HK1131550B - L-oddc prodrugs for cancer - Google Patents

Description

Prodrugs of L-OddC for cancer

Technical Field

The present invention relates to nucleoside compounds for the treatment of cancer, in particular non-small cell lung cancer and pancreatic cancer. The present invention relates to the use of certain prodrug forms of L-OddC or troxacitabine (troxacitabine) for the treatment of cancer, in particular non-small cell lung cancer and pancreatic cancer.

RELATED APPLICATIONS

Priority of the U.S. provisional application US60/842,085 entitled "prodrugs of troxacitabine for the treatment of cancer, in particular non-small cell lung cancer", filed 2006, 9/1, is hereby incorporated by reference in its entirety.

Background

Trixacitabine (Troxatyl)^TM(ii) a L-OddC; (-) -2 '-deoxy-3' -oxacytidine)¹Is the first L-nucleoside analogue that has shown anticancer activity, is currently being evaluated in a critical phase II/III clinical trial for the third line therapy (the third line treatment) of Acute Myeloid Leukemia (AML), and phase I/II dose trials are being conducted in patients with refractory pancreatic cancerAnd (4) testing the range. This compound has the same intracellular activation pathway as the common antitumor nucleosides (gemcitabine and cytarabine), resulting in the formation of active triphosphates, which then enter the DNA immediately leading to chain termination.²Unlike the nucleosides described above, troxacitabine has a unique cellular uptake and metabolic pattern that makes it insensitive to the common mechanisms of resistance to cytotoxic nucleoside analogues. Indeed, troxacitabine has been shown to be delivered into cells by passive diffusion, rather than through nucleoside-specific membrane transporters such as ENT and CNT, and therefore does not experience ENT and CNT-mediated hindrance (resistance)³. However, this will depend on the type of cell. In addition, troxacitabine is resistant to deoxycytidine deaminase (dCD), thus retaining its activity against tumors with high dCD levels.⁴The pharmacokinetic behavior of the D-configured nucleoside analogue is characterized by a rapid disappearance from plasma due to dCD-mediated deamination, in contrast to troxacitabine which exhibits a favourable long plasma half-life (82 hours) and a systemic clearance (systemic clearance) comparable to the glomerular filtration rate.⁵These data indicate that troxacitabine may have activity against refractory tumors. However, although troxacitabine showed relatively long intracellular retention times and low systemic clearance, pharmacokinetic studies showed that its concentration in cancer cells was slow compared to other vector-delivered nucleosides.³Troxacitabine, like most other anticancer nucleosides, is a hydrophilic agent and must be administered intravenously in frequent dosage regimens, which may result in greater toxicity than a single dosage regimen.ⁱ

In view of these shortcomings, a library (library) of twenty troxacitabine prodrugs was synthesized in the work of the present invention to assess the relationship between the lipophilicity of these prodrugs and their antitumor activity. Prodrug strategies have been used to overcome the undesirable properties of many drugs, thereby optimizing their clinical applications.⁷Examples are prodrugs of capecitabine, 5FU⁸(ii) a And CP-4055, a 5' -hydroxy modified lipophilic prodrug of Ara-C, bypasses (bypass) ENT and has activity against Ara-C resistant xenografts (xenografts).⁹Similarly, gemcitabine analogs, CP-4126 modified at the amino group, also bypass nucleoside transporters (Bergman, 2004). Anticancer and antiviral nucleoside structural modifications have been made in sugars as well as in heterocyclic moieties.^10，11However, in our current study, we decided to protect the amino group of the cytosine moiety rather than the 5' -hydroxyl group to increase the lipophilicity of troxacitabine, thereby avoiding the large amount of esterase in plasma.

Drawings

FIG. 1 shows a general overview of scheme 1, general synthetic chemistry, parallel synthesis (parallel synthesis) and preferred compounds for use in the present invention.

FIG. 2 is the most interesting prodrug of troxacitabine on two non-small cell lung cancer cell lines^aA549，^bActivity curve of SW 1573. IC (integrated circuit)₅₀Expressed as mean + SEM of 3 experiments.

FIG. 3 is the LogP and IC of the linear aliphatic prodrug on two non-small cell lung cancer cell strains A549 and SW1573₅₀The relationship between them. LogP was evaluated using ChemDraw 8.0 ultratra. IC (integrated circuit)_50sExpressed as the average of three experiments.

Figure 4 shows some prodrug compounds according to the invention tested against pancreatic cancer cell lines. Figure 4a shows the synthesis of a prodrug of troxacitabine. Reagent: (RCO)₂O, MeOH, 55 ℃ for 6 hours.^bThe structure of the aliphatic side chain attached to troxacitabine and 4b represent the lipophilicity (LogP) of the compound, which was assessed using Chemdraw 8.0 ultrar.

FIG. 5 is a drawing showing^aBxPC-3 and^bpanc-02 pancreatic cancer cell line on troxacitabine and oleophilic analogsH，I，JAndK(see FIG. 4).

Summary of The Invention

The present invention relates to a compound according to the following chemical structure:

wherein R is optionally substituted C₃-C₇Cyclic hydrocarbon, optionally substituted C₁-C₂₂Straight or branched chain alkyl or optionally substituted phenyl;

R²is H, or a fully or partially protonated monophosphate, diphosphate or triphosphate group in the free acid form, or a phosphodiester group.

The compounds of the invention are useful for the treatment of tumors, including cancerous tumors, particularly non-small cell lung cancer or pancreatic cancer.

In a pharmaceutical composition aspect of the invention, the pharmaceutical composition of the invention comprises an effective amount of at least one compound as disclosed herein, optionally in admixture with pharmaceutically acceptable carriers, additives and excipients.

A method of treating tumors, including cancer, comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The cancers that can be effectively treated include a wide variety of cancers, including particularly non-small cell lung cancer and pancreatic cancer, because the L-OddC prodrug compounds of the present invention exhibit unexpected bioavailability in the treatment of these cancers, apparently due to enhanced absorption of the L-OddC prodrug compound by cancer cells. This is an unexpected result. Thus, the prodrug compounds of the present invention exhibit increased bioavailability consistent with selective absorption, particularly in non-small cell lung cancer cells and pancreatic cancer cells.

When the compounds of the present invention are used to treat various cancers, they have unique and outstanding activity in the treatment of non-small cell lung cancer and pancreatic cancer, either alone or in combination with other anticancer agents, due to their increased bioavailability, which is believed to be due to the selective absorption of these compounds by cancer cells.

It is noted that the use of the LOddC prodrug form of the present invention co-administered with other anti-cancer agents to treat cancer in a subject is significantly more effective than the use of other anti-cancer agents alone, which is an unexpected result. Furthermore, in many cases, an effective amount of one of the prodrug nucleoside compounds of the present invention and the other anticancer agent ("another anticancer agent") results in a synergistic enhancement of the anticancer activity of the other anticancer agent (i.e., not just an additive).

The foregoing and/or other aspects of the present invention are readily apparent from the following detailed description of the invention.

Detailed Description

The term "patient" or "subject" as used throughout refers to an animal, typically a mammal and preferably a human, to which treatment, including prophylactic treatment, is provided with a composition of the invention. For the treatment of an infection, condition or disease state specific to a particular animal (e.g., human) patient, the term patient refers to that particular animal.

As used herein, unless otherwise specified, the term "compound" refers to any specific chemical compound disclosed herein. When used in this context, the term generally refers to a single compound, preferably various racemates or enantiomerically enriched (at least 75%, 85%, 95%, 98%, 99 +%, 100%) in the form of an (L- β anomer) prodrug of the nucleoside L-OddC or L-OddC prodrug, as otherwise described herein. The compounds of the invention are also less toxic, if at all, to host cells when used to treat cancer, and show unexpected results that are particularly effective in non-small cell lung cancer and pancreatic cancer.

The term "effective" as used herein, unless otherwise indicated, refers to an amount of a compound which, in the context of the present application, is used to produce or affect the intended result which is directed to the treatment of cancer, including oncogenic tumors or other cancers, including in particular non-small cell lung cancer or pancreatic cancer. In certain aspects, the invention relates to combination therapies with other anti-cancer agents or anti-cancer compounds. The term includes all other effective amounts or concentrations of the term that are otherwise used in this application. With respect to the anticancer effect, the effect means one or more of the following effects: inhibiting further growth of tumor or cancer cells; reducing the likelihood or eliminating metastasis or producing cell death in tumor or cancer cells; leading to tumor shrinkage or a reduction in the number of cancer cells; or preventing tumor or cancer regeneration after remission of the tumor or cancer in the patient. As indicated, the compounds of the invention may exhibit anti-cancer effects alone and/or may enhance the ability of other anti-cancer agents to exhibit anti-cancer effects.

The term "pharmaceutically acceptable salt" as used throughout this document refers to a salt form (referred to as a phosphate salt in a particularly preferred aspect of the invention) of one or more compositions, the presence of which increases the solubility of the compound in physiological saline for parenteral delivery or in the gastric juices of the gastrointestinal tract of a patient, to enhance the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those formed with acids known in the pharmaceutical art, as well as many other alkali metal (e.g., potassium and sodium), alkaline earth metal (e.g., calcium, magnesium) and ammonium salts. Sodium and potassium salts are particularly preferred as the neutralizing salts of the carboxylic acids and free acid phosphoric acid (free acid phosphate) contained in the compositions of the present invention. The term "salt" shall mean any salt consistent with the use of the compounds of the present invention. In the case of compounds used for pharmaceutical indications (pharmaceutical indications) including the treatment of neoplasia, including cancer, the term "salt" shall denote a pharmaceutically acceptable salt, which is consistent with the use of the compound as a medicament. In the case of the phosphate group, the phosphate group may be present in the free acid form (i.e., all groups are protonated) or in the form of a drug salt (where one or more of the free acid groups in the phosphate group are converted to its salt form).

The term "pharmaceutically acceptable derivative" or "derivative" as used throughout the specification refers to any pharmaceutically acceptable prodrug form (such as an ester or ether or other prodrug group) which, when administered to a patient, provides, directly or indirectly, a compound of the invention or an active metabolite of a compound of the invention.

The term "alkyl" shall mean C in its context₁-C₂₂Preferably C₈-C₁₈Straight, branched or cyclic, fully saturated hydrocarbon radicals, which are optionally substituted, for example by phenyl.

The term "phosphate ester" or "phosphodiester" as used throughout the specification means that a monophosphate group is present at the 5' position of the sugar synthon, said group being diester-formed such that the phosphate group is neutral, i.e. has a neutral charge. Phosphate esters useful in the present invention include those represented by the following structure:

wherein each R₅Independently selected from H, optionally substituted C₁～C₂₀Linear, branched or cyclic alkyl, optionally substituted alkoxyalkyl, optionally substituted aryloxyalkyl such as phenoxymethyl, optionally substituted aryl and optionally substituted alkoxy, provided that two R are₅Not H or a pharmaceutically acceptable salt thereof. The preferred monophosphate (phosphodiester) for use in prodrug forms of the invention is when R is₅Is C₁～C₂₀Monophosphates (phosphodiesters) of linear or branched alkyl radicals, more preferably R₅Is C₁～C₃Alkyl or a pharmaceutically acceptable salt thereof.

The term "optionally substituted" refers to substituents on alkyl, alkoxyalkyl, aryloxyalkyl, aryl (particularly phenyl), or alkoxy groups, which are substituted at chemical positions in the hydrogen-containing compound with non-hydrogen groups. Can be used in the present inventionThe substituents of (A) include, in this context, for example, hydroxy, carboxy (C)₁-C₆Acid or ester), halogen (F, Cl, Br, I or mixtures thereof), C₁-C₆(preferably C)₁-C₃) Alkyl radical, C₁-C₆Alkoxy or phenyl. It is noted here that the individual substituents may themselves also be substituted by substituents. The term "unsubstituted" means that a hydrogen atom is present at the indicated position.

The term "neoplasia" or "cancer" as used throughout the specification refers to the pathological process of formation or growth of an oncogenic or malignant neoplasm, i.e., abnormal tissue, which grows from cell proliferation, generally grows more rapidly than normal tissue and continues to grow after the stimulus causing new growth ceases. Malignant tumors lack structural organization and functional coordination with normal tissue, mostly invade surrounding tissues, metastasize to multiple sites, and are likely to regenerate after attempted resection and cause death unless the patient receives appropriate treatment. As used herein, the term neoplasia refers to all cancerous diseases and encompasses and includes pathological processes associated with malignant hematogenous (hepatogenous), ascites (ascitic) and solid tumors. Representative cancers include, for example, stomach, colon, rectal, liver, pancreatic, lung, breast, cervical, uterine body, ovarian, prostate, testicular, bladder, renal, brain/CNS, head and neck (head and rock), throat, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, wilms' tumor, neuroblastoma, hairy cell leukemia, oral/throat, esophageal, throat, kidney (kidney) and lymphoma, among others, which can be treated with one or more of the compounds of the present invention. In a particularly preferred aspect of the invention, the targeted disease is non-small cell lung cancer or pancreatic cancer, and the compounds of the invention exhibit particular activity against both cancers.

The term "tumor" is used to refer to a malignant or benign growth or swelling (tumefacient).

The term "non-small cell lung cancer" is used to refer to a disease in which malignant (cancerous) cells form in the tissues of the lung. There are many types of non-small cell lung cancer. Each type of non-small cell lung cancer has different types of cancer cells. Each cancer cell grows and spreads in a different way. The types of non-small cell lung cancer are named for the cell type found in the cancer and the appearance of the cell under the microscope:

squamous cell carcinoma: the cancer formed in the squamous epithelium is a thin, flat cell that looks like a fish scale. Also known as epidermoid carcinoma.

Large cell carcinoma: cancers that can develop in large cells of many types.

Adenocarcinoma: cancers that form in cells lining the alveoli and secreting material such as mucus.

Other less common types of non-small cell lung cancer are: pleomorphic carcinoid tumors (carcinoid tumors), salivary gland carcinoma tumors and nonclassical tumors. The invention can be used for treating all types of non-small cell lung cancer.

Treatments for non-small cell lung cancer may include radiation therapy, chemotherapy (including in particular the compounds of the invention or the compounds of the invention in combination with other anti-cancer agents), palliative therapy (palliative therapy), surgery, laser therapy and biological therapy, among others combinations of these therapies.

Anticancer agents that may be used in combination with the prodrug form of LOddC of the present invention to treat non-small cell lung cancer include, for example, ixabepilone (ixabepilone), Bortezomib (Bortezomib), Bortezomib in combination with docetaxel, photosensitizer (porfimer sodium), paclitaxel (taxol) (paclitaxel), paclitaxel in combination with cisplatin, gemcitabine (gemcitabine), and tarceva (erlotinib)).

The term "pancreatic cancer" is used to describe malignant tumors of the pancreas. Pancreatic cancer is referred to as a "silent" disease because early stage pancreatic cancer usually does not cause any symptoms. If the tumor blocks the common bile duct, bile cannot flow into the digestive system, the patient's skin and eyes become yellow (jaundice), and urine becomes dark as a result of the accumulation of bile pigments, called bilirubin.

The pancreas is divided by its function into the endocrine pancreas (producing insulin and other hormones) and the exocrine pancreas (producing pancreatic enzymes to aid digestion). Although the present invention is useful for treating cancers of the endocrine pancreas, the invention is primarily useful for treating the exocrine pancreas, which is undoubtedly the most common type of pancreatic cancer.

The prevalence of pancreatic cancer has increased significantly over the past decades and is now ranked the fourth leading cause of cancer death in the united states. Despite the high mortality associated with pancreatic cancer, the causes are poorly understood. Smoking is a known major hazard. People who smoke cigarettes have two to three times the probability of having pancreatic cancer than people who do not smoke. Smoking cessation reduces the risk of pancreatic cancer. At present, pancreatic cancer is rarely cured. The total survival rate is less than 4%. The cure rate is highest (although still typically below 25%) if the tumor is small (less than 2cm in diameter) and accurately localized to the pancreas, but this case accounts for only less than 20% of all pancreatic cancer cases. For patients with advanced cancer, the total survival rate of 5 years in all stages is less than 1%, and most patients die within 1 year. Staging of tumors is important for the diagnosis and identification of patients with diseases that cannot be resected (removed by surgery). Tumor grading is aided by imaging techniques including helical (spiral) computer-assisted tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, Positron Emission Tomography (PET) scans, sonoendoscopy, and laparoscopic tumor grading.

There are no specific tumor markers for pancreatic cancer. The specificity of markers such as serum CA 19-9 is low. Most patients with pancreatic cancer have elevated CA 19-9 at the time of diagnosis. An increase in CA 19-9 levels after or during definitive treatment can identify patients with progressive tumor growth. However, the appearance of normal CA 19-9 did not rule out recurrence of the tumor.

Patients with pancreatic cancer at any stage are candidates for clinical trials because they respond poorly to chemotherapy, radiation therapy and surgery that are routinely used. However, alleviation or relief of symptoms can be achieved with conventional therapeutic approaches. Relief measures may include surgical or radioactive bile decompression (biliary decompression), relief of gastric outlet obstruction, and inhibition of pain. These and other measures can significantly improve the quality of life.

It is important to emphasize the potential obstructive psychological events (potential diagnosis psychological events) that accompany the diagnosis and treatment of pancreatic cancer. The effects of this disease can severely stress the patient and all people in close proximity to him or her.

Many chemotherapeutic agents have been tried to treat pancreatic cancer, but none have been successful. It Seawatt (erlotinib) or its Seawatt (erlotinib) in combination with gemcitabine represents a chemotherapeutic agent that is effective in some cases against pancreatic cancer. Some natural products containing 5, 7, 4' -trihydroxyflavone (apigenin), MGN-3 (from rice bran) and EGCG (from the green tree) are known for their significant anticancer effects against pancreatic cancer. Palliative agents (palliative agents), including opioid narcotics and other analgesics (including NSAIDS), used to ameliorate pain associated with pancreatic cancer are the best methods individually in therapeutic intervention for pancreatic cancer. One or more of the above or other anti-cancer agents that are effective in treating pancreatic cancer may be combined with a compound of the present invention to obtain a beneficial treatment for pancreatic cancer.

The use of the term "additional anti-cancer compound" or "additional anti-cancer agent" refers to any compound (including derivatives thereof) that can be used to treat cancer and can be used in combination with the prodrug compounds of the present invention. Additional anti-cancer compounds, as described hereinafter, may be co-administered with one or more compounds of the present invention, such that the effect of the compounds, which each of these compounds or their derivative compounds has, is enhanced in the treatment of cancer in patients in accordance with the present invention. In many instances, the co-administration of these compounds or their derivatives and another anticancer compound results in a synergistic anticancer effect. As described herein, exemplary anticancer compounds for co-administration with the prodrug form of LOddC for use in the present invention include antimetabolite drugs, which in a broad sense are antimetabolites, inhibitors of topoisomerase I and II, alkylating agents, and microtubule inhibitors (e.g., paclitaxel). Anticancer compounds useful in the present invention include, for example, aldesleukin; alemtuzumab (Alemtuzumab); alitretinoin (alitretinin); allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase enzyme; BCG vaccine; bexarotene capsules (bexarotene capsules); bexarotene gel (bexarotene gel); bleomycin; busulfan for vein; busulfan for oral administration; (ii) carroterone; capecitabine; carboplatin; carmustine; carmustine Implant film (carmustine with Polifeprosan 20Implant) with Polifeprosan 20 as carrier; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposome (cytarabine liposomal); dacarbazine; dactinomycin; actinomycin D; alfa bepotin (Darbepoetin alfa); a daunorubicin liposome (doxorubicin liposomal); daunorubicin, daunorubicin; dinierein-toxin linker (Denileukin diftotox), dexrazoxane; docetaxel; doxorubicin; liposomal doxorubicin (doxorubicin liposomal); drotandrosterone propionate; eliot (Elliott's B Solution); epirubicin; alfa epoetin; estramustine; etoposide phosphate; etoposide (VP-16); exemestane; filgrastim; floxuridine (intra-arterial); fludarabine; fluorouracil (5-FU); fulvestrant (fulvestrant); gemtuzumab ozogamicin (gemtuzumab ozogamicin); goserelin acetate; a hydroxyurea; ibritumomab tiuxetan (ibritumomab tiuxetan); idarubicin; ifosfamide; imatinib mesylate (imatinib mesylate); interferon alpha-2 a; interferon alpha-2 b; irinotecan; letrozole; calcium folinate; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenylpropionate; (ii) a nymphamab; LOddC; an opper interleukin; oxaliplatin; paclitaxel; pamidronic acid (pamidronate); adding enzyme; a pemetrexed; pegylation of filgrastim; pentostatin; pipobroman; (ii) a plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; (ii) a labyrinase; 4, Artocarpus; sargrastim; a streptozocin; telbivudine (talbuvidine) (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); a testosterone ester; thioguanine (6-TG); thiotepa; topotecan; toremifene; tositumomab; trastuzumab (Trastuzumab); tretinoin (ATRA); uramustine; valrubicin; pantocitabine (monovalent LDC); vinblastine; vinorelbine; zoledronic acid salts; and mixtures thereof, and the like. In a preferred aspect of the invention, an effective amount of the LOddC prodrug form is combined with ixabepilone (ixabepilone), Bortezomib (Bortezomib), Bortezomib and docetaxel, photosensitizer (photofrin) (porfimer sodium), paclitaxel (taxol) (paclitaxel), paclitaxel and cisplatin, gemcitabine, tarceva (erlotinib), or mixtures thereof, in the treatment of non-small cell lung cancer. In the case of treatment of pancreatic cancer, the compounds of the present invention may be co-administered with one or more agents selected from the group consisting of: tarceva (erlotinib), tarceva in combination with gemcitabine, 5, 7, 4' -trihydroxyflavone, MGN-3 (from rice bran) and EGCG (from the green tree) or mixtures thereof. Palliative agents (palliative agents), including opioid narcotics and other analgesics (including NSAIDS), may be used in combination with the compounds of the present invention for the treatment of pancreatic cancer.

The use of the terms "co-administration" or "combination therapy" refers to a therapy in which at least two active compounds are used in an effective amount to simultaneously treat the cancers described herein. The results may be additive or better, and in most cases synergistic. Although the term co-administration preferably includes the simultaneous administration of two active compounds to a patient, it is not necessary that the compounds be administered to the patient at the same time, although an effective amount of the individual compounds will still be present in the patient at the same time. Preferably, one or more of the anti-cancer agents or palliatives described herein are administered with a compound of the present invention in an effective amount.

The invention includes, when related, compositions comprising pharmaceutically acceptable salts of the compounds of the invention. In certain instances, acids are used to prepare pharmaceutically acceptable acid addition salts of the foregoing compounds for use in the present invention, including those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [ i.e., 1, 1' -methylene-bis- (2-hydroxy-3-naphthoic acid) ] salts, and the like.

The invention also includes compositions comprising base addition salts (particularly phosphate derivatives) of the compounds of the invention. Chemical bases useful as reagents for preparing pharmaceutically acceptable base addition salts of the compounds of the invention (acidic in nature) are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium salts or water-soluble amine addition salts such as N-methylglucamine- (meglumine), and the base salts of lower alkanolammonium and other pharmaceutically acceptable organic amines, and the like.

The compounds of the present invention relate primarily to nucleoside compounds, characterized as pro-drug forms of β -L nucleosides, but may include other stereoisomers, including optical isomers of the corresponding compounds of the present invention, as well as racemates, diastereomers and other mixtures of these isomers, as well as solvates and polymorphs of the compounds.

The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and may also be administered in the form of a controlled release formulation. Pharmaceutically acceptable carriers for these pharmaceutical compositions include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol and wool fat.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

Sterile forms of the compositions of the invention for injection may be aqueous or oily suspensions. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-and diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as ph.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form including, but not limited to: capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are desired for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

In addition, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. The suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention may also be administered topically, particularly to treat skin cancer, psoriasis, or other diseases occurring in or on the skin. Suitable topical formulations are readily prepared for these areas or organs. For the lower intestinal tract topical administration may be effected in rectal suppository formulations (see above) or in suitable enemas. Topically acceptable transdermal patches may also be used.

For topical administration, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to: mineral oil, liquid paraffin, white soft paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

In addition, the pharmaceutical compositions may be formulated as suitable lotions or emulsions containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable vectors include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetyl/stearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic applications, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or preferably, as solutions in isotonic, pH adjusted, sterile saline, with or without preservatives such as benzalkonium chloride. Furthermore, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment such as petrolatum.

The pharmaceutical compositions of the present invention may also be administered by nasal aerosol or nasal inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in physiological saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional co-solvents or dispersants.

The amount of compound in the pharmaceutical compositions of this invention combined with a carrier material to produce a single dosage form will vary depending upon the host and disease being treated, the particular mode of administration. Preferably, the composition should be formulated to contain from about 0.5mg to about 750mg, more preferably from about 1mg to about 600mg, and even more preferably from about 10mg to about 500mg of the active ingredient.

The compounds/compositions of the present invention are administered in an amount effective to treat the particular condition or disease state. The amount of active compound administered will depend on the condition of the patient, the disease or condition to be treated and the route of administration. The amount of active compound administered is from about 0.001 mg/kg/day to 100 mg/kg/day or more, from about 0.005 mg/kg/day to about 10 mg/kg/day, from about 0.01 mg/kg/day to about 1 mg/kg/day of the patient, or any amount deemed effective in the context of the use of the active compound. The compound may be administered in a concentration and for a duration effective to treat a disease state or condition in a patient. Although the compounds of the present invention may be administered by essentially any route, oral administration is preferred because using this route of administration, administration is convenient and more patient-compliant.

It will be understood that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and judgment of the treating physician, and the severity of the particular disease or condition being treated.

Chemistry

The development of the combination technology brings important influence to the method for drug development^12，13. Indeed, over the last fifteen years, combinatorial chemistry coupled with high throughput screening methods has allowed many biologically active compounds to be discovered¹⁴. Recently, the liquid-phase combination (solution-phase combination) method has attracted attention as an alternative to the solid-phase method for drug development and lead optimization. The key advantages of the liquid phase combinatorial approach over the solid phase approach are:¹⁵1) an unlimited number of reactions can be used, thus providing maximum structural diversity; 2) unlimited reactions allow the preparation of sufficient numbers of libraries for testing over a wide range of assays; 3) shorter reaction sequences because no linking manipulation (linker manipulation), linking to the resin or separation from the resin is required; 4) the intermediate and final products obtained can be used directly for purification and assay; 5) the reaction can be monitored using conventional analytical methods (TLC, HPLC-MS, GC-MS and NMR).

We describe herein the use of a direct parallel liquid phase (strained parallel liquid phase)Solution-phase) method (scheme 1) a library (library) of troxacitabine prodrugs 6a-t was synthesized. According to well known methods¹⁶The synthesis of troxacitabine 5 was started from L-gulose, and troxacitabine 5 was dissolved in anhydrous methanol and treated with twenty different anhydrides in an Argonaut Quest 210 organic synthesizer. Some of the above anhydrides (2l-n and 4p-s) are not commercially available and are prepared using two different methods as shown in scheme 1^17，18. After 6 hours at 55 ℃, the reaction mixture was briefly filtered and then purified over a small silica flash column (gradient elution). Thus, troxacitabine prodrugs 6a-t were prepared and fully characterized as described in the experimental section.

Results and discussion

Compounds 6a-t were evaluated in two non-small cell lung cancer cell lines (a549 and SW1573) using the ammonium thiocyanate-b (srb) assay and compared for antitumor activity with the parent drug (troxacitabine) and with gemcitabine and cytarabine (table 1). These cell lines were selected because they were previously characterized for sensitivity to gemcitabine and activity of rate-limiting enzymes in the activation of deoxycytidine kinase (dCK) by gemcitabine and troxacitabine; SW 1573: 0.3. + -. 0.08 nmol/h/10⁶Cells¹⁹A5490.99. + -. 0.08 nmol/h/10⁶Cells²⁰. In addition, gemcitabine-containing regimens are routinely used to treat non-small cell lung cancer. Growth inhibition (FIG. 1) indicated long straight aliphatic chain (. gtoreq.8 CH)₂) The 6h-k analogue of (A) is significantly more potent than troxacitabine, with the best derivatives having an IC in the nanomolar range₅₀. It should be noted that they are unlikely to be phosphorylated to a prodrug due to steric hindrance. These preliminary results indicate that lipophilic compounds are more readily absorbed than troxacitabine. In cell lines, we tested whether trafficking (ENT) works by adding dipyridamole to the cells. In A549, dipyridamole induced IC₅₀This increase was 2 fold, but this was not observed on the prodrug. In fact, as shown in figure 2, IC was found for all linear aliphatic prodrugs₅₀And LogP values (for A)549 cell line r²0.8096 and r for SW1573 cell line²0.8199), indicating that passive diffusion across the cell membrane renders the cell more sensitive to the prodrug than to the parent drug. The best compound (6h-k) among NSCLC cell lines was also tested in pancreatic cancer cell line (BxPC3) and found to be similar. It was also found that sensitivity was improved better than that of NSCLC cell line, and IC was observed in compounds 6i-k compared to troxacitabine₅₀The reduction is 700 times. It should also be noted that even though some cycloalkyl and aromatic derivatives (6l-t) have better lipophilicity gain, they are less effective than troxacitabine. These are located at the N of the compounds 6l-t₄The cycloalkyl and aromatic moieties at the positions are likely to make these compounds substrates for undesirable intracellular deaminases. We therefore speculate that amidase-catalysed hydrolysis of prodrugs may be important for allowing the release of troxacitabine to the intracellular compartment (component) for activation (triphosphorylation). The better activity profile of the prodrug 6h-k may be the result of increased absorption due to high lipophilicity and high rate of hydrolysis of linear aliphatic derivatives catalyzed by intracellular deaminase.

In summary, a direct method for the parallel synthesis of novel troxacitabine prodrugs 6a-t was developed. Some of these compounds showed better anti-cancer activity against a549 and SW1573 non-small cell lung cancer cell lines. LogP and IC of linear aliphatic prodrugs have also been found₅₀A good inverse linear relationship between them. On the basis of these attractive main findings, other biological assessments and further improvements of troxacitabine were warranted.

Experimental part/examples

General methods (General considerations)

Parallel synthesis was performed on an Argonaut Quest 210 organic synthesizer. Melting points were determined using a Mel-temp II laboratory instrument and were not corrected. NMR spectra were recorded using a Bruker AMX400MHz fourier transform spectrometer; chemical shifts are expressed in ppm- (delta), and signals are reported as s (singlet), d (doublet), t (triplet), m (multiplet)Peak) and dd (doublet of doublets). UV spectra were obtained from a Beckman DU-650 spectrophotometer. Optical rotation was measured using a JASCO DIP-370, digital polarimeter. TLC was performed on Uniplates (silica gel) from analtech, inc, and elemental analysis was performed on Atlantic microlab inc, Norcross, GA. All anhydrides available commercially were used without further purification. Cyclopropane, cyclopentane and cyclohexane carboxylic anhydrides were synthesized according to reported methods and used without further purification¹⁶. Synthesis of 4-fluorobenzoic anhydride, 4-chlorobenzoic anhydride, 4-bromobenzoic anhydride and 2, 4-dichlorobenzoic anhydride according to reported procedures¹⁷。

Experimental synthesis method

General procedure for parallel liquid phase Synthesis of 4- (N-acyl substituted) -L-OddC prodrugs (6a-t)

Compound 5(2g) was dissolved in anhydrous MeOH (20mL), then 1mL of the resulting solution (100mg, 1 equivalent of 5) was added separately to each micro-frit (microfrit) equipped reaction kettle (RV), followed by 9mL of methanol. The appropriate anhydride (3 equivalents) was then added and stirred vigorously (50% uprush, 1 second) at 55 ℃ for 6 hours. After 6 hours, the RV was drained and the collected crude product was evaporated to dryness under reduced pressure and then purified on a short (short) flash column (gradient elution, 60% hexane: 40% ethyl acetate-100% ethyl acetate).

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-acetyl-cytosine (6 a): a white solid. The yield was 92%; melting point 176.0-178.0 ℃; [ alpha ] to]²⁴ _D-68.005(c 0.04，MeOH)；UV(H₂O)λ_max 245nm(ε9033pH 2)，246nm(ε16703pH 7.4)，270nm(ε9760pH 11)；¹H-NMR(CDCl₃)δ8.60(d，1H，J＝7.32Hz)，6.24(m，1H)，5.12(m，1H)，4.33-4.25(m，2H)，3.90(m，2H)，2.21(s，3H)；¹³C NMR(CD₃OD) δ 180.1, 171.6, 163.1, 156.8, 145.1, 106.1, 96.2, 83.4, 72.0, 60.2, 23.2; IR (pure) 1716, 1654, 1562, 1494cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-propionyl-cytosine (6 b): a white solid. The yield was 56%; melting point 161.5-163.5 deg.C; [ alpha ] to]²⁸ _D-105.02(c 0.022，MeOH)；UV(H₂O)λ_max 246nm(ε14465pH 2)，246nm(ε15845pH 7.4)，270nm(ε8368pH 11)；¹H-NMR(CDCl₃)δ8.46(d，1H，J＝7.32Hz)，7.43(d，1H，J＝7.32Hz)，6.20(dd，1H，J₁＝1.47Hz，J₂＝4.90Hz)，5.13(m，1H)，4.35-4.24(m，2H)，3.99(m，2H)，2.48(q，2H，J＝7.32Hz)；1.20(t，3H，J＝7.32Hz)；¹³C NMR(CDCl₃) δ 171.6, 162.6, 156.1, 144.9, 105.8, 96.4, 83.5, 72.7, 60.8, 30.8, 8.8; IR (pure) 1694, 1651, 1556, 1493cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-butyryl (butirryl) -cytosine (6 c): a white solid. The yield was 82%; melting point 118.0-120.0 deg.C; [ alpha ] to]²⁴ _D-48.43(c 0.042，MeOH)；UV(H₂O)λ_max 246nm(ε16430pH 2)，246nm(ε18353pH 7.4)，244nm(ε10155pH 11)；¹H-NMR(CDCl₃)δ8.49(d，1H，J＝7.33Hz)，7.44(d，1H，J＝7.33Hz)，6.20(m，1H)，5.12(m，1H)，4.34-4.23(m，2H)，3.97(m，2H)，2.45(t，2H，J＝7.32Hz)；1.70(m，2H)，0.97(t，3H，J＝7.32Hz)；¹³C NMR(CDCl₃) δ 171.6, 162.5, 155.6, 144.9, 105.7, 96.2, 83.6, 72.7, 61.1, 39.6, 18.3, 13.6; IR (pure) 1693, 1651, 1554, 1500cm^-1.C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. Measurement values: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-isobutyryl (isobutrryl) -cytosine (6 d): a white solid. The yield was 94%; melting point 78.0 ℃; (decomposition) [ alpha ]]²⁷ _D-55.38(c0.042，MeOH)；UV(H₂O)λ_max 246nm(ε14907pH 2)，246nm(ε16108pH 7.4)，244nm(ε13387pH11)；¹H-NMR(CDCl₃)δ8.50(d，1H，J＝7.33Hz)，7.44(d，1H，J＝7.33Hz)，6.21(dd，1H，J₁＝1.46Hz，J₂＝5.36Hz)，5.12(m，1H)，4.33(m，1H)，4.25(m，1H)，3.98(m，2H)，2.66(m，1H)；1.21(d，6H，J＝6.83Hz)；¹³CNMR(CDCl₃) δ 171.6, 162.8, 155.8, 145.3, 105.9, 96.4, 83.5, 72.6, 60.9, 36.5, 19.1; IR (pure) 1739, 1654, 1558, 1490cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-pentanoyl-cytosine (6 e): a white solid. The yield was 84%; melting point 143.0-144.0 deg.C; [ alpha ] to]²⁴ _D-53.34(c 0.5，MeOH)；UV(H₂O)λ_max 246nm(ε13393pH 2)，246nm(ε14436pH 7.4)，246nm(ε12188pH 11)；¹H-NMR(CDCl₃)δ8.49(d，1H，J＝7.32Hz)，7.44(d，1H，J＝7.32Hz)，6.20(m，1H)，5.12(m，1H)，4.32(m，1H)，4.23(m，1H)，3.97(m，2H)，2.47(t，2H，J＝7.32Hz)；1.65(m，2H)，1.36(m，2H)；¹³C NMR(CDCl₃) δ 173.8, 162.8, 155.6, 145.2, 105.8, 96.4, 83.5, 72.6, 61.0, 37.4, 26.9, 22.2, 13.7; IR (pure) 1690, 1648, 1552, 1494cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-hexanoyl-cytosine (6 f): white colourAnd (3) a solid. The yield was 76%; melting point 158.0-160.0 deg.C; [ alpha ] to]²⁶ _D-84.09(c 0.028，MeOH)；UV(H₂O)λ_max 246nm(ε14043pH 2)，246nm(ε14495pH 7.4)，246nm(ε12069pH11)；¹H-NMR(CDCl₃)δ8.50(d，1H，J＝7.32Hz)，7.45(d，1H，J＝7.32Hz)，6.20(m，1H)，5.12(m，1H)，4.32(m，1H)，4.23(m，1H)，3.97(m，2H)，2.46(t，2H，J＝7.32Hz)；1.66(m，2H)，1.32(m，4H)，0.89(t，3H，J＝7.32Hz)；¹³C NMR(CDCl₃) δ 173.8, 162.8, 155.6, 145.3, 105.8, 96.4, 83.5, 72.6, 61.0, 37.6, 31.2, 24.6, 22.4, 13.9; IR (pure) 1693, 1649, 1553, 1494cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1-12- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-heptanoyl-cytosine (6 g): a white solid. The yield was 84%; melting point 151.0-153.0 deg.C; [ alpha ] to]²⁵ _D-56.82(c 0.044，MeOH)；UV(H₂O)λ_max 246nm(ε14223pH 2)，246nm(ε15665pH 7.4)，246nm(ε14519pH 11)；¹H-NMR(CDCl₃)δ8.49(d，1H，J＝7.32Hz)，7.44(d，1H，J＝7.32Hz)，6.19(m，1H)，5.12(m，1H)，4.33(m，1H)，4.23(m，1H)，3.97(m，2H)，2.46(t，2H，J＝7.32Hz)；1.66(m，8H)，1.28(m，4H)，0.89(t，3H，J＝7.32Hz)；¹³C NMR(CDCl₃) δ 173.7, 162.7, 155.6, 145.2, 105.8, 96.4, 83.5, 72.7, 61.0, 37.7, 31.5, 28.8, 24.8, 22.5, 14.0; IR (pure) 1693, 1649, 1553, 1494cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-nonanoyl-cytosine (6 h): a white solid. The yield was 72%; melting point is 135.0-137.0 ℃; [ alpha ] to]²⁷ _D-51.58(c 0.03，MeOH)；UV(H₂O)λ_max 246nm(ε14101pH 2)，246nm(ε15201pH 7.4)，246nm(ε11582pH 11)；¹H-NMR(CDCl₃)δ8.49(d，1H，J＝7.81Hz)，7.45(d，1H，J＝7.81Hz)，6.19(m，1H)，5.12(m，1H)，4.33(m，1H)，4.23(m，1H)，3.97(m，2H)，2.46(t，2H，J＝7.32Hz)；1.66(m，2H)，1.28(m，10H)，0.88(t，3H，J＝7.32Hz)；¹³C NMR(CDCl₃) δ 173.7, 162.7, 155.6, 145.2, 105.8, 96.3, 83.5, 72.7, 61.0, 37.7, 31.8, 29.1, 24.9, 22.6, 14.1; IR (pure) 1689, 1649, 1553, 1496cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-decanoyl-cytosine (6 i): a white solid. The yield was 66%; melting point 141.0-143.0 deg.C; [ alpha ] to]²⁵ _D-35.59(c 0.028，MeOH)；UV(H₂O)λ_max 246nm(ε11850pH 2)，246nm(ε13056pH 7.4)，246nm(ε8256pH 11)；¹H-NMR(CDCl₃)δ8.49(d，1H，J＝7.32Hz)，7.44(d，1H，J＝7.32Hz)，6.19(m，1H)，5.12(m，1H)，4.33(m，1H)，4.24(m，1H)，3.97(m，2H)，2.45(t，2H，J＝7.32Hz)；1.66(m，2H)，1.29(m，12H)，0.88(t，3H，J＝7.32Hz)；¹³CNMR(CDCl₃) δ 173.6, 162.7, 155.6, 145.2, 105.7, 96.3, 83.5, 72.7, 61.0, 37.8, 31.9, 29.4, 29.3, 29.2, 29.1, 24.9, 22.7, 14.1; IR (pure) 1690, 1650, 1553, 1499cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-lauryl-cytosine (6 j): a white solid. The yield was 54%; melting point 137.0-138.5 deg.C; [ alpha ] to]²⁷ _D-61.75(c 0.039，MeOH)；UV(MeOH)λ_max 241nm(ε7442)；¹H-NMR(CDCl₃)δ8.48(d，1H，J＝7.32Hz)，7.45(d，1H，J＝7.32Hz)，6.19(m，1H)，5.12(m，1H)，4.33(m，1H)，4.24(m，1H)，3.97(m，2H)，2.46(t，2H，J＝7.32Hz)；1.66(m，2H)，1.25(m，16H)，0.88(t，3H，J＝7.32Hz)；¹³C NMR(CDCl₃) δ 173.6, 162.7, 155.7, 145.2, 105.8, 96.3, 83.5, 72.7, 61.0, 37.7, 31.9, 29.6, 29.5, 29.4, 29.1, 24.9, 22.7, 14.1; IR (pure) 1690, 1650, 1553, 1499cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-palmitoyl-cytosine (6 k): a white solid. The yield was 23%; melting point is 134.5-135.5 ℃; [ alpha ] to]²⁹ _D-79.34(c 0.02，MeOH)；UV(MeOH)λ_max 244nm(ε11145)；¹H-NMR(CDCl₃)δ8.46(d，1H，J＝7.32Hz)，7.43(d，1H，J＝7.32Hz)，6.19(m，1H)，5.13(m，1H)，4.34(m，1H)，4.26(m，1H)，3.98(m，2H)，2.42(t，2H，J＝7.32Hz)；1.66(m，2H)，1.25(m，24H)，0.88(t，3H，J＝7.32Hz)；¹³C NMR(CDCl₃) δ 162.4, 150.0, 145.0, 105.6, 96.0, 83.6, 72.8, 61.1, 37.9, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 24.9, 22.7, 14.1; IR (pure) 1690, 1651, 1553, 1499cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-cyclopropyl-cytosine (6 l): a white solid. The yield was 66%; melting point 169.0-170.5 deg.C; [ alpha ] to]²⁶ _D-62.83(c 0.033，MeOH)；UV(H₂O)λ_max 247nm(ε16457pH 2)，247nm(ε18447pH 7.4)，247nm(ε16191pH 11)；¹H-NMR(CDCl₃)δ8.48(d，1H，J＝7.32Hz)，7.41(d，1H，J＝7.32Hz)，6.21(m，1H)，5.10(m，1H)，4.31(m，1H)，4.23(m，1H)，3.95(m，2H)，1.86(m，1H)，1.07(m，2H)，0.92(m，2H)；¹³C NMR(CDCl₃) δ 174.6, 162.7, 155.8, 145.2, 105.9, 96.7, 83.4, 72.5, 61.0, 15.9, 9.7; IR (pure) 1709, 1651, 1560, 1491cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-cyclopentyl-cytosine (6 m): a white solid. The yield was 58%; melting point 59.0 deg.C (decomposition); [ alpha ] to]²⁷ _D-31.48(c 0.031，MeOH)；UV(H₂O)λ_max 247nm(ε15014pH 2)，247nm(ε16397pH 7.4)，247nm(ε12296pH 11)；¹H-NMR(CDCl₃)δ8.49(d，1H，J＝7.33Hz)，7.43(d，1H，J＝7.33Hz)，6.20(m，1H)，5.12(m，1H)，4.31(m，1H)，4.24(m，1H)，3.97(m，1H)，2.86(m，1H)，1.92-1.59(m，8H)；¹³C NMR(CDCl₃) δ 176.7, 162.7, 155.8, 145.2, 105.8, 96.4, 83.5, 72.6, 61.0, 46.7, 30.1, 26.0; IR 1717, 1650, 1558, 1489cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-cyclohexyl-cytosine (6N): a white solid. The yield was 64%; melting point 77.0 deg.C (decomposition); [ alpha ] to]²⁷ _D-76.27(c 0.039，MeOH)；UV(H₂O)λ_max 247nm(ε14885pH 2)，247nm(ε15887pH 7.4)，247nm(ε14220pH 11)；¹H-NMR(CDCl₃)δ8.49(d，1H，J＝7.32Hz)，7.43(d，1H，J＝7.32Hz)，6.20(m，1H)，5.12(m，1H)，4.32(m，1H)，4.24(m，1H)，3.97(m，1H)，2.39(m，1H)，1.90(m，2H)，1.80(m，2H)，1.69(m，1H)，1.45(m，2H)，1.24(m，3H)；¹³C NMR(CDCl₃)δ176.4，162.8，155.8，145.1，105.8，96.4，83.5，72.6，61.0，46.2，29.2，25.6, 25.4; IR (pure) 1738, 1654, 1558, 1489cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N-benzoyl-cytosine (6): a white solid. The yield is 85%; the melting point is 194.5-195.5 ℃; [ alpha ] to]²⁸ _D-56.71(c 0.060，MeOH)；UV(H₂O)λ_max 258nm(ε19660pH 2)，258nm(ε19802pH 7.4)，311nm(ε14641pH 11)；¹H-NMR(CD₃OD)δ8.67(d，1H，J＝7.32Hz)，7.98(d，2H，J＝7.80Hz)，7.63(m，2H)，7.54(m，2H)，6.24(m，1H)，5.11(m，1H)，4.31(m，1H)，4.27(m，1H)，3.90(m，2H)；¹³C NMR(CD₃OD) δ 134.0, 129.7129.0, 107.3, 98.0, 84.6, 73.3, 61.4; IR (pure) 1699, 1654, 1558, 1488cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N- (p-fluorobenzoyl) -cytosine (6 p): a white solid. The yield was 61%; melting point 163.0-165.0 ℃; [ alpha ] to]²⁷ _D-96.55(c 0.036，MeOH)；UV(H₂O)λ_max 259nm(ε23324pH 2)，258nm(ε24194pH 7.4)，314nm(ε21234pH 11)；¹H-NMR(CD₃OD)δ8.57(d，1H，J＝7.32Hz)，7.98(m，2H)，7.63(m，2H)，7.55(d，1H，J＝7.32Hz)，6.14(m，1H)，5.04(m，1H)，4.24(m，1H)，4.18(m，1H)，3.87(m，2H)；¹³C NMR(CD₃OD) δ 145.4, 130.8, 116.1, 116.0, 106.3, 97.3, 83.6, 72.7, 60.7; IR (pure) 1695, 1650, 1560, 1487cm^-1。C₁₅H₁₄BrN₃O₅Calculated analytical values of (a): c, 45.47; h, 3.56; n, 10.61. Measurement values: c, 45.57; h, 3.55; n, 10.45.

(-)- (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N- (p-chlorobenzoyl) -cytosine (6 q): a white solid. The yield was 29%; melting point is 190.0-191.5 ℃; [ alpha ] to]²⁸ _D-84.15(c 0.021，MeOH)；UV(H₂O)λ_max 263nm(ε24465pH 2)，263nm(ε24744pH 7.4)，314nm(ε18485pH 11)；¹H-NMR(CD₃OD)δ8.53(d，1H，J＝7.32Hz)，7.88(m，2H)，7.54(d，1H，J＝7.32Hz)，7.42(m，2H)，6.16(m，1H)，5.06(m，1H)，4.26(m，1H)，4.21(m，1H)，3.88(m，2H)；¹³C NMR(CD₃OD) δ 132.5, 130.3, 129.7, 107.0, 97.9, 84.3, 73.1, 61.1; IR (pure) 1698, 1651, 1557 and 1483cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. measurement: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N- (p-bromobenzoyl) -cytosine (6 r): a pale yellow solid. The yield was 56%; melting point 189.0-191 ℃; [ alpha ] to]²⁶ _D-74.00(c 0.039，MeOH)；UV(H₂O)λ_max 265nm(ε28850pH 2)，265nm(ε30085pH 7.4)，316nm(ε23659pH11)；¹H-NMR(CD₃OD)δ8.66(d，1H，J＝7.32Hz)，7.88(m，2H)，7.71(m，2H)，7.59(d，1H，J＝7.32Hz)，6.24(m，1H)，5.10(m，1H)，4.31(m，1H)，4.25(m，1H)，3.88(m，2H)；¹³C NMR(CD₃OD) δ 146.4, 132.9, 130.7, 107.2, 98.0, 84.5, 73.2, 61.2; IR (pure) 1697, 1651, 1557, 1483cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. Measurement values: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N- (p-methoxybenzoyl) -cytosine (6 s): a white solid. The yield was 68%; melting point 181.0-181.5 deg.C; [ alpha ] to]²⁷ _D-54.79(c0.028，MeOH)；UV(H₂O)λ_max 303nm(ε28704pH 2)，302nm(ε29283pH 7.4)，302nm(ε25191pH 11)；¹H-NMR(CD₃OD)δ8.63(d，1H，J＝7.32Hz)，7.97(m，2H)，7.58(d，1H，J＝7.32Hz)，7.05(m，2H)，6.24(m，1H)，5.10(m，1H)，4.31(m，1H)，4.25(m，1H)，3.89(m，5H)；¹³C NMR(CD₃OD) delta 146.5, 131.3, 115.1, 107.5, 98.1, 84.8, 73.3, 61.6, 56.1; IR 1646, 1567, 1488cm^-1。C₁₂H₁₇N₃O₅Calculated analytical values of (a): c, 50.88; h, 6.05; n, 14.83. Measurement values: c, 50.90; h, 6.15; and N, 13.97.

(-) - (2S, 4S) -1- [2- (hydroxymethyl) -1, 3-dioxolan-4-yl]-4-N- (2, 4-dichlorobenzoyl) -cytosine (6 t): a white solid. The yield was 84%; melting point is 185.0-187.0 ℃; [ alpha ] to]²⁵ _D-83.18(c0.036，MeOH)；UV(H₂O)λ_max 253nm(ε22561pH 2)，253nm(ε23043pH 7.4)，305nm(ε21989pH 11)；¹H-NMR(CD₃OD)δ8.71(d，1H，J＝7.32Hz)，7.62(m，2H)，7.56(d，1H，J＝7.32Hz)，7.49(m，1H)，6.25(m，1H)，5.13(m，1H)，4.34(m，1H)，4.28(m，1H)，3.92(m，2H)；¹³C NMR(CD₃OD) δ 147.0, 131.5, 131.0, 128.6, 107.5, 97.8, 84.8, 73.3, 61.5; IR (pure) 1705, 1647, 1557, 1490cm^-1。C₁₅H₁₃Cl₂N₃O₅Calculated analytical values of (a): c, 46.65; h, 3.39; n, 10.88. Measurement values: c, 47.04; h, 3.42; n, 10.82.

Biological evaluation-non-small cell lung cancer

Compounds were evaluated on two non-small cell lung cancer cell lines (a549 and SW 1573). These cell lines have been used to characterize the sensitivity of deoxyribonucleoside analogs and dCK activity.

The chemosensitivity assay used in this study was ammonium thiocyanate B (sulforhodamine B) (SRB) assay as described previously (Keepers et al, Eur J. cancer, 1991; Rubinstein et al, J. Natl. cancer Inst., 1990). On day 0, cells were transferred to 96-well plates; on day 1, serial dilutions of the drug were prepared from the stock solution and added to the cells, in triplicate. After 72 hours of incubation, cells were fixed with 50% trichloroacetic acid at 4 ℃ for 1 hour, washed, air dried and stained with 0.4% SRB. The optical density was measured at 492nm with a microplate reader (Tecan, Salsburg, Austria).

The results are expressed as a percentage of the control growth:

	(OD (day 4)Treated by-OD (day 1)
			% growth inhibition	(OD (day 4)Control-OD (day 1)	x 100％

The data were plotted as images to obtain growth inhibition curves. On this growth inhibition curve, the IC50 value was determined by interpolation (interpolluting) at the 50% growth level. The results are shown in table 1, below. FIG. 3 shows LogP and IC for linear aliphatic prodrugs on non-small cell lung cancer cell lines A549 and SW1573₅₀The relationship between them. LogP was evaluated using ChemDraw 8.0 ultratra. IC is expressed using the mean of three experiments₅₀。

Table 1 calculated LogP for cytotoxic activity and troxacitabine prodrug 6a-t of two non-small cell lung cancer cell lines (a549 and SW 1573).

^aEvaluated according to the SRB test and expressed as the average of 3 tests.

^bCalculation Using Chem Draw Ultra 8.0

Experimental part of pancreatic cancer

Materials and methods

A small library (smalllibrary) of troxacitabine prodrugs was synthesized using the direct parallel liquid phase method described above. Synthesis of troxacitabine starting from L-glucose according to known methods^[11]It was then dissolved in anhydrous methanol and treated with different anhydrides in an Argonaut Quest 210 organic synthesizer. After 6 hours at 55 deg.C, the reaction mixture was briefly filtered and then purified by gradient elution (ethane: ethyl acetate) on a small silica flash column from which the prodrug of troxacitabine was obtained2H-KAs a white solid. (see FIG. 4)

By SRB cytotoxicity assay^[12]Sensitivity of four different length linear aliphatic prodrugs was determined and IC of drug in different cell lines was determined by interpolating growth inhibition curves₅₀The value is obtained. These experiments were performed on BxPC-3 and Panc-02 pancreatic cancer cell lines.

Results and discussion

The lipophilicity of the troxacitabine increased by adding the aliphatic chain remarkably improves the sensitivity of the pancreatic cancer cell strain to drugs. Trixacitabine analogues compared to TrixacitabineI、JAndKdisplay deviceMaximally regulated, analogs in BxPC-3J160-fold increase in sensitivity, analogs in Panc-02ISensitivity was increased 1400-fold (fig. 3). It appears that₂)₈Increase in lipophilicity of (A) makes IC₅₀Decreasing to the optimum value, continued increase in lipophilicity does not appear to have a positive effect on the sensitivity of these cell lines. The effect of increased lipophilicity may be explained by increased injection further bypassing the nucleoside transporter, or by increased retention time of the prodrug in the cell. Ara-C prodrugs, which also contain aliphatic side chains, show increased activity in Ara-C resistant leukemia cell lines. The length of the aliphatic side chain determines the activity of the compound, the amount of double bonds determines to a lesser extent the activity of the compound, the compound with the shortest side chain (chain length: 16) and one double bond shows the best activity^[13]. Another aliphatic prodrug of Ara-C, NOAC, which contains C₁₈Aliphatic side chains, also show increased activity in xenograft models against leukemia and solid tumors^[14]. The desorption rate from the membrane has been shown to be related to the chain length of the fatty acid^[15]. This may explain why these appear to be the best lipophilicities, after which no further enhancement of the drug is observed. The exact mechanism of entry and retention of the aliphatic side chain-containing compound in the cell can be further investigated.

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Claims (9)

1. Use of a compound according to the following chemical structure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating non-small cell lung cancer:

wherein R is C₃-C₇Cycloalkyl radical, C₁-C₂₂A straight or branched alkyl group or an optionally substituted phenyl group, wherein said phenyl group, when substituted, is substitutedOne or two of the following groups: F. cl, Br, OMe or mixtures thereof;

R²is H, or a fully or partially protonated monophosphate, diphosphate or triphosphate group, or a phosphodiester group;

the compound or pharmaceutically acceptable salt thereof is optionally combined with a pharmaceutically acceptable carrier, additive or excipient.

2. Use according to claim 1, wherein R is C₃-C₆A cycloalkyl group.

3. Use according to claim 1, wherein R is C₁-C₁₅Straight or branched chain alkyl.

4. Use according to claim 1, wherein R²Is H, or a phosphate group in free acid or salt form.

5. Use according to claim 2, wherein R²Is H, or a phosphate group in free acid or salt form.

6. Use according to claim 3, wherein R²Is H, or a phosphate group in free acid or salt form.

7. Use of a compound according to the following chemical structure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating pancreatic cancer:

wherein R is C₁-C₂₂A linear or branched alkyl group;

R²is H, or a fully or partially protonated monophosphate, diphosphate or triphosphate group, or phosphoric acidA diester group;

the compound or pharmaceutically acceptable salt thereof is optionally combined with a pharmaceutically acceptable carrier, additive or excipient.

8. Use according to claim 7, wherein R is C₈-C₁₅A linear alkyl group.

9. Use according to claim 8, wherein R²Is H, or a phosphate group in free acid or salt form.