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Matched Legal Cases: ['art 1', 'Application No. 2', 'Application No. 2', 'Application No. 2', 'Application No. 99', 'Application No. 99', 'Application No. 99', 'Application No. 2', 'Application No. 2', 'Application No. 99', 'Application No. 99', 'Application No. 99', 'art 1']

Patent US7863327 - Chemopreventative treatment of diseases such as cancer, Alzheimer's disease ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsCompounds and methods useful for chemopreventative treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, and multiple sclerosis....http://www.google.com/patents/US7863327?utm_source=gb-gplus-sharePatent US7863327 - Chemopreventative treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel disease, and multiple sclerosisAdvanced Patent SearchPublication numberUS7863327 B2Publication typeGrantApplication numberUS 11/121,316Publication dateJan 4, 2011Filing dateMay 3, 2005Priority dateJun 19, 1998Fee statusPaidAlso published asCA2335505A1, CA2335505C, EP1089724A1, EP1089724A4, EP1089724B1, EP2062577A1, US6326507, US6552075, US7288568, US8034955, US8586775, US20020042535, US20030236303, US20050288363, US20080220057, US20080234368, US20130237721, WO1999065478A1Publication number11121316, 121316, US 7863327 B2, US 7863327B2, US-B2-7863327, US7863327 B2, US7863327B2InventorsGordon W. Gribble, Tadashi Honda, Michael B. Sporn, Nanjoo SuhOriginal AssigneeTrustees Of Dartmouth CollegeExport CitationBiBTeX, EndNote, RefManPatent Citations (53), Non-Patent Citations (479), Referenced by (1), Classifications (31), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetChemopreventative treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel disease, and multiple sclerosisUS 7863327 B2Abstract Compounds and methods useful for chemopreventative treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, and multiple sclerosis.
BACKGROUND OF THE INVENTION The present invention relates to compounds which have been found to be useful for prevention or treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, rheumatoid arthritis, and other inflammatory diseases.
SUMMARY OF THE INVENTION The present invention provides methods and compositions for the prevention or treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The methods of the invention involve administering to a subject a therapeutic compound of the formula:
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates the efficacy of a composition of the invention, 2-cyano-3,12-dioxoolean-1,9-dien-28oic acid (CDDO) (denoted �TP-151�), in suppressing interleukin-1β (IL-1β)-induced COX-2 expression and prostaglandin E2 (PGE2) in human colon myofibroblast 18Co cells;
FIG. 2 is a comparison of the efficacy of various compounds on NO production induced by lipopolysaccharide (LPS) in rat microglia cells (brain macrophage cells), showing activity of TP151 favorable to that of dexamethasone, a glucocorticoid, thus indicating how a composition of the invention may be used to prevent or treat a neurodegenerative disease. �TP-82� refers to 3,11-dioxoolean-1,9-dien-28oic acid;
DETAILED DESCRIPTION OF THE INVENTION Before further description of the invention, certain terms employed in the specification, examples and appended claims are, for convenience, collected here.
Definitions As used herein, the term �organic moiety� is intended to include carbon based functional groups such as alkyl, alkylamino, alkoxy, aryl, aralkyl, aryloxy, alkylthio, and alkylcarboxyl.
As used herein, the term �inorganic moiety� is intended to include non carbon-based groups or elements such as hydrogen, halo, amino, nitro, thiol, and hydroxyl.
As used herein, the term �electron withdrawing moiety� is known in the art, and refers to a group which has a greater electron-withdrawing than hydrogen. A variety of electron-withdrawing groups are known, and include halogens (e.g., fluoro, chloro, bromo, and iodo groups), nitro, cyano, �NR3 +, �SR2 +, �NH3 +, �SO2R, SO2Ar, �COOH, �OAr, �COOR, �OR, �COR, �SH, �SR, �OH, �Ar, and �CH═CR2, where Ar is aryl, and R represents any appropriate organic or inorganic moiety and, preferably, alkyl moiety.
As used herein, the term �halosubstituted alkyl moieties� is intended to include alkyl moieties which have halogen moieties in the place of at least one hydrogen.
As used herein, the term �amino� means �NH2; the term �nitro� means �NO2; the term �halogen� designates �F, �Cl, �Br or I; the term �thiol� means SH; and the term �hydroxyl� means �OH. Thus, the term �alkylamino� as used herein means an alkyl group, as defined above, having an amino group attached thereto. The term �alkylthio� refers to an alkyl group, as defined above, having a sulfhydryl group attached thereto. The term �alkylcarboxyl� as used herein means an alkyl group, as defined above, having a carboxyl group attached thereto.
The term �alkyl� refers to the saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
Moreover, the term �alkyl� (including �lower alkyl�) as used throughout the specification and claims is intended to include both �unsubstituted alkyls� and �substituted alkyls�, the latter of which refers to alkyl moieties having moieties replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such moieties can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the moieties described above. An �aralkyl� moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
The term �alkoxy�, as used herein, refers to a moiety having the structure �O-alkyl, in which the alkyl moiety is described above.
The term �aryl� as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, unsubstituted or substituted benzene, pyrrole, furan, thiophene, imidazole, oxazole, triazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. The aromatic ring can be substituted at one or more ring positions with such moieties, e.g., as described above for alkyl groups. Preferred aryl groups include unsubstituted and substituted phenyl groups.
The term �aryloxy�, as used herein, refers to a group having the structure �O-aryl, in which the aryl moiety is as defined above.
As used herein, the term �subject� is intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the subject is a primate. In an even more preferred embodiment, the primate is a human. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with an Alzheimer's-type neuropathology. A subject can be a human suffering from a neurodegenerative disease, such as Alzheimer's disease, or Parkinson's disease.
As used herein, the term �IC50� refers to an inhibitory dose which is 50% of the maximum response obtained.
Active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a subject. A �therapeutically effective dosage� preferably reduces the amount of symptoms of the condition in the infected subject by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in humans, such as the model systems shown in the Example and Figures.
R1 may be an electron-withdrawing group, e.g., cyano, aryl, and halosubstituted alkyl moieties. Preferably, R1 may include cyano, halo, or �OR′, wherein R′ is H or an organic moiety, e.g., acetyl or carboxyl group. R1 may be substituted anywhere on the six-membered ring denoted by positions 1 through 10, but in a preferred embodiment R1 is at position 2 and in a more preferred embodiment R1 is a cyano group at position 2.
In a more preferred embodiment of formula (I), B is a double bond, X is O, R3 is �OH, and R1 is a cyano group, preferably at position 2. Examples of preferred compounds include 3,11-dioxoolean-1,12-dien-28oic acid, 2-cyano-3,11-dioxoolean-1,12-dien-28oic acid and 2-cyano-3,12-dioxoolean-1,9-dien-28oic acid.
Example 1 Compounds were synthesized as below:
a: HCO2Et/MeONa/THF, b: PhSeCl/AcOEt; 30% H2O2/THF, c: NH2OH�HCl/EtOH/H2O, d: MeONa/MeOH/Et2O, e: KOH/MeOH, f: Jones, g: HCO2Et/MeONa/PhH, h: LiI/DMF
<1.0b 3
For the following examples, stock solutions of CDDO (0.01 M) were made in DMSO and aliquots frozen at −20� C. Serial dilutions were made in DMSO before addition to cell culture media. Primary rat microglia and hippocampal neurons were isolated and cultured as described by Flaris et al., 1993 and Ren and Flanders, 1996.
Example 2 Induction of Differentiation in Myelogenous Leukemia Cells, PC12 Pheochromocytoma Cells, and 3T3-L1 Fibroblasts CDDO induces monocytic differentiation in the poorly differentiated LCDB acute myelogenous leukemia cell line, derived from a chemotherapy-resistant patient at the NCI Pediatric Oncology Branch. FIG. 11 illustrates LCDB cells seeded in RPMI 1640/2% FBS, either alone (11A), with 2.5 ng/ml TGF-β1 (11B), with 10−8M CDDO (11C), or with both TGF-β1 and CDDO (11D). After 48 h, cytospin slide preparations were made and stained for α-naphthyl acetate esterase activity (kit from Sigma). PC12 cells were cultured for 5 days in gridded dishes in DMEM/10% FBS and 5% horse serum (Smith et al., 1997), either alone (11E), with 100 ng/ml 7S NGF (11F), with 10−6 M CDDO (11G), or with both NGF and CDDO (11H). Cells were plated in triplicate, and for each treatment similar results were observed in at least two separate platings of cells. Methods for quantitative image analysis of size of cells and neurites have been described (De la Torre et al., 1997). Control cells in FIG. 11E are approximately 10 μm in diameter. 3T3-L1 cells were grown to confluency in DMEM/5% calf serum, and then treated once with CDDO in DMEM/10% FBS (FIG. 12A) or with CDDO and/or LG100268 in DMEM/10% FBS (FIG. 12B). Every two days thereafter, medium was changed to DMEM/10% FBS, without added CDDO or LG100268, Cells were harvested on day 8 (FIG. 12A) or day 6 (FIG. 12B), and GPDH was measured in lysates, using a standard assay for consumption of NADH at 340 nm (Wise and Green, 1979). These cells do not express the monocyte/macrophage marker, α-naphthyl esterase (FIG. 11A). However, within 48 h, CDDO (10−8 M) induced the activity of this enzyme, as determined histochemically (FIG. 11C). Treatment of LCDB cells with TGF-β1 (2.5 ng/ml) also induced α-naphthyl esterase activity (FIG. 11B), and there was an additive effect when both agents are used (FIG. 11D). It has been shown that CDDO has differentiative effects, either by itself or in combination with TGF-β1, on the human monocytic leukemia line, THP-1, and the human promyelocytic leukemia line, NB4 (data not shown).
The rat pheochromocytoma cell line, PC12, has been widely used to study neuronal development and differentiation. Treatment of these tumor cells with NGF is known to induce a neuronal phenotype, with extensive neurite outgrowth (Greene and Rischler, 1976; Guroff 1985). CDDO markedly potentiates these effects of NGF. FIGS. 11E and F show the induction of neurite outgrowth by NGF (100 ng/ml). Although CDDO (10−6 M) by itself does not induce neurite formation, it does cause the cells to adopt a larger, flatter morphology (FIG. 11G). When used in combination with NGF, CDDO (FIG. 11H) almost doubled the number of primary neurites/cell (from 1.2�0.2 S.E.M. to 2.1�0.1, p<0.001), and caused a greater than 3-fold increase in length of neurites (from 28�6 to 99�9 microns, p<0.001), and a 5-fold increase in neurite branching/cell (from 0.23�0.06 to 1.13�0.08, p<0.001). Thus, CDDO enhances neuronal differentiation of PC12 cells by increasing cell size, as well as the extent and complexity of neurite arborization.
Example 3 CDDO Inhibits Proliferation of Many Malignant or Premalignant Cells Inhibitors of cell proliferation are known to be useful chemopreventive and chemotherapeutic agents. CDDO was tested against a wide variety of cells derived from highly aggressive leukemias and carcinomas, as well as from non-neoplastic tissues. NRP-152 cells were grown as described in Danielpour et al., 1994. MCF-7 cells were grown in phenol red-free RPMI 1640/10% charcoal-stripped FBS with added 17-β-estradiol (10 pM). Triterpenoids were added at the time of plating, and 72 h later 3H-thymidine (1 μCi/well) was added for the final 2 h of incubation. Incorporation of thymidine was measured after cells were precipitated with TCA (10%), washed, and solubilized. The symbols used in FIGS. 13(A)-(B) are CDDO, ▪; TP-82, ◯, and oleanolic acid; ●.
ER positive breast carcinoma
3 � 10−8 MDA-MB-231
ER negative breast carcinoma
1 � 10−6 21-MT-1
2 � 10−7 21-MT-2
3 � 10−7 21 -NT
1 � 10−6 21-PT
3 � 10−7 THP-1
5 � 10−8 U937
2 � 10−7 HL-60
1 � 10−7 NB4
4 � 10−8 AML193
4 � 10−7 KG-1
2 � 10−7 ML-1
1 � 10−7 NT2/D1
1 � 10−7 A2058
2 � 10−7 MDA-MB-468a ER negative breast carcinoma
2 � 10−7 SW626a Ovarian carcinoma
3 � 10−7 AsPc-1a Pancreatic carcinoma
1 � 10−7 CAPAN-1a Pacreatic carcinoma
3 � 10−7 All cells were obtained from ATCC, except as noted. They were grown under standard conditions in either DMEM, DMEM/F12, or RPMI 1640 media plus 5-10% FBS. CDDO, over the dose range 10−6 to 10−10 M, was added to cultures at the time of seeding. Three or 4 days later, cells were treated with 3H-thymidine for 2 h (12 h in the case of leukemia cells), and then incorporation was measured. �ER� means estrogen receptor.
Example 4 CDDO Blocks De Novo Synthesis of iNOS and COX-2 CDDO is highly active in blocking the ability of several inflammatory cytokines to induce de novo formation of the enzymes, iNOS and COX-2 (FIG. 14). FIG. 14(A) illustrates Western blots; primary mouse macrophages; IFN-γ, 10 ng/ml; LPS, 2 ng/ml were added to cultures together with triterpenoids or dexamethasone (concentrations shown as μM); cells were harvested at 12 h. FIG. 14(B) illustrates Northern blots, RAW 264.7 macrophage-like cell line. IFN-γ, 10 ng/ml; LPS, 1 ng/ml; TNF-α, 10 ng/ml, were added to cultures together with CDDO or dexamethasone. RNA prepared after 12 h; GAPDH used as a loading control. FIG. 14(C) illustrates suppression of production of NO and PGE2 in primary macrophages. For NO studies, cells were treated with IFN-γ, 10 ng/ml, together with CDDO (▪), dexamethasone (◯), TP-82 (□), or oleanolic acid (▴). After 48 h, supernatants were analyzed for NO by the Griess reaction. For PGE2 studies, cells were treated with IFN-γ, 5 ng/ml, and LPS, 5 ng/ml, together with the same set of inhibitors. After 48 h, PGE2 was measured in supernatants by immunoassay. Control values (no inhibition) for NO and PGE2 were 4.7 nmol/2�105 cells and 2.2 ng/ml/2�105 cells, respectively. FIGS. (14D) and (14E) illustrate (human colon myofibroblasts) 18Co cells grown in MEM/10% FBS; other methods are the same as reported above for macrophages. FIG. 14(D) illustrates Northern blots showing dose-response for suppression of COX-2 mRNA after induction with IL-1β (30 pg/ml). CDDO was added together with IL-1. In FIG. (E), Western blots show suppression of COX-2 protein; CDDO was added together with IL-1β (30 pg/ml). Also shown is suppression of cumulative production of PGE2 in cell supernatants by CDDO.
Example 5 CDDO Suppresses iNOS and Protects Against Cell Death in Rat Brain Cells The roles of inflammatory mediators, as well as aberrant programs for cell survival and apoptosis, in the genesis of cancer and Alzheimer's Disease are now undergoing serious investigation (McGeer and McGeer, 1995; Merrill and Benveniste, 1996; Akama et al., 1998). CDDO was tested in this example as a suppressor of de novo formation of iNOS in cultured microglia (the resident macrophages of the brain), as well as its ability to protect cultured hippocampal neurons from cell death induced by β-amyloid. It was found that CDDO acts in primary microglial cultures in a manner similar to that reported above for primary peritoneal macrophages. Thus, LPS (5 ng/ml) induced iNOS in primary microglial cultures and caused a 27-fold increase in production of NO within 18 h. Concomitant treatment of these cultures with CDDO at either 10−6 or 10−7 M inhibited this induction by 73% and 52%, respectively. We have also explored the possibility that CDDO can protect cultured hippocampal neurons from cell death induced by the peptide β-amyloid, since NO has been implicated (Akama et al., 1998) in the neurotoxic actions of this peptide which is central to the pathogenesis of Alzheimer's disease (Selkoe, 1997). Hippocampal neurons were isolated and cultured from 16 day rat embryos and then treated with CDDO for 24 h before adding the β-amyloid peptide fragment, amino acids 25-35, at a final concentration of 10 μM. This dosing with β-amyloid alone caused death of more than half of the neurons in the culture within 24 h, as measured by MTT assay. However, pretreatment of the neuronal cultures with CDDO (10−8 and 10−7 M) totally prevented this cell death, and some protective activity of CDDO was found at doses as low as 10−10 M.
SUMMARY As seen above, compounds of the invention such as CDDO are potent, multifunctional molecules having a wide range of actions, many of them potentially useful for prevention or treatment of diseases such as cancer. Proliferation of many human tumor cell lines, including those derived from estrogen receptor-positive and -negative breast carcinomas, myeloid leukemias, and several carcinomas that bear a Smad-4 mutation are inhibited. The ability of various inflammatory cytokines, such as interferon-γ, interleukin-1, or tumor necrosis factor-α to induce de novo formation of the enzymes, inducible nitric oxide synthase (iNOS) or inducible cyclooxygenase (COX-2) in either mouse peritoneal macrophages, rat brain microglia, or human colon fibroblasts is suppressed. Also, brain hippocampal neurons are protected from cell death induced by β-amyloid. The above indicates that the compounds of the invention, e.g., CDDO, are useful in vivo, either for chemoprevention or chemotherapy of malignancy, as well as for neuroprotection.
EQUIVALENTS It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.
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Pharmaceutical Sciences, 91 (8): 1863-1872, 2002.479Zou et al., "c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells," Cancer Res., 64:7570-7578, 2004.Referenced byCiting PatentFiling datePublication dateApplicantTitleUS8513436Dec 19, 2011Aug 20, 2013Reata Pharmaceuticals, Inc.Pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulatorsClassifications U.S. Classification514/521, 558/423, 514/463, 558/415, 514/519, 514/522, 514/520International ClassificationA61K31/35, C07C255/03, A61K31/275, A61P25/16, C07J63/00, A61P1/04, A61P19/02, A61P21/04, A61P29/00, A61K31/19, A61K31/56, A61K31/277, A61P25/00, A61P35/00, A61P25/28Cooperative ClassificationA61K31/275, A61K31/277, A61K31/35, A61K31/19, C07C255/47European ClassificationA61K31/275, A61K31/35, A61K31/19, A61K31/277Legal EventsDateCodeEventDescriptionJun 11, 2014FPAYFee paymentYear of fee payment: 4May 1, 2012CCCertificate of correctionNov 29, 2011ASAssignmentFree format text: CONFIRMATORY LICENSE;ASSIGNOR:DARTMOUTH COLLEGE;REEL/FRAME:027290/0544Owner name: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. 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