practice of the present therapeutic method that does not exhibit undesirable bioactivities due to inhibition of cyclooxygenase (COX) that are exhibited by some NSAIDs. However, the preferred compounds of formula would not be considered NSAIDs by the art, as they would not exhibit significant anti-inflamnatory activity.
Thus, there is also provided a method for determining whether or not a particular cancer patient, such as a prostate cancer patient, is amenable to treatment by a compound of formula comprising isolating cancer cells and evaluating in vitro the relative level of PPAR-y and/or Mcl-1 and/or Bag-1 relative to the level in a cancer cell line, such as prostate cancer cell line, known to be susceptible to treatment by a compound of formula There is also provided a method to determine the ability of a test agent to inhibit cancer cells, such as prostate cancer cells, comprising contacting a population of cancer cells, as from a prostate cancer cell line, with said agent and determining whether the agent increases expression of PPAR-y, N:VCDDU.lrQS.\e BiBpateb\4 -4e9f9\Ft ep491.KU\pediE\zV lB.ac f12/06/0712/06/07 COMS ID No: SBMI-07730632 Received by IP Australia: Time 14:00 Date 2007-06-12 WO 02/12188 PCT/US01/24978 or decreases the expression of Mcl-1 and/or Bag-1 (or does both). The present invention also provides a general multilevel screening method to evaluate etodolac analogs, other NSAIDs or other agents for their ability to inhibit cancer, preferably etodolac-sensitive cancers, such as prostate cancer, CLL and MM.
Agents that exhibit a positive activity, preferably at least equal to that of etodolac, or do not exhibit a negative activity, are no more active than etodolac, are passed to the next screen.
Test agents are first evaluated for their ability to competitively inhibit the binding of etodolac, radiolabeled etodolac to its receptor(s) on etodolac-sensitive cancer cells such as CLL cells. Agents that can compete effectively with etodolac for etodolac binding site(s) on the cells are then evaluated in an assay to determine if they can increase Ca 2 uptake in cancer cells, such as CLL cells, preferably as effectively as etodolac. Agents that can induce intracellular Ca 2 uptake are screened to determine if they can induce chemokinetic activity (chemokinesis or chemotaxis) in a population of lymphocytes, such as B-CLL lymphocytes, preferably as effectively as etodolac. Agents that are positive in this screen are then evaluated to determine if they can induce apoptosis or pro-apoptotic factors, such as increased caspase activity in cancer cells, such as CLL cells and other cancer cells known to be etodolac sensitive, at least as effectively as etodolac.
Agents that test positive in this screen are evaluated for their ability to deplete lymphocytes in mice, and those that are no more active than etodolac are then evaluated in animal models of cancer to see if they can inhibit the induction of, or spread of cancer.
As used herein with respect to cancer or cancer cells, the term "inhibition" or "inhibit" includes both the reduction in cellular proliferation, blockage of cellular proliferation, or killing some or all of said cells. Thus, the term can be used in both the context of a prophylactic treatment to prevent development of cancer or as a treatment that will block, or slow the spread of established cancer. Whether or not the level of expression of a marker of susceptibility to etodolac treatment is sufficiently elevated to continue treatment WO 02/12188 PCT/US01/24978 with etodolac or an analog thereof is determined by comparison between the relative levels of expression of said marker in resistant and susceptible cancer cell lines, as disclosed hereinbelow.
Brief Description of the Figures Figure 1 is a graph depicting the sensitivity of nonnal peripheral blood lymphocytes (PBL) to racemic etodolac.
Figure 2 is a graph depicting the sensitivity of CLL cells to racemic etodolac.
Figure 3 is a graph depicting the synergistic effect of a combination of racemic etodolac and fludarabine against CLL cells.
Figure 4 is a graph depicting the synergistic effect of a combination of IM etodolac with 10 iM 2CdA or 10 mM Fludara against CLL cells.
Figure 5 is a graph depicting the sensitivity of CLL cells to S- and Retodolac.
Figures 6 and 7 depict the viability of CLL cells from two patients before and after etodolac administration.
Figure 8 depicts a flow cytometric analysis of CLL cells before and after etodolac treatment.
Figures 9 and 10 depict the selective action of R(-)-etodolac against MM cells from two patients.
Figure 11 is a photocopy of a SDS-PAGE gels demonstrating that etodolac induces a rapid downregulation in Mcl-1 (Panel A) and Bag-1 (Panel that is blocked by MG-132.
Figure 12 is a photocopy of an SDS-PAGE gel depicting expression of PPAR-y by seven cancer cell lines.
Figure 13 is a graph depicting induction of PPAR-y expression by etodolac and indomethacin.
Figure 14 is a graph depicting expression of CD36 induced by etodolac and TGZ, in the presence and absence of TPA in human monocytes.
12/06 2007 13:55 FAX 61 3 92438333 GRIFFITH HACK 4 IPAUSTRALIA 01009 0
O
C1 Figure 15 is a photocopy of sections of prostate cancer tissue, untreated S(A) or treated C, D) with etodolac.
Detailed Description of the Invention Indole compounds of the present inventions include compounds of formula 'q R 5
R
4 C4' R 3 00 NC (R6)N R 2 o I Y-Z c
R
7
R'
wherein R' is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, phenyl, benzyl and 2-thienyl, R 2
R
3
R
4 and R s are the same or different and are each selected from the group consisting of hydrogen and lower alkyl, each R 6 is individually selected from the group consisting of hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro and halo, n is 1-3, R 7 is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl, X is selected from the group consisting of oxy and thio, Y is selected from the group consisting of (CH 2 )1- 3 and (CH 2 1 -3SO 2 and Z is selected from the group consisting of hydroxy, lower alkoxy optionally substituted with OH, 4-pyridyl, amino, lower alkylamino, di(lower alkyl)amino, or N-morpholino; amino, lower alkylamino, ((carboxy)(lower alkyl))amino, di(lower)alkylamino, phenylamino, OH, (C 2 C4)acyloxy, S03H, P04- 2 N(NO)(OH), SO2NH2, PO(OH)NIH2, OCH 2
CH
2
N(CH
3 3 amino, lower alkylamino, di(lower alkyl)amnino, phenylamino, or tetrazolyl; or a pharmaceutically acceptable salt thereof. Lower allcyl, alkenyl, alkanoyl, etc. indicates a branched, cyclic or straight chain C 1
-C
6 group, preferably a C 1
-C
4 group, including cycloalkyl and (cycloalkyl)alkyl. (Hydroxy)lower alkyl or alkoxy is preferably I- or 2bydroxyethyl.
As discussed above, the relatively low water solubility of the enantiomer of etodolac can reduce its usefulness against cancer when 8 al \elbourne\CmseB\Patenu\E OOO-4lB9ss\Pl 491 .AnXAJU\peis\AMENlM .doC 1Z/06/0712/06/07 COMS ID No: SBMI-07730632 Received by IP Australia: Time 14:00 Date 2007-06-12 WO 02/12188 PCT/US01/24978 administered orally, or in an aqueous vehicle. Therefore, the present invention also provides novel indole compounds that exhibit enhanced water solubility and/or bioavailability over the free acid or the simple alkyl esters of etodolac.
Such analogs include (pyridinyl) lower alkyl esters, (amino)lower alkyl esters, (hydroxy)lower alkyl esters and 1'-D-glucuronate esters of etodolac, e.g., compounds of formula (II) wherein Y is carbonyl and Z is pyridyl)(C 2
-C
4 alkoxy), 9 amino)(C 2
-C
4 alkoxy), wherein R 8 and R 9 are each H, (C 1
-C
3 )alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 N(R 8 S or nonperoxide 0; an amino acid ester of(o-
(HO)(C
2
-C
4 )alkoxy, the L-valine or L-glycine ester of 2-hydroxyethoxy, 1 D-glucuronyloxy; and the pharmaceutically acceptable salts thereof, with organic or inorganic acids. Other analogs of increased water solubility include amino acid amides, where Y is carbonyl and Z is N(RS)CH(R 8
)CO
2 H, and the pharmaceutically acceptable salts thereof.
Such compounds can be prepared as disclosed in U.S. Pat. No.
3,843,681, U.S. Pat. Application Serial No. 09/313,048, Ger. Pat. No. 2,226,340 (Amer. Home Products), R. R. Martel et al., Can. J. Pharmacol., 54, 245 (1976); Demerson et al., J. Med. Chem., 19, 391 (1976); PCT application Serial No.
US/00/13410 and Rubin Pat. No. 4,337,760).
The resolution ofracemic compounds of formula can be accomplished using conventional means, such as the formation of a diastereomeric salt with a optically active resolving amine; see, for example, "Stereochemistry of Carbon Compounds," by E. L. Eliel (McGraw Hill, 1962); C. H. Lochmuller et al., J Chromatog., 113, 283 (1975); "Enantiomers, Racemates and Resolutions," by J.
Jacques, A. Collet, and S. H. Wilen, (Wiley-Interscience, New York, 1981); and S. H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 33, 2725 (1977). For example, the racemate has been resolved by fractional crystallization of RSetodolac using optically active 1-phenylethylamine and HPLC has been used to determine racemic etodolac and enantiomeric ratios of etodolac and two hydroxylated metabolites in urine Becker-Scharfenkamp et al., J.
Chromatog., 621, 199 (1993)). B. M. Adger et al. Patent No. 5,811,558), WO 02/12188 PCT/US01/24978 disclosed the resolution of etodolac using glutamine and N(C 1
-C
4 alkyl)glutamine salts.
Etodolac itself (1,8-diethyl-1,3,4,9-tetrahydro [3,4-6]indole-1-acetic acid) is a NSAID of the pyranocarboxylic acid class, that was developed in the early 1970s. Its structure is depicted as formula below, wherein denotes the chiral center. See also, The Merck Index, (11th at page 608.
C
2
H
5
CH
2
COOH
H
N (II)OC2H 4 The pharmacokinetics of etodolac have been extensively reviewed by D.
R. Brocks et al., Clin. Pharmacokinet., 26, 259 (1994). Etodolac is marketed as the racemate. The absolute configurations of the enantiomers were found to be and which is similar to that for most other NSAIDs. However, Demerson et al., J. Med. Chem., 26, 1778 (1983) found that the S(+)-enantiomer of etodolac possessed almost all of the anti-inflammatory activity of the racemate, as measured by reduction in paw volume of rats with adjuvant polyarthritis, and prostaglandin synthetase inhibitory activity of the drug. No anti-inflammatory activity was discernible with the (-)-enantiomer, and it is not converted significantly to the enantiomer in vivo. Hence, etodolac is not a NSAID. However, as disclosed below, etodolac paradoxically was found to have potent activity against cancer cells that is at least equivalent to that of the enantiomer.
Etodolac possesses several unique disposition features due to their stereoselective pharmacokinetics. In plasma, after the administration of RSetodolac, the concentrations of the "inactive" R-enantiomer of etodolac are about higher thanthose of the active S-enantiomer, an observation that is novel among the chiral NSAIDs. See, D. R. Brocks et al., Clin. Pharmacokinet., 26, 259 (1994). After a 200 mg dose in six elderly patients, the maximum plasma concentration of the R-enantiomer was about 33 nM. In contrast, the maximum WO 02/12188 PCT/US01/24978 concentration of the S-enantiomer was 5-fold lower. The typical dosage of the racemic mixture of etodolac is 400 mg BID, and the drug has an elimination half-life between 6-8 hours. Moreover, it is likely that the administration of the purified R-enantiomer will not display the side effects associated with cyclooxygenase (COX) inhibitors, such as ulcers and renal insufficiency, and thus can be given at considerably higher dosages. Nonetheless, the relatively low solubility of R(-)-etodolac in water can ihmpede attaining plasma levels in humans that can inhibit cancer cells, particularly prostate cancer cells. However, the compounds of formula can be dissolved in water and other aqueous carriers at substantially higher concentrations than etodolac.
The compounds of formula can also be prepared in the form of their pharmaceutically acceptable salts or their non-pharmaceutically acceptable salts.
The non-pharmaceutically acceptable salts are useful as intermediates for the preparation of pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, ptoluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and salts formed from elemental anions such as chlorine, bromine, and iodine. Preferred carboxylic acid salts are those ofhydrophilic amines, such as glucamine or N-(Ci-C 4 )alkylglucamine (see, Adger et al. Pat. No.
5,811,558)).
The magnitude of a prophylactic or therapeutic dose of a compound or compounds of formula in the acute or chronic management of cancer, i.e., prostate cancer, will vary with the type and/or stage of the cancer, the adjunct chemotherapeutic agent(s) or other anti-cancer therapy used, and the route of WO 02/12188 PCT/US01/24978 administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, condition, and response of the individual patient. In general, the total daily dose range for a compound or compounds of formula for the conditions described herein, is from about 50 mg to about 5000 mg, in single or divided doses. Preferably, a daily dose range should be about 100 mg to about 4000 mg, most preferably about 1000-3000 mg, in single or divided doses, 750 mg every 6 hr of orally administered compound. This can achieve plasma levels of about 500-750 FM, which can be effective to kill cancer cells. In managing the patient, the therapy should be initiated at a lower dose and increased depending on the patient's global response. It is further recommended that infants, children, patients over 65 years, and those with impaired renal or hepatic function initially receive lower doses, particularly of analogs which retain COX inhibitory activity, and that they be titrated based on global response and blood level. It may be necessary to use dosages outside these ranges in some cases. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust or terminate therapy in conjunction with individual patient response. The terms "an effective inhibitory or amount" or "an effective sensitizing amount" are encompassed by the abovedescribed dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of formula For example, oral, rectal, parenteral (subcutaneous, intravenous, intramuscular), intrathecal, transdermal, and like forms of administration may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The compound may be administered prior to, concurrently with, or after administration of chemotherapy, or continuously, in daily doses, during all or part of, a chemotherapy regimen. The compound, in some cases, may be combined with the same carrier or vehicle used to deliver the anti-cancer chemotherapeutic agent.
Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an WO 02/12188 PCT/US01/24978 inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrated agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. Tablets, capsules, pills, granules, microparticles and the like can also comprise an enteric coating, such as a coating of one of the Eudragit® polymers, that will permit release of the active compound(s) in the intestines, not in the acidic environment of the stomach. This can be advantageous in the case of elderly or frail cancer patients treated with any compound that retains a significant COX-inhibitory activity, and concomitant ulceration.
A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in WO 02/12188 PCT/US01/24978 preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant.
Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for. example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
WO 02/12188 PCT/US01/24978 In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No. 4,938,949.
Due to the ability of compounds of formula that elevate PPAR-y levels, to lower the expression of the androgen receptor known to be overexpressed in hormone-refractory prostate cancer, compounds that upregulate PPAR-y are advantageously used in combination with steroidal and nonsteroidal anti-androgens used in the treatment of prostate cancer. These compounds include leuprolide or goserelin acetate, bicalutamide and flutamide, nilutamide, cycloproterone acetate, among others.
Due to the ability of compounds of formula that reduce PPAR-y levels to sensitize prostate cancer cells to killing by conventional chemotherapeutic agents, such compounds can be employed with chemotherapeutic agents used to treat cancers such as prostate cancer, including estramustine, vinblastine, mitoxanthrone, prednisone and the like, or melphalan to treat MM. Other chemotherapeutic agents, irradiation or other anti-cancer agents such as anti-tumor antibodies, or cytokines can be used with the present compounds. See, Remington's Pharmaceutical Sciences (18th ed. 1990) at pages 1138-1162.
The invention will be further described by reference to the following detailed examples.
Example 1. Sensitivity of Normal Peripheral Blood Lymphocytes and CLL Cells to Etodolac Mononuclear cells were isolated from the peripheral blood of B-CLL patients and normal donors using density gradient centrifugation (Ficoll-Paque).
WO 02/12188 PCT/US01/24978 Cells were cultured at 2 x 106 cells per mL in RPMI with 20% autologous plasma in 96-well plates with or without the indicated tM concentrations of etodolac (racemic, S-etodolac, R-etodolac) and in combination with 2-chloro-2'deoxyadenosine (2CdA) or fludarabine. At indicated times (12, 24, 36, 48, 72 hours), viability assays were performed using the erythrocin B exclusion assay, as described by D. Carson et al., PNAS USA, 89, 2970 (1992).
As shown in Figure 1, significant death of normal PBLs occurred only at 800 racemic etodolac, a concentration which cannot be obtained in vivo.
Peripheral blood lymphocytes from a normal donor were cultured with 1.0 mM etodolac for 24 hours. Then B lymphocytes were identified by staining with anti-CD 19 antibody, and viability was assessed by DiOC 6 fluorescence.
Etodolac under these conditions did not reduce the viability of the normal B cells, compared to control cultures. When the same viability assay was run with purified CLL cells from the peripheral blood of a CLL patient, the results were different. As shown in Figure 2, 50% of the CLL cells were killed by a 48 hour exposure to 200 pM racemic etodolac. More than 95% of the treated cells were malignant B lymphocytes.
Example 2. Synergistic Combinations of Etodolac and Chemotherapeutic Agents Fludarabine is a nucleoside analog commonly used for the treatment of CLL. In this experiment the in vitro survival of CLL cells at the indicated time points was compared in cultures containing medium alone squares), fludarabine 10 nM (diamonds), etodolac 10 pIM (closed circles), and fludarabine 10 nM plus etodolac 10 pM (open circles). The two drugs together exhibited a synergistic cytotoxic effect. Figure 3 shows that the combination killed 50% of CLL cells during 48 hours of culture, while either drug alone was ineffective.
Figure 4 demonstrates synergy between 50 pM etodolac and 10 nM 2chlorodeoxyadenosine and fludarabine, under the same test conditions.
WO 02/12188 PCT/US01/24978 Example 3. Effect of and Etodolac Against CLL Cells Etodolac tablets were ground in a mortar and extracted from the formulation using ethyl acetate. The resulting racemic mixture of enantiomers was separated into R and S isomers on a preparative scale by fractional crystallization by the procedure of Becker-Scharfenkamp and Blaschke, J.
Chromatog., 621, 199 (1993). Thus, the racemic mixture solid was dissolved in absolute 2-propanol and S-l-phenylethylamine was added to the solution. The resulting salt solution was stored in the refrigerator for 4 days. The crystalline white salt product was filtered and washed with cold 2-propanol and recrystallized two more times from 2-propanol. The same procedure was repeated for the R isomer only using R-l-phenylethylamine as the resolving agent. Finally, the R and S salts were decomposed using 10% sulfuric acid (v/v) and extracted with ethyl acetate. The chiral purity of each isomer was verified by HPLC using a Chiral-AGP column from ChromTech.
The toxicities of the two enantiomers to CLL cells cultured in RPMI 1640 medium with 10% autologous plasma were compared at the indicated concentrations and time points, as shown in Figure 5. The R- and S-enantiomers are equivalently cytotoxic to the CLL cells.
Example 4. Viability of CLL Cells Before and After Etodolac Treatment Heparinized blood was taken from two patients (JK and NA) with CLL.
Then each patient immediately took a 400 mg etodolac tablet, and a second tablet 12 hours later. After another 12 hours, a second blood specimen was obtained. The CLL cells were isolated and their survival in vitro were compared in RPMI 1640 medium containing 10% autologous plasma, as described in Example 1. The circles show CLL cells before etodolac treatment. In Figures 6- 7, the upward pointing triangles represent CLL cell viability after etodolac treatment, wherein the cells are dispersed in medium containing the pretreatment plasma. The downward pointing triangles are CLL cells after treatment maintained in medium with the post-treatment plasma.
WO 02/12188 PCT/US01/24978 Figure 6 shows the different survivals of the two cell populations from patient JK. Note that the cells after treatment had a shortened survival compared to the cells before treatment. Figure 7 shows a less dramatic but similar effect with patient NA. Figure 8 is a flow cytometric analysis of CLL cells from patient JK before and after etodolac treatment. DiOC 6 is a dye that is captured by mitochondria. When cells die by apoptosis, the intensity of staining decreases. The X axis on the four panels in Figure 8 shows the DiOC 6 staining.
An increased number of dots in the left lower box indicates cell death by apoptosis. If one compares the cells taken from the patient before etodolac treatment, and after etodolac treatment, one can see that the number of dots in the left lower box is much higher after the drug. This effect is detectable at 12 hours, and increases further after 24 hours.
To conduct the flow cytometric analysis, the mitochondrial transmembrane potential was analyzed by 3,3' dihexyloxacarboncyanide iodide (DiOC 6 cell membrane permeability by propidium iodide (PI) 3 and mitochondrial respiration by dihydrorhodamine 123 (DHR) (See J. A. Royall et al., Arch. Biochem. Biophys., 302, 348 (1993)). After CLL cells were cultured for 12 or 24 hours with the indicated amount of etodolac, the cells were incubated for 10 minutes at 37°C in culture medium containing 40 nM of DiOC 6 and 5 pg/ml PI. Cells were also cultured for 3 hours with the indicated amount of etodolac, spun down at 200 x g for 10 minutes and resuspended in fresh respiration buffer (250 mM sucrose, 1 g/L bovine serum albumin, 10 mM MgCl 2 10 mM K/Hepes, 5 mM KH2PO 4 (pH and cultured for 10 minutes at 370 C with 0.04% digitonin. Then cells were loaded for 5 minutes with 0.1 M dihydrorhodamine (DHR). Cells were analyzed within 30 minutes in a Becton Dickinson FAC-Scalibur cytofluorometer. After suitable comprehension, fluorescence was recorded at different wavelength: DiOC 6 and DHR at 525 nm (Fl-1) and PI at 600 nm (FL-3).
As a general matter a reduction of 10% in the survival of the posttreatment malignant cells, compared to the pretreatment malignant cells, at 16 WO 02/12188 PCT/US01/24978 hours after culture in vitro is considered a "positive" in this test, and indicates the use of etodolac, etodolac in CLL or other cancer therapy.
Example 5. Ability of R(-)-Etodolac to Selectively Kill MM Cells Bone marrow was obtained from two patients with multiple myeloma.
The marrow contained a mixture of malignant cells, as enumerated by high level expression of the CD38 membrane antigen, and normal cells. The suspended marrow cells were incubated for 72 hours in RPMI 1640 medium with 10% fetal bovine serum, and various concentrations of the purified R-enantiomer of etodolac. Then the dead cells were stained with propidium iodide, and the multiple myeloma cells were stained with fluorescent monoclonal anti-CD3 8 antibodies. The data were analyzed by fluorescent activated cell sorting.
Figures 9-10 show that R-etodolac did not kill the normal bone marrow cells (light bars), but dose-dependently killed the multiple myeloma cells (dark shaded areas), in the marrow cells from both patients.
Example 6. Etodolac Cytotoxicity to Cancer Cell Lines Table 1 summarizes the cytotoxic effects ofR(-)-etodolac toward prostate cancer cell lines and one colon cancer cell line are indeed within clinically achievable concentrations, given that a 1 gram dosage of R(-)-etodolac should yield a maximal plasma concentration in a human subject of about 400 uM. The fact that the and S(+)-enantiomers are both cytotoxic indicates that the anti-prostate cancer activity is COX independent. Note that etodolac, which is devoid of anti-inflammatory activity, nonetheless is more toxic to prostate cancer cells than is etodolac.
WO 02/12188 PCT/US01/24978 Table 1 Cell line Origin Etodolac R/S Etodolac R Etodolac S Phenoty PC-3 Prostate 340 20* 150 15* 800 30* Sensitive LNCaP-FGC Prostate 400 35 270 50 220 20 Sensitive Alva-31 Prostate >1000 >1000 >1000 Resistant OVCAR-3 Ovarian >1000 >1000 >1000 Resistant MDA-MB-231 Breast >1000 >1000 >1000 Resistant HCT-116 Colon 450 15 280 20 420 50 Sensitive SW260 Colon 1000 120 ND ND Resistant A549 Lung >1000 >1000 >1000 Resistant IC,, (pM) of Etodolac R/S, R or S. Cytotoxicity was assessed by MTT assay after three days continuous exposure to decreasing concentrations of the agent.
The results were confirmed by FACS using propidium iodide uptake.
Example 7. Etodolac Downregulation of Mel-1 and Bag-1 As planar hydrophobic compounds, etodolac and other NSAIDS can readily insert into cell and organ membranes, and can disrupt their structure and function B. Abramson et al., Arthritis and Rheumatism, 32, 1 (1989)). The proteins Mcl-1 and Bag-1 are anti-apoptotic members of the bcl-2 family that are found in mitochondria Wang et al., Exp. Cell Res., 235, 210 (1997)). As early as two hours after incubation with 100 pM etodolac, Mcl-1 and Bag-1 levels fell in an etodolac sensitive prostate cancer cell line (LNCaP). The fall in Mcl-1 and Bag-1 levels was prevented by co-incubation of the prostate cells with [iM MG-132, a recently described inhibitor of the proteasome (Figure 11, Panels A and B, respectively) H. Lee at al., Trends Cell Biol., 8, 397 (1998)).
Detergent lysates (20 [g per lane) were subjected to SDS-PAGE and immunoblotted with anti-Mcl-1 and anti-Bag-1 antibodies. Pre-incubation of the cells with Z-VAD, a broad-spectrum caspase inhibitor, did not prevent the Mcl-1 and Bag-1 downregulation. Etodolac incubation did not alter Bcl-2 and Bax levels (data not shown). Thus, etodolac did not interfere with Mcl-1 synthesis, but probably accelerated its turnover. Both R- and S-etodolac induced Mcl-1 degradation at equivalent concentrations.
WO 02/12188 PCT/US01/24978 Example 8. Expression of PPAR-y in Cancer Cell Lines Although etodolac has not been previously studied, high concentrations of other NSAIDs have been reported to activate the nuclear hormone receptor PPAR-y M. Lehmann et al., J. Biol. Chem., 272, 3406 (1997). Moreover, maximal activation of PPAR-y induces apoptosis in human macrophages (G.
Chinetti et al., J. Biol. Chem., 273, 25579 (1998). Therefore, it was of interest to determine if prostate cells express PPAR-y, and to compare the expression level with other cancer types. Detergent lysates (20 ig per lane) obtained from subconfluent cell lines were subjected to SDS-PAGE and immunoblotted with anti-PPAR-y antibodies. To normalize the PPAR-y content, the membrane was reblotted with an anti-actin monoclonal antibody. Lane 1: PC-3, Lane 2: SW260, Lane 3: A549, Lane 4: MDA-MB-231, Lane 5: Alva-31, Lane 6: LNCaP, Lane 7: HCT-116 (see Table It was observed that some etodolacsusceptible prostate cells (PC3 especially) expressed remarkably high levels of immunoreactive PPAR-y (Figure 12).
Example 9. Activation of PPAR-y by Etodolac RAW264.7 cells were transfected at a density of 3 x 105 cells/mi in six well plates using lipofectamine with the PPAR-y expression vector pCMX- PPAR-y (0.1 pg), and the PPAR-y reporter construct (AOx) 3 -TK-Luc (1 Ig) as previously described by M. Ricote et al., Nature, 391, 79 (1998). Cells were treated for 24 hours with the compounds indicated on Figure 13, harvested and assayed for luciferase activity. Results are expressed as the mean SD. As shown in Figure 13, both the R- and S- enantiomers of etodolac activated a PPAR-y reporter gene construct at concentrations readily achieved in human plasma after in vivo administration. THP-1 human monocytic cells (ATCC) were incubated in the presence or absence ofphorbol ester (40 ng TPA) and 200 pM racemic etodolac or 20 piM troglitazone. After three days of culture, the surface expression of the scavenger receptor CD36 was measured by flow cytometry. As shown in Figure 14, both R- and S-etodolac caused the WO 02/12188 PCT/US01/24978 expression of CD36, a marker of PPAR-y activation, in the human cell line THP-1 during macrophage differentiation.
Example 10. Etodolac Treatment of Prostate Cancer Tissue Samples Freshly obtained prostatectomy samples were cut into 3 mm 3 pieces, and incubated for 72 hours in RPMI-1640 supplemented with 10% FBS and antibiotics in the absence 400X) or presence ofracemic etodolac 400X) or the purified R enantiomer 400X; and D, 630X). The tissues were next fixed in 4% paraformaldehyde in PBS, embedded in paraffin, sectioned and stained with hematoxylin and eosin. Figure 15A shows the infiltrating tumor cells (large nuclei) and some residual normal epithelium. Figures 15 B to 15 D show the effect of etodolac: note the abundant presence of pyknotic apoptotic nuclei (dark arrows, B and and the disintegration of the neoplastic glandular architecture Etodolac was found to be selectively toxic to the tumor cells, but did not affect normal basal cells. The racemic mixture and the purified R and S analogs were found both active.
Example 11. Prospective Protocol for Screening to Identify Etodolac Analogs A. Screening of analogs by competition against radiolabeled R-etodolac Etodolac-sensitive chronic lymphocytic leukemia [CLL] cells, or other cancer cells, will be utilized for drug screening in radioreceptor binding assay.
In brief, frozen CLL cells will be washed three times in Hanks' Balanced Salt Solution (HBSS) and resuspended in HBSS-HEPES. The assay will be done in a total volume of 200 pil containing approximately 2 million cells, [3H]-R- Etodolac [sp.act.20-25 Ci/mmol, prepared by Sibtech] and potential competitors or buffer are incubated in at varying temperatures [4 and 37°C] and times [0-60 minutes]. For each sample, triplicate 50 Il aliquots will be layered over 300 ptl sucrose in HBSS-HEPES in 1.5 ml polypropylene snap top tubes and pelleted for 2.5 minutes at 15000 rpm in a Beckman microfuge. This procedure rapidly separates the cell-bound and cell-free etodolac. The tube tips will be cut WO 02/12188 PCT/US01/24978 off and the cell pellets will be solubilized and counted in a scintillation counter.
Some of the incubation mixtures will contain excess unlabeled etodolac as a control. Specific binding is the difference in the bound cpm in tubes containing the radiolabeled etodolac minus the cpm in the tubes containing the radiolabeled etodolac and the excess cold competitor etodolac. Test agents are compared to the unlabeled cold competitor etodolac for their abilities to inhibit radiolabeled etodolac binding. Compounds that can inhibit the binding of radiolabeled etodolac to its receptor(s) are advanced to the next screen.
B. Intracellular Ca 2t mobilization in CLL Increase of intracellular calcium levels in CLL cells by test compounds such as etodolac analogs will be measured by a flow cytometric assay (FACS) and by using a fluorometric imaging plate reader system (FLIPR, Molecular Devices Corp., Sunnyvale, CA) using the Fluo-4 dye (Molecular Probes).
Briefly, CLL cells (5 x 10 6 /ml) will be loaded for 30 min with 4 pM of Fluo-4 at 37°C in serum-free medium, washed twice, and resuspended for an additional min in normal cell culture medium. The loaded cells will be then mixed in FACS tubes with medium containing a test agent, and immediately thereafter the fluorescence will be followed by FACS analysis over a period of 3 minutes. For high-throughput screening (HTS) assays, the FLIPR-based assay will allow screening in a 96-well plate format, using the same fluorometric dye (Fluo-4).
Positive controls will be performed using the calcium ionophore ionomycin at ng/ml final concentration, with chemokines such as SDF-1 and IP-10, and with anti-IgM cross-linking antibodies. Compounds that increase the Ca 2 uptake by CLL cells, preferably to at least the level induced by R(-)-etodolac are advanced to the next screen.
C. Chemotaxis and chemokinesis assays Cell migration will be measured in a 24-well modified Boyden chamber (Transwell, Corning-Costar, NY). The recombinant human IP-10 chemokine (R&D Systems, McKinley Place, NE) will be diluted in RPMI-1640 medium at 200 ng/ml, and used to evaluate the chemotactic properties oflymphocytes from B-CLL patients. Polycarbonate membranes with pore size of 3 mm will be used.
WO 02/12188 PCT/US01/24978 A total of 600 mL of chemokines or control medium will be added to the bottom wells, and 100 mL of 2 to 5.0 x 106 cells/ml cells resuspended in RPMI-1640 will be added to the top wells. The chamber will be incubated at 37"C with
CO
2 for 2 hours. The membranes will then be removed, and the cells present on the bottom well will be quantified by flow cytometry. For cell quantification, a fixed acquisition time of 30 seconds will be used per sample, and beads will be run during each experiment to ensure a reproducible acquisition. Test agents that induce a chemokinetic response in the lymphocytes, such a chemotactic response, preferably at least as effectively as etodolac, will be advanced to the next screen.
D. Induction of apoptosis in cancer cells The pro-apoptotic activity of the test agents, the R-etodolac analogs, will be tested in primary CLL cells, as well as in other tumor cells, by using the MTT assay and by measuring the catalytic activation of caspase-3 using a fluorometric assay. In brief, cells will be incubated for up to 3 days in presence of serial dilutions of the selected test agents. Cells viability will be quantified in 96-well plates by adding the MTT reagent (at 1 mg/ml final) for 2-4 hours followed by SDS cell lysis and spectrophotometric analysis at 570 nm. Caspase catalytic activity will be measured in a 96-well plate assay using a specific fluorometric substrate (DEVD-AMC), after lysing the treated cells with a lysing buffer followed by fluorometric analysis. Test agents that exhibit pro-apoptotic activity, that increase caspase activity, preferably at least as effectively as R(-)-etodolac, will be advanced to the next screen.
E. Lymphocvte depletion in mouse The selected test agent will be orally delivered to mice of various backgrounds in a single dose of 25 and 100 mg/kg. The number of white blood cells will be counted using a neubauer chamber after 4, 24 hrs, 7 and 14 days post treatment. Test agents that do not lower white cell levels substantially, preferably no more than does etodolac, will be advanced to the next screen.
12/06 2007 13:55 FAX 61 3 92438333 GRIFFITH HACK -*IPAUSTRALIA Q(010 F. Tumor animal model The anti-cancer and preventive activity of the R-etodolac analogs will be tested using the pristane-induced mouse myeloma model, and the transgenic (Nq adenocarcinoma mouse prostate (TRAMP) model. The mice will receive a diet S supplemented with 0.05% to 0.5% of the selected test agent or control. The experimental diets will be in the form of sterile pellets containing the test agent (provided by Dyets Inc., PA). For prevention of cancer experiments in the mouse myeloma model, the diet will be initiated at the same time as the first pristane injection.
00 For the transgenic prostate cancer model, the diet will begin at birth. For therapeutic 10 experiments, the diet will begin in the TRAMP mice at week 10, when the first obistological pathologic markers are usually observed. Analogs will advance to clinical 0 trials or further development based on their activity to inhibit cancer in at least one of these screens.
All of the publications and patent documents cited hereinabove are incorporated by reference herein. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.
In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.
COMS ID No: SBMI-07730632 Received by IP Australia: Time 14:00 Date 2007-06-12
Claims (29)
1. A compound of formula R R3 (R)n R2 N N C I Y-Z O R R wheein Ri is lower alkyl, lower alkenyl, lower alkynyl, phenyl, benzyl or 2-thienyl, R R R and R are the same or different and are each hydrogen or lower alkyl; each R6 is individually hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo, n is 1-3, R is hydrogen, lower alkyl or lower alkenyl, X is oxy and thio, Y is (CH2)1-3, Or (CH2)1-3S02, and Z is (m-(4-pyridyl)(C2-C4 alkoxy), amino)(C2-C4 alkoxy), wherein Ra and R? are each H, (CI-C3)alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 S or nonperoxide 0; an amino acid ester of C4))alkoxy, N(R )C(RO)CO2H, I'-D-glucuronyloxy, OH, (C2-C4)acyloxy, SO3H, P04H2, N(NO)(OH), SO2NH2, PO(OH)(NH2), OCH2CHzN(CH3)3 amino, lower alkylamino, di(lower alkyl)amino, phenylamino,or tetrazolyl; provided that when n is 1, R is hydrogen, and R1 is methyl, then-Y-Z is not -CH2CH2-OH, -CH2-OI-I, -CI-2CH2- OC(0)CH43, or -CH2-OC(0)CH3; and provided that when n is 1, R is 8-ethyl, and R1 is ethyl, then -Y-Z is not -CHCH-OH, or -CH2CH2-OC(O)CH3; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein Z is the L-valine or L-glycine ester of 2- hydroxyethoxy.
3. The compound of claim I wherein Z is N-morpholinoethoxy. 26 vr \elournacanuaraernteconP -1esa\nea .nU\C1s~cisNWDNT.de 1/06/0712/05/U7 COMS ID No: SBMI-07730632 Received by IP Australia: Time 14:00 Date 2007-06-12
4. The compound of claim 1 wherein each R 8 is H, CH 3 or i-Pr.
The compound of claim 1 wherein Z is OCH 2 CH 2 N(CH 3 3
6. A composition comprising the compound of any one of claims 1 to 5 in combination with a pharmaceutically acceptable carrier.
7. The composition of claim 6 which is a tablet, granule or capsule.
8. The composition of claim 6 wherein the carrier is an aqueous vehicle.
9. The composition of claim 8 which is an aqueous solution.
A method of inhibiting cancer comprising administering an effective amount of the compound of any one of claims 1 to 5 to a mammal afflicted with cancer.
11. A method of inhibiting cancer comprising administering an effective amount of the composition of any one of claims 6 to 9 to a mammal afflicted with cancer.
12. The method of claim 10 or 11 wherein the cancer is prostate cancer.
13. The method of claim 10 or 11 wherein the cancer is multiple myeloma.
14. The method of claim 10 or 11 wherein the cancer is chronic lymphocytic leukemia. The method of any one of claims 11 to 14 wherein the composition is administered orally.
H:\suzannet\Keecp\Spcci2001283224. Claims.doc 19/08/04 12/06 2007 13:56 FAX 61 3 92438333 GRIFFITH HACK IPAUSTRALIA Q012 0 0 Cl
16. The method of claim 15 wherein an enterically coated dosage form is Sadministered. c,
17. The method of any one of claims 11 to 14 wherein the composition is administered parenterally.
S18. The method of claim 11 wherein the composition is administered in combination with a chemotherapeutic agent. 00
19. The method of claim 12 wherein the composition is administered in Scombination with a chemotherapeutic agent.
The method of claim 18 wherein the chemotherapeutic agent is mitoxanthrone, prednisone, estramustine, vinblastine or a combination thereof.
21. The method of claim 12 wherein the chemotherapeutic agent is an anti- androgen.
22. The method of claim 21 wherein the anti-androgen is bicafutamide, nilutamide, flutamide, cycloproterone acetate or a combination thereof.
23. The method of claim 21 wherein the anti-androgen is leuprolide acetate, goserelin acetate or a combination thereof.
24. The compound as described in any one of claims 1 to 5 for use in medical therapy.
The use of a compound as described in any one of claims 1 to 5 for the manufacture of a medicament useful for the treatment of a disease in a mammal.
26. The use of claim 25 wherein the mammal is a human. 28 Nl \Hefltune\cBer\PBatnt\tB000-4B,99\P44B91.Jl\peCi\EMflf TS-oC d 2100'912/O6(07 COMS ID No: SBMI-07730632 Received by IP Australia: Time 14:00 Date 2007-06-12 12/06 2007 13:56 FAX 61 3 92438333 GRIFFITH HACK 4 IPAITSTRALIA 013
27. The use of claim 25 or 26 wherein the disease is cancer.
28. Compounds of formula compositions containing them or methods or uses involving them, substantially as hereinbefore described with reference to the examples and/or drawings.
29 N:\eHboue~acruc \Eate \OOO-4B93\l4s49 \sp 12/061o7lz106107 COMS ID No: SBMI-07730632 Received by IP Australia: Time 14:00 Date 2007-06-12
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US09/634,207 US7151100B1 (en) | 1999-07-23 | 2000-08-09 | Indole compounds useful for the treatment of cancer |
US09/634,207 | 2000-08-09 | ||
PCT/US2001/024978 WO2002012188A2 (en) | 2000-08-09 | 2001-08-09 | Indole compounds useful for the treatment of cancer |
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AU2001283224A1 AU2001283224A1 (en) | 2002-05-16 |
AU2001283224B2 true AU2001283224B2 (en) | 2007-06-28 |
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AU2001283224A Ceased AU2001283224B2 (en) | 2000-08-09 | 2001-08-09 | Indole compounds useful for the treatment of cancer |
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AU8322401A Pending AU8322401A (en) | 2000-08-09 | 2001-08-09 | Indole compounds useful for the treatment of cancer |
Country Status (5)
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EP (1) | EP1307459A2 (en) |
JP (1) | JP2004518615A (en) |
AU (2) | AU8322401A (en) |
CA (1) | CA2419060A1 (en) |
WO (1) | WO2002012188A2 (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2255287T3 (en) | 1998-07-09 | 2006-06-16 | Cephalon, Inc. | COMPOSITIONS FOR THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA. |
US7105560B1 (en) | 1999-07-23 | 2006-09-12 | The Regents Of The University Of California | Use of etodolac in the treatment of multiple myeloma |
US7151100B1 (en) | 1999-07-23 | 2006-12-19 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
US7129262B2 (en) | 1999-07-23 | 2006-10-31 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
US7361680B2 (en) | 1999-07-23 | 2008-04-22 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
US6545034B1 (en) | 1999-07-23 | 2003-04-08 | The Regents Of The University Of California | Use of etodolac for the treatment of chronic lymphocytic leukemia |
US20040152672A1 (en) * | 2000-08-09 | 2004-08-05 | Carson Dennis A. | Indole compounds useful for the treatment of cancer |
AU2003295336A1 (en) | 2002-09-19 | 2004-04-08 | Dennis A. Carson | Use of etodoclac to treat hyperplasia |
JP2007507524A (en) | 2003-10-02 | 2007-03-29 | セフアロン・インコーポレーテツド | Indole derivatives |
FR2869231B1 (en) * | 2004-04-27 | 2008-03-14 | Sod Conseils Rech Applic | THERAPEUTIC COMPOSITION CONTAINING AT LEAST ONE PYRROLOBENZODIAZEPINE DERIVATIVE AND FLUDARABINE |
CN107898791A (en) | 2010-06-03 | 2018-04-13 | 药品循环有限责任公司 | The application of bruton's tyrosine kinase (BTK) inhibitor |
CN110801454A (en) * | 2011-10-19 | 2020-02-18 | 药品循环有限责任公司 | Use of Bruton's Tyrosine Kinase (BTK) inhibitors |
KR20150032340A (en) | 2012-07-24 | 2015-03-25 | 파마시클릭스, 인코포레이티드 | Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk) |
US9885086B2 (en) | 2014-03-20 | 2018-02-06 | Pharmacyclics Llc | Phospholipase C gamma 2 and resistance associated mutations |
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EP0289262A2 (en) * | 1987-04-27 | 1988-11-02 | Syntex Pharmaceuticals International Limited | Omega-quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal antiinflammatory drugs |
WO1998009603A2 (en) * | 1996-09-06 | 1998-03-12 | Loma Linda University Medical Center | Compositions including r-nsaids and therapeutic and prophylactic methods employing said compositions |
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US3843681A (en) * | 1971-06-01 | 1974-10-22 | American Home Prod | 1-carboxamido pyrano(thiopyrano)(3,4-6)indole derivatives |
US4337760A (en) * | 1978-10-13 | 1982-07-06 | Adolf Schwimmer | Method for the treatment of tumors with β-glucuronidase activity dependent pharmaceuticals |
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2001
- 2001-08-09 JP JP2002518166A patent/JP2004518615A/en active Pending
- 2001-08-09 AU AU8322401A patent/AU8322401A/en active Pending
- 2001-08-09 WO PCT/US2001/024978 patent/WO2002012188A2/en active IP Right Grant
- 2001-08-09 EP EP01962006A patent/EP1307459A2/en not_active Withdrawn
- 2001-08-09 CA CA002419060A patent/CA2419060A1/en not_active Abandoned
- 2001-08-09 AU AU2001283224A patent/AU2001283224B2/en not_active Ceased
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US3974179A (en) * | 1971-06-01 | 1976-08-10 | American Home Products Corporation | 1,3,4,9-Tetrahydropyrano[3,4-b]indole-1-acetamides and derivatives |
EP0289262A2 (en) * | 1987-04-27 | 1988-11-02 | Syntex Pharmaceuticals International Limited | Omega-quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal antiinflammatory drugs |
WO1998009603A2 (en) * | 1996-09-06 | 1998-03-12 | Loma Linda University Medical Center | Compositions including r-nsaids and therapeutic and prophylactic methods employing said compositions |
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Also Published As
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WO2002012188A2 (en) | 2002-02-14 |
WO2002012188A3 (en) | 2002-10-03 |
AU8322401A (en) | 2002-02-18 |
EP1307459A2 (en) | 2003-05-07 |
JP2004518615A (en) | 2004-06-24 |
WO2002012188B1 (en) | 2003-03-20 |
CA2419060A1 (en) | 2002-02-14 |
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