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WO2007062030A2 - Derives de quinuclidinone utilises comme agents anticancereux - Google Patents

Derives de quinuclidinone utilises comme agents anticancereux Download PDF

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Publication number
WO2007062030A2
WO2007062030A2 PCT/US2006/045045 US2006045045W WO2007062030A2 WO 2007062030 A2 WO2007062030 A2 WO 2007062030A2 US 2006045045 W US2006045045 W US 2006045045W WO 2007062030 A2 WO2007062030 A2 WO 2007062030A2
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Prior art keywords
derivatives
alkyl
prodrugs
metabolites
compound
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PCT/US2006/045045
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English (en)
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WO2007062030A3 (fr
Inventor
Stephen C. Bergmeier
Susan C. Evans
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Ohio University
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Publication of WO2007062030A2 publication Critical patent/WO2007062030A2/fr
Publication of WO2007062030A3 publication Critical patent/WO2007062030A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • C07D491/12—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 three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • chemotherapeutic agents have been developed and use clinically.
  • a significant problem with most chemotherapeutic agents is the development of resistance and non-specific cytotoxicity.
  • Chemotherapeutic agents largely act through one of three mechanisms of action at the molecular level (antimetabolites, DNA interaction, and tubulin targeting).
  • Antimetabolites are commonly used chemotherapeutic agents.
  • Typical drugs include methotrexate, and 5-fluoracil (5-FU).
  • 5-fluoracil 5-fluoracil
  • an antimetabolite is gemcitabine.
  • Antimetabolites interfere with the formation or use of a normal cellular metabolite. Most antimetabolites interfere with the synthesis of DNA and consequently many of the antimetabolites bear a strong structural similarity to components of DNA ' ⁇ eTg., 5- ' FCTf ' of " critical co factors (e.g. methotrexate). Antimetabolites are often associated with significant toxicity due to interruption of normal cellular pathways.
  • Small molecules that interact with DNA are another widely used class of anticancer drugs. These include DNA alkylating agents and intercalators that exert their selective cytotoxicity by targeting the difference in growth rate between cancer cells and normal cells.
  • DNA alkylating agents include DNA alkylating agents that crosslink DNA.
  • a classic nitrogen mustard is cyclosphamide. These agents tend to target guanine rich sequences.
  • Other alkylating agents include aziridines and nitrosoureas.
  • a particularly interesting class of alkylating agent that has some sequence specificity are the CC- 1065 analogs.
  • CC- 1065 is an antibiotic isolated from a streptomycin species and binds to the minor groove of DNA to 5'-Pu-N-T-T-A or 5'-A-A-A-A sequences.
  • the anthraquinones are one of the best known examples of intercalating agents.
  • the planar ring system of these molecules is inserted perpendicular to the long axis of the double helix. This leads to multiple mechanisms of DNA damage, including inhibition of topoisomerases.
  • Topoisomerase inhibitors are an efficient group of new drugs that induce apoptosis and are used to treat cancer.
  • the main pathways leading from topoisomerase- mediated DNA damage to cell death involve activation of caspases in the cytoplasm by proapoptotic molecules released from mitochondria, hi some cells, the apoptotic response also involves the cancer receptor Fas (APO-1/CD95).
  • apoptotic signaling pathways The activation of these apoptotic signaling pathways is tightly controlled by upstream regulatory pathways that respond to DNA lesions induced by topoisomerase inhibitors in cells undergoing apoptosis. These include the proapoptotic Chk2, c-Abl and SAPK/JNK pathways, the survival PI(3)kinase-Akt-dependent pathway and the transcription factors p53 and NF-kappaB. Initiation of cellular responses to DNA lesions induced by topoisomerase inhibitors is ensured by the protein kinases DNA-PK, ATM and ATR, which bind to DNA breaks. It is believed that topoisomerase I inhibitors stabilize a DNA/topoisomerase I complex and interact with replication machinery to cause cell death. Many of these topoisomerase I inhibitors also act as radiosensitizers by producing enzyme-mediated DNA damage.
  • Etoposide was the first anticancer drug to be demonstrated to exert its antineoplastic effect though inhibition of topoisomerase II. It induces massive apoptosis in germ-cell malignancies, lung cancer, non-Hodgkin's lymphoma, leukemia, Kaposi's sarcoma, neuroblastoma, and soft-tissue sarcomas through activation of caspase-3, -8 and -9 and endonucleases.
  • anticancer agents that target tubulin have been developed. Probably the most well-known is paclitaxel. This compound promotes microtubule assembly, which causes arrest of the cell cycle at the G2/M transition and ultimately leads to apoptosis.
  • a new class of microtubule drugs is exemplified by epothilone B.
  • chemotherapeutic agents based on quinuclidinone analogs.
  • One particular set of new chemotherapeutic agents is that of formula I:
  • R 1 and R 2 may be the same or different and are selected from the group consisting of H, halo, alkyl, cycloalkyl, haloalkyl, aryl, haloaryl, alkylaryl, alkoxyaryl, hydroxyl, acetate, ketal, alkoxy, and combinations thereof; and R 3 is selected from the group consisting of O and hydroxy! "
  • R 1 and R 2 may form a ring, as with an alkyl, alkenyl, substituted alkyl or substituted alkenyl bridge.
  • derivatives, metabolites, and prodrugs thereof are also encompassed.
  • Figure 1 shows four small molecules reported to restore function to p53.
  • Figure 2 shows the effect of quinuclidinone derivatives on cell viability of H1299 cells in the presence and absence of 4Gy of gamma radiation. Each data point is an average of three independent experiments and expressed as M ⁇ SD. All experiments were carried with a 100 ⁇ M concentration of quinuclidinone analogs.
  • Figure 3 shows dose response curves of 8a and 8b in H1299 cells alone or in the presence of 4 Gy gamma radiation. Each data point is an average of three independent experiments and expressed as M ⁇ SD.
  • chemotherapeutic agents based on quinuclidinone analogs.
  • One particular set of new chemotherapeutic agents is that of formula I:
  • R 1 and R 2 may be the same or different and are selected from the group consisting of H, halo, alkyl, cycloalkyl, haloalkyl, aryl, haloaryl, alkylaryl, alkoxyaryl, hydroxyl, acetate, ketal, alkoxy, and combinations thereof; and R 3 is selected from the group consisting of O and hydroxyl.
  • R 1 and R 2 may form a ring, as with an alkyl, alkenyl, substituted alkyl or substituted alkenyl bridge. Also encompassed are derivatives, metabolites, and prodrugs thereof.
  • R 1 and R 2 are hydroxyl, and R 3 is a O.
  • R 1 , R 2 and R 3 are all hydroxyl.
  • R 1 and R 2 are both alkyl.
  • R 1 is H
  • R 1 and R 2 together may form a ring, wherein the ring may be an alkyl or aryl ring.
  • the compounds described herein are useful in the treatment of unwanted rapidly proliferating cells, such as cancer cells.
  • the compounds preferably induce apoptosis in the unwanted rapidly dividing cells.
  • the compounds may restore function to mutant p53 or may induce apoptosis by a p53-independent mechanism.
  • the compounds described herein may also be used as part of a combination therapy, for example, a subject being treated with the compounds described herein may be simultaneously treated with radiation therapy to further decrease survival of unwanted cells.
  • Tumors are complex collections of cells that respond to therapies differently depending on the organ site and type of cells.
  • Chemotherapeutic agents are developed through empirical screens to identify compounds or molecules that kill cancer cells. Most cytotoxic agents used to treat cancer act by inducing apoptosis. 1 ' 2 [0022J TKe ' combination bfradiotherapy and chemotherapy is a unique and effective therapy. The role of radiotherapy is to control the primary tumor, while chemotherapy can be used to diminish distant metastases. 3 ' 4 Some chemotherapeutic drugs destroy tumor cells directly by their own cytotoxic action but may also enhance the effects of radiotherapy. Many studies show the advantages of combining radiotherapy with chemotherapy, both in terms of better local control of cancer and metastasis prevention. 5'7
  • the quinuclidinone derivative 4 is also reported to induce apoptosis in a number of cell types. 13 ' 14 This quinuclidinone also restores the active conformation of mutant p53. Original reports suggested 4 induced conformational change in p53. However, our study has indicated that this compound decreases cell proliferation and induces apoptosis in a p53-independent mechanism. The quinuclidinone 4 was identified through the screening of a library of low molecular weight molecules. 14 Consequently no structural activity studies have been reported for this interesting molecule.
  • the quinuclidine ring system itself is a common structural element of a number of pharmacologically active small molecules, especially cholinergic ligands. hi general, these ligands lack the 3-keto group seen in 4. 15 ' 16 This lack of a carbonyl group at C-3 has significant implications for the basicity of the tertiary amine.
  • the pKa of the conjugate acid of quinuclidine is 11.4 while that of the conjugate acid of quinuclidinone is only 7.5. 17
  • DMEM Dulbecco's modified essential media
  • FBS Fetal bovine serum
  • streptomycin 100 Units/mL
  • MTT assay 4000-5000 cells/well in 100 mL of medium were seeded in a 96-well plate for 24 h prior to drug treatment. The media was then changed to media with derivative compounds and cells were treated with either gamma or UV radiation. At the end of incubation (24 h), 10 mL of 5 mg/mL MTT reagent (ATCC) was added to each well for 4 h.
  • ATCC MTT reagent
  • this compound showed no activity.
  • the initial lead compound 4 showed excellent activity with less than 10% of the cells remaining viable.
  • the first is that the hydroxyl, while able to engage in similar types of non-covalent contacts, is no longer in an appropriate position.
  • the lower basicity of the quinuclidinones is important for activity.
  • the diacetate 7 showed similar activity to the lead compound 4 indicating that the free hydroxyls were not necessary.
  • the acetal derived from cyclohexanone (8c) showed decreased activity relative to both the parent acetonide (8b) as well as the diol.
  • IR Gamma irradiation
  • Table 1 shows the effect of the provided compounds (4 mM) on cell viability of Hl 299 null for p53 and transfected wild-type p53 cells, with and without gamma radiation:
  • treating is meant curing, ameliorating or tempering the severity of the cancer or the symptoms associated therewith.
  • treatment refers to curative therapy, prophylactic therapy, and preventative therapy.
  • Preventing means preventing the occurrence of the cancer, or tempering the severity of the cancer if it is develops subsequent to the administration of the instant compositions. This preventing the onset of a clinically evident unwanted cell proliferation altogether or preventing the onset of a preclinically evident stage of unwanted rapid cell proliferation in individuals at risk. Also intended to be encompassed by this definition is the prevention of metastatis of malignant cells or to arrest or reverse the progression of malignant cells. This includes prophylactic treatment of those at risk of developing precancers and cancers.
  • terapéuticaally effective and “pharmacologically effective” are intended to qualify the amount of each agent which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
  • subject for purposes of treatment includes any human or animal subject having a neoplasia, such as cancer or precancer.
  • the subject is any human or animal subject, and preferably is a human subject who is at risk of developing a cancer.
  • the subject may be at risk due to exposure to carcinogenic agents, being genetically predisposed to disorders characterized by unwanted, rapid cell proliferation, and so on.
  • the compounds of the present invention are also useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
  • subject means a human.
  • the term "derivative" is intended to encompass compounds which are structurally related to . the quinuclidinone analogs described herein or which possess the substantially equivalent activity to the parent quinuclidinone analogs, as measured by the derivative's ability to inhibit cell viability as measured via the methyl tetrazolium (MTT) mitochondrial activity assay described herein.
  • such compounds may include, but are not limited to, esters and prodrugs thereof.
  • Such compounds may be formed in vivo, such as by metabolic mechanisms.
  • alkyl is used, either alone or with other terms, such as haloalkyl or alkylaryl, it includes C 1 to C 10 linear or branched alkyl radicals, examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and so forth.
  • haloalkyl includes C 1 to C 10 linear or branched alkyl radicals substituted with one or more halo radicals. Some examples of haloalkyl radicals include trifluoromethyl, 1,2-dichloroethyl, 3-bromopropyl, and so forth.
  • halo includes radicals selected from F, Cl, Br, and I.
  • aryl used alone or in combination with other terms such as alkylaryl, haloaryl, or haloalkylaryl, includes such aromatic radicals as phenyl, biphenyl, and benzyl, as well as fused aryl radicals such as naphthyl, anthryl, phenanthrenyl, fluorenyl, and indenyl on so forth.
  • aryl also encompasses "heteroaryls,” which are aryls that have carbon and one or more heteroatoms, such as O, N, or S in the aromatic ring. Examples of heteroaryls include indolyl, pyrrolyl, and so on.
  • Alkylaryl or “arylalkyl” refers to alkyl-substituted aryl groups such as butylphenyl, propylphenyl, ethylphenyl, methylphenyl, 3,5-dimethylphenyl, tert- butylphenyl and so forth.
  • the agents of the present invention may be administered orally, intravenously, intranasally, rectally, or by any means which delivers an effective amount of the active agent to the tissue or site to be treated. It will be appreciated that different dosages may be required for treating different disorders.
  • An effective amount of an agent is that amount which causes a statistically significant decrease in neoplastic cell count, growth, or size.
  • Neoplastic disorders responsive to the agents of the present invention include, but are not limited to, breast cancer.
  • the dosage form and amount can be readily established by reference to known treatment or prophylactic regiments.
  • the amount of therapeutically active compound that is administered and the dosage fegi yogaTfof treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex, and medical condition of the subject, the severity of the disease, the route and frequency of administration, the particular compound employed, the location of the unwanted proliferating cells, as well as the pharmacokinetic properties of the individual treated, and thus may vary widely.
  • the dosage will generally be lower if the compounds are administered locally rather than systemically, and for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the dosage regime or therapeutically effective amount of the inhibitor to be administrated may need to be optimized for each individual.
  • the pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 200 mg.
  • the daily dose can be administered in one to four doses per day.
  • the active agents may be administered along with a pharmaceutical carrier and/or diluent.
  • the agents of the present invention may also be administered in combination with other agents, for example, in association with other chemotherapeutic or immunostimulating drugs or therapeutic agents.
  • pharmaceutical carriers or diluents useful in the present invention include any physiological buffered medium, i.e., about pH 7.0 to 7.4 comprising a suitable water soluble organic carrier. Suitable water soluble organic carriers include, but are not limited to corn oil, dimethylsulfoxide, gelatin capsules, etc.
  • the pharmaceutically acceptable salts thereof are the pharmaceutically acceptable salts thereof.
  • pharmaceutically acceptable salts connotes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • esters thereof are esters thereof. Esters of the heteroaryl-containing isoflavone compounds may be prepared by conventional methods known to those skilled in the art.
  • Suitable pharmaceutically acceptable acid addition salts of quinuclidinone analogs may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, " carboxyl ⁇ c, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, ambonic, pamoic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, /?-hydroxybutyric, gal
  • Suitable pharmaceutically acceptable base addition salts of quinuclidinone analogs include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine may be used form base addition salts of the heteroaryl-containing isoflavone compounds.
  • AU of these salts may be prepared by conventional means from the corresponding heteroaryl-containing isoflavone compounds by reacting, for example, the appropriate acid or base with the heteroaryl-containing isoflavone compounds.
  • Adjunct therapy in defining use of one or more quinuclidinone analogs of the present invention and one or more other pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace coadministration of these agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of these active agents, or in multiple, separate formulations for each agent.
  • antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be selected for treatment of cancers or other neoplasias by combination drug chemotherapy.
  • Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.
  • other anti-neoplastic agents such as metallomatrix proteases inhibitors may be used. Suitable agents which may be used in combination therapy will be recognized by those of skill in the art.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • examples are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • the compound may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile.
  • the formulations may be present in unit or multi-dose containers such as sealed ampoules or vials.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne de nouveaux composés représentés par la formule (I) dans laquelle R1 et R2 peuvent être identiques ou différents et sont sélectionnés parmi H, halo, alkyle, cycloalkyle, haloalkyle, aryle, haloaryle, alkylaryle, alcoxyaryle, hydroxyle, acétate, cétal, alcoxy et des combinaisons de ceux-ci ou R1 et R2 peuvent former un noyau avec un pont alkyle, alcényle, alkyle substitué ou alcényle substitué et R3 désigne O ou hydroxyle. Cette invention concerne également des dérivés, des métabolites et des promédicaments de ceux-ci. Cette invention concerne également des procédés de préparation des analogues de quinuclidinone ci-décrits, ainsi que des méthodes de traitement, de prévention ou de retardement de l'apparition d'un cancer chez un sujet nécessitant un tel traitement consistant à administrer une quantité efficace d'un composé représenté par la formule (I) ou d'un dérivé, d'un métabolite ou d'un promédicament de celui-ci à un sujet chez qui on a diagnostiqué un cancer ou susceptible de développer un cancer.
PCT/US2006/045045 2005-11-21 2006-11-21 Derives de quinuclidinone utilises comme agents anticancereux WO2007062030A2 (fr)

Applications Claiming Priority (2)

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US73867305P 2005-11-21 2005-11-21
US60/738,673 2005-11-21

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WO2007062030A2 true WO2007062030A2 (fr) 2007-05-31
WO2007062030A3 WO2007062030A3 (fr) 2008-01-24

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104860994A (zh) * 2014-02-20 2015-08-26 中国药科大学 3-奎宁环酮类含磷化合物的制备及其医药用途
WO2020058458A1 (fr) 2018-09-20 2020-03-26 Aprea Therapeutics Ab Dérivés de quinuclidine-3-one et leur utilisation dans le traitement du cancer
WO2022175402A1 (fr) 2021-02-18 2022-08-25 Aprea Therapeutics Ab Dérivés de quinuclidine-3-one

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0400708D0 (sv) * 2004-03-22 2004-03-22 Aprea Ab New compounds and use thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104860994A (zh) * 2014-02-20 2015-08-26 中国药科大学 3-奎宁环酮类含磷化合物的制备及其医药用途
WO2020058458A1 (fr) 2018-09-20 2020-03-26 Aprea Therapeutics Ab Dérivés de quinuclidine-3-one et leur utilisation dans le traitement du cancer
WO2022175402A1 (fr) 2021-02-18 2022-08-25 Aprea Therapeutics Ab Dérivés de quinuclidine-3-one

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