SHIELDING AGENTS AND THEIR USE
20210323985 · 2021-10-21
Inventors
Cpc classification
C07F9/3808
CHEMISTRY; METALLURGY
C07F9/4006
CHEMISTRY; METALLURGY
A61K51/0497
HUMAN NECESSITIES
C07C275/16
CHEMISTRY; METALLURGY
A61K31/662
HUMAN NECESSITIES
International classification
C07F9/38
CHEMISTRY; METALLURGY
A61K31/17
HUMAN NECESSITIES
A61K31/662
HUMAN NECESSITIES
Abstract
The present disclosure relates to compounds useful as shielding agents for PSMA therapies. The present disclosure relates to methods of treating PSMA expressing cancers with one or more radiotherapeutics agents in combination with one or more shielding agents. The present disclosure relates to methods of imaging using one or more imaging agents containing a radionuclide in combination with one or more shielding agents. The present disclosure also relates to methods of making shielding agents.
Claims
1. A compound selected from the group consisting of ##STR00074## ##STR00075##
2. A method for treating a cancer in a patient comprising administering a therapeutically effective amount of a radiolabeled therapeutic in combination with a an effective amount of a shielding agent.
3. The method of claim 2, wherein the radiolabeled therapeutic is Compound Ia-Lu of the formula ##STR00076## wherein .sup.177Lu is coordinated thereto or Compound Ia-Ac of the formula ##STR00077## wherein .sup.177Lu is coordinated thereto.
4. The method of claim 3, wherein the cancer is a prostate cancer.
5. The method of claim 4, wherein the cancer is a metastatic prostate cancer.
6. The method of claim 4, wherein the cancer is a metastatic castration-resistant prostate cancer.
7. The method of claim 4, wherein the shielding agent is selected from the group consisting of ##STR00078## ##STR00079## ##STR00080##
8. The method of claim 4, wherein the shielding agent is selected from the group consisting of ##STR00081## ##STR00082##
9.-18. (canceled)
19. A method for imaging a cancer in a patient comprising administering an effective amount of an imaging conjugate in combination with an effective amount of a shielding agent.
20. The method of claim 19, wherein the imaging is a .sup.99mTc labelled imaging conjugate of the formula ##STR00083## or .sup.67Ga or.sup.68Ga labelled an imaging conjugate of the formula ##STR00084## wherein .sup.67Ga or .sup.68Ga is coordinated thereto.
21. The method of claim 19, wherein the cancer is a prostate cancer.
22. The method of claim 21, wherein the cancer is a metastatic prostate cancer.
23. The method of claim 21, wherein the cancer is a metastatic castration-resistant prostate cancer.
24. The method of claim 21, wherein the shielding agent is selected from the group consisting of ##STR00085## ##STR00086## ##STR00087##
25. The method of claim 21, wherein the shielding agent is selected from the group consisting of ##STR00088## ##STR00089##
26.-35. (canceled)
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DEFINITIONS
[0084] As used herein, “functionally active PSMA” means a cell surface membrane-bound glycoprotein that binds to a PSMA ligand. It will be appreciated that PSMA ligands are well known to those skilled in the art such as those described in US patent publication no. US 2010/0324008 A1, incorporated herein by reference.
[0085] As used herein, “clinical benefit” means a response of a patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac, where the response includes overall survival of the patient, ability to receive four or more cycles of therapy (e.g., four weeks of therapy) with Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac, inhibition of tumor growth, stable disease, a partial response, and/or a complete response, among other clinical benefits defined by the Food and Drug Administration in the United States of America.
[0086] As used herein, “inhibition of tumor growth” means reduction in tumor size, complete disappearance of a tumor, or growth of a patient tumor of less than 30% over the course of therapy with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac.
[0087] As used herein, “stable disease” means no material progression of disease in a patient over the course of therapy with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac.
[0088] As used herein, “a partial response” means a decrease in tumor size of 30% or greater in a patient treated with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac.
[0089] As used herein, “a complete response” means the disappearance of detectable disease in a patient treated with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac.
[0090] As used herein, “prior treatment” means the patient has been treated with at least one prior treatment known in the art. It will be appreciated that a prior treatment can be any treatment known to those of skill in the art, including, but not limited, chemotherapeutic agent, surgery, radiation therapy, immunotherapy, photodynamic therapy, stem cell therapy, hyperthermia, and the like. Prior treatments can include systemic treatments including, but not limited to treatment with abiraterone, orteronel, galeterone, seviteronel, apalutamide, enzalutamide, palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.
[0091] As used herein, the term “alkyl” includes a chain of carbon atoms, which is optionally branched. It will be further understood that in certain embodiments, alkyl is advantageously of limited length, including C.sub.1-C.sub.24, C.sub.1-C.sub.8, C.sub.1-C.sub.6, and C.sub.1-C.sub.4. Illustratively, such particularly limited length alkyl groups, including C.sub.1-C.sub.8, C.sub.1-C.sub.6, and C.sub.1-C.sub.4 may be referred to as lower alkyl. It is appreciated herein that shorter alkyl, alkenyl, and/or alkynyl groups may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior. In some embodiments, it will be understood, in each case, that the recitation of alkyl refers to alkyl as defined herein, and optionally lower alkyl. Illustrative alkyl groups include, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. As used herein, a “carboxyalkyl” group includes a combination of an “alkyl” group as described herein with a “carboxy” group. As used herein, a “hydroxyalkyl” group includes a combination of an “alkyl” group as described herein with a “hydroxy” group. As used herein, a “aminoalkyl” group includes a combination of an “alkyl” group as described herein with a “amino” group.
[0092] As used herein, the term “heteroalkyl” includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched. Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
[0093] As used herein, the term “aryl” includes monocyclic and polycyclic aromatic carbocyclic groups having from 6 to 14 ring carbon atoms, each of which may be optionally substituted. Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. As used herein, the term “heteroaryl” includes aromatic heterocyclic groups, having from 5 to 10 ring atoms, each of which may be optionally substituted. Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and the like. As used herein, the term “heteroarylalkyl” includes a combination of an “alkyl” group as described herein with a “heteroaryl” group described herein. As used herein, the term “arylalkyl” includes a combination of an “alkyl” group as described herein with a “aryl” group described herein, for example a benzyl group.
[0094] The term “optionally substituted” as used herein includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
[0095] As used herein, the term “administering” as used herein includes all means of introducing Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac and/or a PSMA ligand-imaging conjugate as described herein to the patient, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like. A combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac and/or a PSMA ligand-imaging conjugate as described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.
[0096] As used herein, “becquerel” means a SI derived unit of radioactivity as it is commonly understood by one of skill in the art. One becquerel is defined as the activity of a quantity of radioactive material in which one nucleus decays per second. A becquerel is therefore equivalent to an inverse second, s-1. The becquerel is known to one of skill in the art as the successor of the curie (Ci), an older, non-SI unit of radioactivity based on the activity of 1 gram of radium-226. The curie is defined as 3.7. 1010 s-1, or 37 GBq.
[0097] As used herein, “curie” or “Ci” means a unit of radioactivity named after the French physicist and chemist Marie Curie as commonly understood by one of skill in the art. The prefixes milli and micro are from the metric system and represent 0.001 and 0.000001, respectively. So, a millicurie (mCi) is 0.001 curie. A microcurie (μCi) is 0.000001 curie.
DETAILED DESCRIPTION
[0098] The embodiments of the numbered clauses provided in the summary above, or any combination thereof, are contemplated for combination with any of the embodiments described in the Detailed Description section of this patent application.
[0099] In one embodiment, the methods described herein can be used for both human clinical medicine and veterinary applications. Thus, a “patient” can be administered Compound I-Lu, Ia-Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates described herein in combination with a shielding agent as described herein, and can be human or, in the case of veterinary applications, can be a laboratory, agricultural, domestic, or wild animal. In one aspect, the patient can be a human, a laboratory animal such as a rodent (e.g., mice, rats, hamsters, etc.), a rabbit, a monkey, a chimpanzee, domestic animals such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.
[0100] In various embodiments, the cancers described herein can be a cancer cell population that is tumorigenic, including benign tumors and malignant tumors, or the cancer can be non-tumorigenic. The cancer can arise spontaneously or by such processes as mutations present in the germline of the patient or somatic mutations, or the cancer can be chemically-, virally-, or radiation-induced. Cancers applicable to the present disclosure described herein include, but are not limited to, a glioma, a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a nasopharyngeal carcinoma, a leukemia, an adenocarcinoma, and a myeloma.
[0101] In some aspects the cancers can be lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphomas, pleural mesothelioma, cancer of the bladder, Burkitt's lymphoma, cancer of the ureter, cancer of the kidney, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioma, brain stem glioma, pituitary adenoma, and adenocarcinoma of the gastroesophageal junction.
[0102] Compound Ia has the formula
##STR00033##
wherein .sup.177Lu is complexed to the compound in Ia-Lu, and .sup.225Ac is complexed to the compound in Ia-Ac.
[0103] In other embodiments, any of a variety of PSMA ligand-imaging conjugates detectable by PET imaging, SPECT imaging, and the like can be used. The exact manner of imaging is not limited to the imaging agents described herein. Collectively, the PSMA ligand-imaging conjugates useful for imaging described herein, including those described by formulas and the agents useful for PET imaging, SPECT imaging, etc. are referred to as “PSMA ligand-imaging conjugates.”
[0104] Shielding agents useful in connection with the present disclosure can be any shielding agent capable of blocking the off target binding of a radiolabeled compound as described herein to PSMA. Suitable shielding agents include, but are not limited to those described in US. patent publication US 2017/0226141, Majer, P. et al., “Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedoic Acid (2-PMPA)” J. Med. Chem., 59, 2810-2819 (2016), and Nedelcovych M. et al , “Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester” Mol. Pharmaceutics, 14, 3248-3257 (2017), the disclosures of which are incorporated by reference. Suitable examples of shielding agents include, but are not limited to those shown in Table 1.
TABLE-US-00001 CPD Structure 1a
[0105] In one embodiment, the Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates described herein bind to PSMA expressed on cancer cells. In some embodiments, the shielding agents described herein bind to PSMA. In one illustrative aspect, the Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates are capable of differentially binding to PSMA on cancer cells compared to normal cells due to preferential expression (or over-expression) of PSMA on the cancer cells. In some embodiments, the shielding agents described herein are capable of blocking the off target binding of Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates to PSMA expressed on, for example, liver cells.
[0106] In some embodiments, Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates described herein may be administered as a formulation in association with one or more pharmaceutically acceptable carriers. The choice of carrier will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates described herein and methods for their preparation will be readily apparent to those skilled in the art. Further, the shielding agents described herein may be administered as a formulation in association with one or more pharmaceutically acceptable carriers. The choice of carrier will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form. Such compositions and methods for their preparation may be found, for example, in Remington: The Science & Practice of Pharmacy, 21th Edition (Lippincott Williams & Wilkins, 2005), incorporated herein by reference.
[0107] In one illustrative aspect, a pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, and combinations thereof, that are physiologically compatible. In some embodiments, the carrier is suitable for parenteral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Supplementary active compounds can also be incorporated into compositions of the present disclosure.
[0108] In various embodiments, liquid formulations may include suspensions and solutions. Such formulations may comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid.
[0109] In one embodiment, an aqueous suspension may contain the active materials in admixture with appropriate excipients. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally-occurring phosphatide, for example, lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol; a condensation product of ethylene oxide with a partial ester derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ascorbic acid, ethyl, n-propyl, or p-hydroxybenzoate; or one or more coloring agents.
[0110] In one illustrative embodiment, dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients, for example, coloring agents, may also be present.
[0111] Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides, for example, soybean lecithin; and esters including partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
[0112] In other embodiments, isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride can be included in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
[0113] Illustrative formats for oral administration include tablets, capsules, elixirs, syrups, and the like.
[0114] Depending upon the cancer type as described herein, the route of administration and/or whether Compound I-Lu ,or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates are administered locally or systemically, a wide range of permissible dosages are contemplated herein, including doses falling in the range from about 1 MBq to about 4 MBq of I-Ac or Ia-Ac. In some embodiments, permissible dosages for I-Lu or Ia-Lu are contemplated herein in the units GBq, including doses falling in the range from about 2 GBq to about 13 GBq. The dosages may be single or divided, and may administered according to a wide variety of protocols, including q.d., b.i.d., t.i.d., or even every other day, biweekly (b.i.w.), once a week, once a month, once a quarter, and the like. In each of these cases it is understood that the therapeutically effective amounts described herein correspond to the instance of administration, or alternatively to the total daily, weekly, monthly, or quarterly dose, as determined by the dosing protocol. In some embodiments, a combination of compounds of the formula I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be administered on independent schedules of once, or once per week, or once every two weeks, or once every three weeks, or once every four weeks, or once every five weeks, or once every six weeks, or once every seven weeks, or once every eight weeks, and the like
[0115] In one aspect, Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates as described herein may be administered directly into the blood stream, into muscle, or into an internal organ. Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intratumoral, intramuscular and subcutaneous delivery. Suitable means for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
[0116] In one illustrative aspect, parenteral formulations are typically aqueous solutions which may contain carriers or excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. In other embodiments, any of the liquid formulations described herein may be adapted for parenteral administration of the Compound 1 or PSMA ligand-imaging conjugates described herein. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization under sterile conditions, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. In one embodiment, the solubility of Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
[0117] In various embodiments, formulations for parenteral administration may be formulated for immediate and/or modified release. In one illustrative aspect, the active agents of the present disclosure (i.e., Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates) may be administered in a time release formulation, for example in a composition which includes a slow release polymer. The active Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates can be prepared with carriers that will protect Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PGLA). Methods for the preparation of such formulations are generally known to those skilled in the art. In another embodiment, Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates described herein or compositions comprising the Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates may be continuously administered, where appropriate.
[0118] In one embodiment, a kit is provided. If a Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugate is to be administered in combination with a shielding agent described herein, two or more pharmaceutical compositions may be combined in the form of a kit suitable for sequential administration or co-administration of the compositions. Such a kit comprises two or more separate pharmaceutical compositions, at least one of which contains Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugate described herein, and another contains at least one shielding agent as described herein, and means for separately retaining the compositions, such as a container, divided bottle, or divided foil packet. In another embodiment, compositions comprising one or more of Compound I-Lu , or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugates described herein, and at least one shielding agent as described herein, in containers having labels that provide instructions for use in patient selection and/or treatment are provided.
[0119] In one embodiment, sterile injectable solutions can be prepared by incorporating the active agent in the required amount in an appropriate solvent with one or a combination of ingredients described above, as required, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active Compound I-Lu, or -Lu, I-Ac, or Ia-Ac and/or PSMA ligand-imaging conjugate, or a shielding agent as described herein, into a sterile vehicle which contains a dispersion medium and any additional ingredients of those described above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof, or the ingredients may be sterile-filtered together.
[0120] The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In one embodiment, the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
[0121] Dose levels of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be measured in GBq and MBq, respectively. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 13 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 4 GBq to about 11 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 5 GBq to about 10 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 9 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 6.5 GBq to about 8.5 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 7 GBq to about 8 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is about 7.4 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from about 15 GBq to about 200 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from about 25 GBq to about 185 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from about 35 GBq to about 150 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from about 40 GBq to about 100 GBq. In some embodiments, the total dose of I-Lu, or Ia-Lu is about 44 GBq. In some embodiments, the maximum duration of treatment of a subject is about 19 to 23 months.
[0122] In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 2 GBq to 20 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 2 GBq to 13 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 4 GBq to 11 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 5 GBq to 10 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 6 GBq to 9 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 6 GBq to 8 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 6.5 GBq to 8.5 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 7 GBq to 8 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is 7.4 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 15 GBq to 200 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 25 GBq to 185 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 35 GBq to 150 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 40 GBq to 100 GBq. In some embodiments, the total dose of I-Lu, or Ia-Lu is 44 GBq. In some embodiments, the maximum duration of treatment of a subject is 19 to 23 months.
[0123] In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 20 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 4 MBq to about 14 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 5 MBq to about 10 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 6 MBq to about 8 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 5 MBq to about 7 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 4 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 2 MBq to about 3 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is about 2.5 MBq.
[0124] In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 1 MBq to 20 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 1 MBq to 10 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 4 MBq to 14 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 5 MBq to 10 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 6 MBq to 8 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 5 MBq to 7 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 1 MBq to 4 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 2 MBq to 3 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is 5 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is 2.5 MBq.
[0125] The PSMA ligand-imaging conjugates, Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac, and shielding agents described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. Accordingly, it is to be understood that the present disclosure includes pure stereoisomers as well as mixtures of stereoisomers, such as enantiomers, diastereomers, and enantiomerically or diastereomerically enriched mixtures. The PSMA ligand-imaging conjugates, Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac, and shielding agents described herein may be capable of existing as geometric isomers. Accordingly, it is to be understood that the present disclosure includes pure geometric isomers or mixtures of geometric isomers. For example, shielding agent 1c is of the formula
##STR00050##
A person skilled in the art will recognize that shielding agent 1c has a chiral center and can thus exist in two enantiomeric forms. A person skilled in the art will recognize that the two enantiomers of shielding agent 1c are
##STR00051##
It will be appreciated that the disclosure of shielding agent 1c as shown above, also includes disclosure of the R-enantiomer and S-enantiomer of shielding agent 1c. Similarly, the disclosure of other shielding agents, PSMA ligand-imaging agents, and Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac also includes disclosure of their respective enantiomers, diasteriomers, and the like.
[0126] It is appreciated that the PSMA ligand-imaging conjugates and Compounds I-Lu, I-Ac, and Ia-Lu, Ia-Ac described herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. The PSMA ligand-imaging conjugates and Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
[0127] In another embodiment, compositions and/or dosage forms for administration of Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac are prepared from Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac with purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%. In another embodiment, compositions and or dosage forms for administration of Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac are prepared from Compounds I-Lu, Ia-Lu, I-Ac, or Ia-Ac with a purity of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.
[0128] In another embodiment, compositions and/or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%. In another embodiment, compositions and or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a purity of at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.
[0129] In another embodiment, compositions and/or dosage forms for administration of radiolabeled PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a radiochemical purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%. In another embodiment, compositions and or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a purity of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.
[0130] The purity of Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac or the PSMA ligand-imaging conjugates described herein may be measured using any conventional technique, including various chromatography or spectroscopic techniques, such as high pressure or high performance liquid chromatography (HPLC), nuclear magnetic resonance spectroscopy, TLC, UV absorbance spectroscopy, fluorescence spectroscopy, and the like.
[0131] In another embodiment, Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac or PSMA ligand-imaging conjugate described herein is provided in a sterile container or package.
[0132] In one aspect, a clinical benefit of the patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be characterized as overall survival (OS). As used herein, the term “overall survival (OS)” means the time from the date of randomization to the date of death from any cause.
[0133] In one aspect, a clinical benefit of the patient to treatment with Compound I-Lu, Ia-Lu, I-Ac, or Ia-Ac can be characterized utilizing Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Illustratively, the criteria have been adapted from the original WHO Handbook (3), taking into account the measurement of the longest diameter for all target lesions: complete response, (CR)—the disappearance of all target lesions; partial response (PR)—at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; stable disease (SD)—neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started; progressive disease (PD)—at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. In another aspect overall disease response rate (ORR) is a clinical benefit and is calculated as the percent of patients who achieve a best response of CR or PR. Overall disease control rate (DCR) can be another clinical benefit and is calculated as the percent of patients who achieve a best response of CR, PR, or SD. In some embodiments, the response can be disease control rate (DCR) as measured by RECIST v1.1 criteria.
[0134] In another aspect, a clinical benefit of the patient to treatment with Compound I-Lu, Ia-Lu, I-Ac, or Ia-Ac can be characterized as radiographic progression-free survival (rPFS). As used herein, “radiographic progression-free survival (rPFS)” means the time from the date of randomization to the date of radiographic disease progression as outlined in Prostate Cancer Working Group 3 (PCWG3) Guidelines or death from any cause. See, for example, Scher H I, Morris M J, Stadler W M, Higano C, Basch E, Fizazi K, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations from the Prostate Cancer Clinical Trials Work Group 3. J Clin Oncol 2016; 34(12):1402-18. In another aspect, a clinical benefit of the patient to treatment with Compound 1 can be characterized as time to a first symptomatic skeletal event (SSE). It will be appreciated that symptomatic skeletal event means a clinically significant pathological fracture, surgery or radiation to bone, or spinal cord compression. As used herein, “time to a first symptomatic skeletal event” means date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or requirement for radiation therapy to relieve bone pain, whichever occurs first.
[0135] In one illustrative example overall survival is the time to death for a given patient defined as the number of days from the first day the patient received protocol treatment (C1D1) to the date of the patient's death. All events of death can be included, regardless of whether the event occurred while the patient was still taking the study drug or after the patient discontinued the study drug. If a patient has not died, then the data can be censored at the last study visit, or the last contact date, or the date the patient was last known to be alive, whichever is last.
[0136] Alternatively, a clinical benefit of the patient as a result of treatment with Compound I-Lu, Ia-Lu, I-Ac, or Ia-Ac can be characterized as inhibition of tumor growth which can be identified in a patient through, for example, follow-up imaging of the patient's cancer after treatment with the Compound. For example, inhibition of tumor growth can be characterized by measuring the size of tumors in a patient after administration of Compound I-Lu, Ia-Lu, I-Ac, or Ia-Ac according to any of the imaging techniques described herein, where the inhibition of tumor growth is indicated by a stable tumor size, or by a reduction in tumor size. It will be appreciated that the identification of inhibition of tumor growth can be accomplished using a variety of techniques, and is not limited to the imaging methods described herein (e.g CT, MRI, PET imaging, SPECT imaging or chest x-ray).
[0137] The embodiments described in the Detailed Description and Summary can be combined with each of the following numbered paragraphs to the extent that such embodiments are not in conflict with one another:
[0138] 1. A compound selected from the group consisting of
##STR00052##
[0139] 2. A method for treating a cancer in a patient comprising administering a therapeutically effective amount of a radiolabeled therapeutic in combination with a an effective amount of a shielding agent.
[0140] 3. The method of clause 2, wherein the radiolabeled therapeutic is Compound Ia-Lu or Ia-Ac.
[0141] 4. The method of clause 2 or 3, wherein the cancer is a prostate cancer. 5. The method of any one of clauses 2 to 4, wherein the cancer is a metastatic prostate cancer.
[0142] 6. The method of any one of clauses 2 to 4, wherein the cancer is a metastatic castration-resistant prostate cancer.
[0143] 7. The method of any one of clauses 2 to 6, wherein the shielding agent is selected from the group consisting of
##STR00053## ##STR00054##
[0144] 8. The method of any one of clauses 2 to 6, wherein the shielding agent is selected from the group consisting of
##STR00055##
[0145] 9. A compound selected from the group consisting of
##STR00056## ##STR00057##
for treating cancer in a patient in need of such treatment in combination with a therapeutically effective amount of a radiolabeled therapeutic.
[0146] 10. The compound of clause 9, wherein the radiolabeled therapeutic is Compound Ia-Lu or Ia-Ac.
[0147] 11. The compound of clause 9 or 10, wherein the cancer is a prostate cancer.
[0148] 12. The compound of any one of clauses 9 to 11, wherein the cancer is a metastatic prostate cancer.
[0149] 13. The compound of any one of clauses 9 to 11, wherein the cancer is a metastatic castration-resistant prostate cancer.
[0150] 14. Use of compound selected from the group consisting of
##STR00058## ##STR00059##
in the manufacture of a medicament for treating cancer in a patient in combination with a therapeutically effective amount of a radiolabeled therapeutic.
[0151] 15. The use of clause 14, wherein the radiolabeled therapeutic is Compound Ia-Lu or Ia-Ac.
[0152] 16. The use of clause 14 or 15, wherein the cancer is a prostate cancer.
[0153] 17. The use of any one of clauses 14 to 16, wherein the cancer is a metastatic prostate cancer.
[0154] 18. The use of any one of clauses 14 to 16, wherein the cancer is a metastatic castration-resistant prostate cancer.
[0155] 19. A method for imaging a cancer in a patient comprising administering an effective amount of an imaging conjugate in combination with an effective amount of a shielding agent.
[0156] 20. The method of clause 19, wherein the imaging is .sup.99mTc labelled imaging conjugate 3a or .sup.67Ga or.sup.68Ga labelled imaging conjugate 4.
[0157] 21. The method of clause 19 or 20, wherein the cancer is a prostate cancer.
[0158] 22. The method of any one of clauses 19 to 21, wherein the cancer is a metastatic prostate cancer.
[0159] 23. The method of any one of clauses 19 to 22, wherein the cancer is a metastatic castration-resistant prostate cancer.
[0160] 24. The method of any one of clauses 19 to 23, wherein the shielding agent is selected from the group consisting of
##STR00060## ##STR00061##
[0161] 25. The method of any one of clauses 19 to 23, wherein the shielding agent is selected from the group consisting of
##STR00062## ##STR00063##
[0162] 26. A compound selected from the group consisting of
##STR00064## ##STR00065## ##STR00066##
for imaging cancer in a patient in need of such treatment in combination with an effective amount of an imaging conjugate.
[0163] 27. The compound of clause 26, wherein the imaging conjugate is .sup.99mTc labelled imaging conjugate 3a or .sup.67Ga or .sup.68Ga labelled imaging conjugate 4.
[0164] 28. The compound of clause 26 or 27, wherein the cancer is a prostate cancer.
[0165] 29. The compound of any one of clauses 26 to 28, wherein the cancer is a metastatic prostate cancer.
[0166] 30. The compound of any one of clauses 26 to 28, wherein the cancer is a metastatic castration-resistant prostate cancer.
[0167] 31. Use of compound selected from the group consisting of
##STR00067## ##STR00068## ##STR00069##
in the manufacture of a medicament for imaging cancer in a patient in combination with an effective amount of n imaging conjugate.
[0168] 32. The use of clause 31, wherein the imaging conjugate is .sup.99mTc labelled imaging conjugate 3a or .sup.67Ga or .sup.68Ga labelled imaging conjugate 4.
[0169] 33. The use of clause 31 or 32, wherein the cancer is a prostate cancer.
[0170] 34. The use of any one of clauses 31 to 33, wherein the cancer is a metastatic prostate cancer.
[0171] 35. The use of any one of clauses 31 to 34, wherein the cancer is a metastatic castration-resistant prostate cancer.
[0172] In another embodiment, the methods described herein include the following examples. The examples further illustrate additional features of the various embodiments of the present disclosure. However, it is to be understood that the examples are illustrative and are not to be construed as limiting other embodiments of the present disclosure. In addition, it is appreciated that other variations of the examples are included in the various embodiments of the present disclosure. In addition, it will be appreciated that all ranges described herein, such as those described in connection with the various embodiments, are exemplary and not intended to be limiting. One of skill in the art will appreciate that all ranges described by an lower and upper bound, such as about 1 to about 20, includes all possible values contained in the lower and upper bound, and includes all possible ranges of values available by the set of possible values contained in the lower and upper bound.
EXAMPLES
Example 1
Preparation of Compound 1a
[0173] ##STR00070##
Step 1: Preparation of (S)-1-benzyl 5-octyl 2-((tert-butoxycarbonyl)amino)pentanedioate
[0174] To a stirring solution of Boc-Glu-OBn (1.00 g, 2.96 mmol, 1.00 equiv), n-octanyl alcohol (699 μL, 4.44 mmol, 1.50 equiv), DIPEA (1.54 mL, 8.88 mmol, 3.00 equiv), DMAP (36.2 mg, 0.296 mmol, 10 mol %) in 29.6 mL of DCM was added HATU (1.35 g, 3.55 mmol, 1.20 equiv). The reaction was allowed for 5 h at room temperature before it was diluted with 100 mL of DCM, washed with 30 mL of 2M HCl (aq), 30 mL of water, 30 mL of brine, dried over Na.sub.2SO.sub.4, and filtered. The solution was concentrated under reduced pressure. The desired product was further purified by silica chromatography (5-85% EtOAc in Pet. Ether) to yield a white solid (1.04 g, 81.1%).
[0175] Shielding agents 1m and 1n were prepared according to the same method using 1-butanol and 1-dodecanol in place of 1-octanol, respectively.
Step 2: Preparation of (S)-dibenzyl 2-((phenoxycarbonyl)amino)pentanedioate
[0176] In a 100 mL round-bottom flask, Dibenzyl L-glutamate para-toluenesulfonate (5.00 g, 10.0 mmol, 1.00 equiv) and 4-nitrophenyl chloroformate (1.64 g, 10.5 mmol, 1.05 equiv) were dissolved in 30.3 mL of dichloromethane at 0° C. and was stirred under argon for 30 min. Diisopropylethylamine (3.80 mL, 22.0 mmol, 2.20 eq.) was added drop-wise at 0° C. and the reaction mixture was stirred for 5 minutes before it was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction mixture was then concentrated to a thick light yellow oil. The product was further purified via silica chromatography (0-55% ethyl acetate in petroleum ether) to yield the desired product as a white solid (3.54 g, 78.1%).
Step 3: Preparation of (S)-dibenzyl 2-(3-((S)-1-(benzyloxy)-5-(octyloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate
[0177] (S)-1-benzyl 5-octyl 2-((tert-butoxycarbonyl)amino)pentanedioate (500mg, 1.11 mmol, 1.00 equiv) was dissolved in dry DCM (5.00 mL). The solution was cooled down to 0° C. and TFA (5.00 mL) was added and the reaction mixture was allowed to slowly heated up to room temperature and stirred for 30 min. DCM and TFA were evaporated in vacuo and the residue was dissolved in toluene (2 mL×3) and coevaporated to remove traces of TFA. The crude product was dissolved in 2.22 mL of DCM and added slowly to a stirring solution of EC3517 (496 mg, 1.11 mmol, 1.00 equiv) dissolved in 2.22 mL of DCM at 0° C. Diisopropylethylamine (424 μL, 2.44 mmol, 2.20 equiv) was added drop-wise at 0° C., and the reaction mixture was stirred for 30 minutes before it was allowed to warm to room temperature. The reaction mixture was stirred for one hour at room temperature before the reaction was concentrated under reduced pressure. The product was extracted from 50 mL of water with DMC (25 mL×3). The combined organic layers were washed with brine (25 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The product was further purified by silica gel chromatography (10-100% EtOAc in Pet. Ether) to yield the desired product at a thick oil (678 mg, 87.0%).
Step 4: Preparation of (S)-2-(3-((S)-1-carboxy-4-(octyloxy)-4-oxobutyl)ureido)pentanedioic acid (1a)
[0178] Preparation of (S)-dibenzyl 2-(3-((S)-1-(benzyloxy)-5-(octyloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate (441 mg, 0.628 mmol, 1.00 equiv) was dissolved in 6.28 mL of THF/Methanol (3:2). 10% Pd/C (66.6 mg, 0.0628 mmol, 10 mol %) was added under a strong stream of argon. The head space was evacuated and back filled with argon followed by hydrogen (×2). The reaction mixture was then stirred at room temperature for 6 h. The crude product was filtered through a 45 μm Nylon/Fiberglass membrane and concentrated. The product was further purified by reverse phase chromotograph (0-30% ACN in 0.1% TFA aqueous buffer). After two days of lyophilization the desired product was obtained as a white solid (210 mg, 77.3%).
Example 2
Preparation of Compound 1c
[0179] ##STR00071##
Step 1: Preparation od 5-(3-(benzyloxy)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
[0180] To a solution of 3-hydroxybenzyl propionic acid (2.00 g, 10.3 mmol, 1.00 equiv), Meldrum's Acid (2.08 g, 14.4 mmol, 1.40 equiv), diisopropylethylamine (DIPEA) (5.01 mL, 28.8 mmol, 2.8 equiv), 4-(dimethylamino)pyridine (DMAP) (159 mg, 1.30 mmol, 10 mol %) in 103 mL of DCM was added dicyclohexylcarbodiimide (DCC) (2.66 g, 12.9 mmol, 1.25 equiv) portion-wise over 1 h at 0° C. The reaction was allowed to warm to room temperature and stirred overnight (16 h) at room temperature. The white precipitate was filtered off, and the filtrate was washed with 10% KHSO.sub.4 (aq) three times, brine, dried over Na.sub.2SO.sub.4, and filtered. The solution was acidified with acetic acid (7.08 mL, 124 mmol, 12 equiv) at −10° C., and sodium borohydride (NaBH.sub.4) (584 mg, 15.45 mmol, 1.5 equiv) was added portion-wise over the period of 1 h. The reaction mixture was stirred −10° C. overnight (16 h), quenched with water, washed with bring, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The desired product was further purified by silica chromatography (5-50% EtOAc in Pet. Ether) to yield a white solid (2.47 g, 82%). LC/MS and .sup.1H NMR spectra analysis agreed with the assigned structure of the desired product.
Step 2: Preparation of tert-butyl 5-(benzyloxy)-2-methylenepentanoate
[0181] 5-(3-(benzyloxy)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.25 g, 4.28 mmol, 1.00 equiv) and Eschenmoser's salt (N,N-dimethylmethyleneiminium iodide) (1.97 g, 10.7 17.2 mmol, 2.50 equiv) were added to a dry round-bottom flask. The head space was evacuated and back-filled with argon. 42.8 mL of absolute tert-butyl alcohol (tBuOH) was added to the solids. The reaction mixture was heated to 65° C. and stirred for 30 h. The reaction was concentrated under high vacuum and the residue was loaded onto silica column and purified by chromatography (0-80% EtOAc in Pet. Ether) to yield the desired product as a clear oil (856 mg, 72.5%). LC/MS and .sup.1H NMR spectra analysis agreed with the assigned structure of the desired product.
Step 3: Preparation of tert-butyl 5-(benzyloxy)-2-((diethoxyphosphoryl)methyl)pentanoate
[0182] A solution of 2M trimethylaluminum in hexanes (5.80 mL, 2.90 mmol, 1.00 equiv) was added drop-wise to a stirring solution of diethyl phosphite (373 μL, 2.90 mmol, 1.00 equiv) in 41.4 mL of dichloromethane (DCM) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. A solution of tert-butyl 5-(benzyloxy)-2-methylenepentanoate (800 mg, 2.90 mmol, 1.00 equiv) in 7.25 mL of dichloromethane slowly, and the reaction mixture was then allowed to warm to room temperature. The reaction mixture was stirred overnight (17 h) at room temperature. The reaction was quenched with 10 mL of 2M HCl (aq) and extracted with diethyl ether (10 mL×3). The organic layers were combined, washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The product was further purified via silica chromatography (10-85% EtOAc in Pet. Ether) to yield the desired product as a clear oil (906 mg, 79.7%). LC/MS and .sup.1H NMR spectra analysis agreed with the assigned structure of the desired product.
Step 4: Preparation of tert-butyl 2-((diethoxyphosphoryl)methyl)-5-hydroxypentanoate
[0183] tert-butyl 5-(benzyloxy)-2-((diethoxyphosphoryl)methyl)pentanoate (450 mg, 1.09 mmol, 1.00 eq) was dissolved in 10.9 mL of tetrahydrofuran (THF), and argon was bubbled through the solution for 15 min. 10% Pd/C (57.7 mg, 0.055 mmol, 5 mol %) was added under a strong stream of argon. The head space was evacuated and back filled with argon followed by hydrogen (x 2). The reaction mixture was then stirred at room temperature for 4 h. The reaction mixture was then filtered through a pad of celite and wash with 10 mL of dichloromethane. The solution was then concentrated and the residue was held under high vacuum for 1 h to yield the desired product as a colorless oil. The crude product was used without further purification.
Step 4: Preparation of 5-(tert-butoxy)-4-((diethoxyphosphoryl)methyl)-5-oxopentyl nonanoate
[0184] To a stirring solution of nonanoic acid (130 μL, 0.743 mmol, 1.20 equiv), tert-butyl 2-((diethoxyphosphoryl)methyl)-5-hydroxypentanoate (200 mg, 0.619 mmol, 1.00 equiv), DIPEA (301 μL, 1.73 mmol, 2.8 equiv), DMAP (8.0 mg, 0.0619 mmol, 10 mol %) in 7.43 mL of DCM was added HATU (306 mg, 0.805 mmol, 1.30 equiv). The reaction was allowed for 5 h at room temperature before it was diluted with 20 mL of DCM, washed with 10 mL of 2M HCl (aq), 10 mL of water, 10 mL of brine, dried over Na.sub.2SO.sub.4, and filtered. The solution was concentrated under reduced pressure. The desired product was further purified by silica chromatography (5-75% EtOAc in Pet. Ether) to yield a white solid (255 mg, 58.5%). LC/MS and .sup.1H NMR spectra analysis agreed with the assigned structure of the desired product.
Step 6: Preparation of 5-(nonanoyloxy)-2-(phosphonomethyl)pentanoic acid (1c)
[0185] 2.2 mL of trifluoroacetic acid (TFA) was added slowly to the stirring solution of 5-(tert-butoxy)-4-((diethoxyphosphoryl)methyl)-5-oxopentyl nonanoate (200 mg, 0.432 mmol, 1.00 equiv) in 2.2 mL of DCM at 0° C. The reaction was allowed to heat up to room temperature and stirred for 2 h. The solvent was evaporated under reduced, and the residue was brought up in toluene and concentrated under high vacuum (x 3). The crude product was dissolved in 4.32 mL anhydrous DCM, and bromotrimethylsilane (342 μL, 2.59 mmol, 6.00 equiv) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h, and then was slowly allowed warmed to room temperature. It was then stirred overnight (12 h) and was concentrated under reduced pressure, and the residue was brought up in toluene and concentrated under high vacuum (×3). The resulting residue was dissolved in ACN/H.sub.2O (4:1, 5 mL) and stirred for 30 min. The reaction was concentrated and loaded onto a C18 column and purified by reverse phase chromotograph (0-35% ACN in 0.1% TFA aqueous buffer). After two days of lyophilization the desired product was obtained as a colorless oil (94 mg, 62.0%). LC/MS and .sup.1H NMR spectra analysis agreed with the assigned structure of the desired product.
Example 3
Preparation of Compound 1d
[0186] ##STR00072##
Step 1: Preparation of 1-(tert-Butyl)-5-dodecyl-2-((diethoxyphosphoryl)methyl)pentanedioate (1-3)
[0187] To a solution of compound 1 (0.092 g, 0.27 mM) which was prepared according to the methods described in Nedelcovych 2017, in dry DCM (3 mL) was added 1-dodecanol (0.101 g, 0.54mM) and DIPEA (0.142 mL, 0.82 mM) respectively. HATU (0.124 g, 0.33 mM) and DMAP (3.32 mg, 0.03 mM) were added. The reaction was allowed to stir at RT for 1 h. LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated that the reaction was complete. The reaction mixture was concentrated and dried. Residue was purified using combiflash (SiO.sub.2) column eluting with 0-100% ethyl acetate in petroleum ether to yield pure 1-3 (0.107 g, 78%).
Step 2: Preparation of 5-Dodecoxy-2-(tert-Butoxycarbonyl)-5-oxopentyl phosphonic acid (1-4)
[0188] To a solution of 1-3 (0.096 g, 0.19 mM) in dry DCM (3 mL), under Argon blanket, at 0° C., was added TMSBr (0.116 g, 0.76 mM) very slowly over 5 min. The reaction was warmed to RT over 2 h and stirred for 18 h. LCMS analysis (20 mM NH.sub.4HCO.sub.3, pH 7.4) indicated that the reaction was complete. DCM was removed, TMSBr was co-evaporated with toluene (3×3 mL) and dried. Residue was dissolved in acetonitrile/water (5:1; 6 mL) and stirred at RT for 30 min. Concentrated under reduced pressure, co-evaporated with toluene (3×3 mL) and dried. The crude product des-ethyl 1-4 (0.086 g, quantitative) was directly used for next reaction.
Step 3: Synthesis of 5-Dodecoxy-5-oxo-2-(phosphonomethyl)pentanoic acid (1d)
[0189] To a solution of des-ethyl 1-4 (0.086 g, 0.19 mM) in dry DCM (2 mL), at 0° C., was added trifluroacetic acid (2 mL) very slowly over 5 min. The reaction was warmed to RT and stirred for 2 h. LCMS analysis (20 mM NH.sub.4HCO.sub.3, pH 7.4) indicated that the reaction was complete. TFA/DCM was removed and dried. Residue was dissolved in DMSO and purified on Biotage column (C.sub.18; 0-50% acetonitrile and 0.1% TFA in water). Pure fractions were combined, acetonitrile was removed and freeze dried to yield 1d (0.062 g, 83%).
[0190] Compound 1b was prepared according to the same method as compound 1d, except that 1-octcanol was used in place of 1-dodecanol.
Example 4
Preparation of Compound 1e
[0191] ##STR00073##
Step 1: Preparation of 1-(tert-Butyl)-2-((diethoxyphosphoryl)methyl)-5-(octylamino)-5-oxopentanoate (1-1)
[0192] To a solution of Compound 1 (0.100 g, 0.30 mM) which was prepared according to the methods described in Nedelcovych 2017, cited above, in dry DCM (3 mL) was added 1-octyl amine (0.077 g, 0.59mM) and DIPEA (0.155 mL, 0.892 mM) respectively. HATU (0.135 g, 0.36 mM) was added. The reaction was allowed to stir at RT for 1 h. LCMS analysis (20 mM NH.sub.4HCO.sub.3, pH 7.4) indicated that the reaction was complete. The reaction mixture was concentrated and dried. Residue was purified using combiflash (SiO.sub.2) column eluting with 0-100% ethyl acetate in petroleum ether to yield pure 1-1 (0.088 g, 66%).
Step 2: Preparation of 5-(Octylamino)-2-(tert-Butoxycarbonyl)-5-oxopentyl phosphonic acid (1-2)
[0193] To a solution of compound 1-1 (0.088 g, 0.20 mM) in dry DCM (3 mL), under Argon blanket, at 0° C., was added TMSBr (0.119 g, 0.78 mM) very slowly over 5 min. The reaction was warmed to RT over 2 h and stirred for 24 h. LCMS analysis (20 mM NH.sub.4HCO.sub.3, pH 7.4) indicated that the reaction was complete. DCM was removed, TMSBr was co-evaporated with toluene (3×5 mL) and dried. Residue was dissolved in acetonitrile/water (5:1; 6 mL) and stirred at RT for 30 min. Concentrated under reduced pressure, co-evaporated with toluene (3×5 mL) and dried. The crude product compound 1-2 (0.077 g, quantitative) was directly used for next reaction.
Step 3: Preparation of 5-(Octylamino)-5-oxo-2-(phosphonomethyl)pentanoic acid (1e)
[0194] To a solution of des-ethyl 1-2 (0.077 g, 0.20 mM) in dry DCM (2.5 mL), at 0° C., was added trifluroacetic acid (2.5 mL) very slowly over 5 min. The reaction was warmed to RT and stirred for 20 h. LCMS analysis (20 mM NH.sub.4HCO.sub.3, pH 7.4) indicated that the reaction was complete. TFA/DCM was removed and dried. Residue was dissolved in DMSO and purified on Biotage column (C.sub.18; 0-50% acetonitrile and 0.1% TFA in water). Pure fractions were combined, acetonitrile was removed and freeze dried to yield compound 1e (0.040 g, 60%).
Biology Examples:
Example 5
Biodistribution of Shielding Agents of the Present Disclosure
[0195] The shielding agents of the present disclosure were administered in combination with an imaging agent of the disclosure, and the biodistribution was analyzed. Results are shown in