WO2013173583A1 - Inhibiteurs de psma - Google Patents

Inhibiteurs de psma Download PDF

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Publication number
WO2013173583A1
WO2013173583A1 PCT/US2013/041353 US2013041353W WO2013173583A1 WO 2013173583 A1 WO2013173583 A1 WO 2013173583A1 US 2013041353 W US2013041353 W US 2013041353W WO 2013173583 A1 WO2013173583 A1 WO 2013173583A1
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Prior art keywords
benzyl
homoserine
phosphoryl
butyl
compound
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PCT/US2013/041353
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English (en)
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WO2013173583A8 (fr
Inventor
Clifford BERKMAN
Svetlama A STEKHOVA
Holger Siebeneicher
Keith Graham
Ralf Lesche
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Cancer Targeted Technology, Llc
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Publication of WO2013173583A1 publication Critical patent/WO2013173583A1/fr
Publication of WO2013173583A8 publication Critical patent/WO2013173583A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

Definitions

  • the present invention relates to small molecules having high affinity and specificity to prostrate-specific membrane antigen (PSMA), methods for making the molecules, and their use for diagnostic purposes.
  • PSMA prostrate-specific membrane antigen
  • Prostate-specific membrane antigen is uniquely overexpressed on the surface of prostate cancer cells as well as in the neovasculature of a variety of solid tumors.
  • PSMA has attracted attention as a clinical biomarker for detection and management of prostate cancer.
  • these approaches utilize an antibody specifically targeted at PSMA. to direct imaging or therapeutic agents.
  • ProstaScint Cytogen, Philadelphia, PA
  • which has been approved by the FDA for the detection and imaging of prostate cancer utilizes an antibody to deliver a chelated radioisotope (Indium- 1 1 1)
  • a chelated radioisotope Indium- 1 1 1
  • PSMA protein kinase inhibitor
  • diagnostic compounds and methods for PSMA presenting cells such as prostate cancer, that capitalize on the potency and specific affinity of small- molecule inhibitors.
  • the diagnostic agents can be used to monitor and stratify patients for treatment with appropriate therapeutic agents.
  • the disclosure provides compounds that are in the form of formula (1),
  • R is phenyl or pyridyl, each substituted with either one [ ! 8 F] -Fiuoro group or one [ l9 F]-Fluoro group and optionally substituted with a second group selected from the group consisting of chloro and cyano;
  • each R is independently hydrogen or a protecting group.
  • compositions comprising a compound of the preceding aspect and a pharmaceutically acceptable carrier.
  • the disclosure provides methods for preparing a compound comprising deproteeting a compound of the formula (F),
  • R is phenyi or pyridyl, each substituted with either one [ j 8 F]-Fluoro group or one [ l9 F]-Fksoro group and optionally substituted with a second group selected from the group consisting of chloro and cyano; and each R p is a protecting group (e.g., t-butyl or benzyl); under conditions suitable for removing each of the R p groups.
  • R is phenyl or pyridyl, each substituted with one leaving group and optionally substituted with a second group selected from the group consisting of chloro and cyano; and each R ? is a protecting group (e.g., i-butyl or benzyl).
  • the disclosure provides methods for preparing a compound (e.g., a compound of formula (I)) comprising contacting a compound of the formula (11), with a fluoride or radiofluoride source.
  • a compound e.g., a compound of formula (I)
  • contacting a compound of the formula (11) with a fluoride or radiofluoride source.
  • the present disclosure provides methods for detecting and/or identifying cells presenting PSMA comprising contacting a cell suspected of presenting PSMA with a compound or a composition of the preceding aspects, wherein R 1 is hydrogen.
  • the present disclosure provides methods for imaging one or more prostate cancer cells in a patient comprising administering to the patient a compound or a pharmaceutical composition of either of the preceding aspects, wherein R ; is hydrogen.
  • the methods herein are useful for imaging of diseases associated with elevated expression of Prostate Specific Membrane Antigen (PSMA).
  • PSMA Prostate Specific Membrane Antigen
  • the present disclosure provides for the use of compounds of general formula I, wherein R 1 is hydrogen, for conducting biological assays and chromatographic identification.
  • the compounds of formula (I) contain a [ l S F]-FIuoro group.
  • the compounds of formula (I) contain a [ 1 F]-F3uoro group.
  • the present disclosure provides for the use of compounds of formula (I) that contain a [ j 9 F]-Fluoro group and wherein R 1 is hydrogen as references and'or measurement agents.
  • the present disclosure provides for the use compounds of formula (I) , wherein R 1 is hydrogen, for the manufacture of an imaging tracer or radiopharmaceutical agent for imaging diseases associated with altered expression of Prostate Specific Membrane Antigen PSMA.
  • altered expression of Prostate Specific Membrane Antigen PSMA refers to elevated expression of Prostate Specific Membrane Antigen PSMA.
  • the present disclosure provides methods for imaging or diagnosing of diseases associated with elevated expression of Prostate Specific Membrane Antigen PSMA comprising, administering to a mammal an effective amount of a compound of formula (I), wherein R 1 is hydrogen; obtaining images of the mammal; and assessing the images.
  • Figure 1 shows PET quantification results for [ ! *F]-SFB-CTT54 in LNCaP bearing nude mice Top: micro-PETCT (10283, 101210, M3, 8,1 MBq, 50-70 min p.i. l 10325); Bottom: PET quantification results.
  • Figure 2 shows [ ⁇ F]-SFB-hCTT54 in LNCaP bearing nude mice. Top: micro- PETCT ( 10284, 101209, M3, 8.6 MBq, 50-70 min p.L); Bottom: PET quantification results.
  • Figure 3 shows [ lS F]-SFB-CTT54 in LNCaP bearing nude mice. Top: micro- PETCT (1 1001, 1 10325, M3, 4,2 MBq, 50-70 min p.L); Bottom: PET quantification results.
  • Figure 4 shows [ iS F]-SFN-hCTT54 in LNCaP bearing nude mice. Top: micro- PETCT ( 1 1003, 1 10228, M2 NMRJ, 8,8 MBq, 50-70 min p.L.); Bottom: PET quantification results.
  • FIG. 5 shows [ ! S F]-SClFN-hCTT54 in LNCaP bearing nude mice. Top: micro- PETCT (1 1004, 1 10317, M3, [ 18 F]-SClFN-hCTT54, 7.4 MBq, 50-70 min p.L); Bottom: PET qua tification results
  • Figure 6 shows [ ; 8 F]-SClFN-hCTT54 in 22RV1 bearing nude mice. Top: micro- PETCT (1 1 168, 1 1 624, Ml , 8.2 MBq, 50-70 min p.L); Bottom: PET quantification results [0029]
  • Figure 7 shows [' s F]-SFN-hCTT54 in 22RV1 bearing nude mice. Top: micro- PETCT (1 1215, 1 10901 , M2, 6.6 MBq, 50-70 min p.L); Bottom: PET quantification results.
  • Figure 8 shows ['*F]-SClFN-hCTT54 in 786-0 bearing nude mice. Top: micro- PETCT (11084, 1 10509, M7, 7.2 MBq, 50-70 min p.L); Bottom: PET quantification results.
  • the disclosure provides compounds that are in the form of formula
  • R is phenyl or pyridyl, each substituted with either one j F]-fluoro group or one [ :9 F]-fluoro group and optionally substituted with a second group selected from the group consisting of chloro and cyano; and
  • each R is independently hydrogen or a protecting group.
  • a "protecting group” as used herein is substituted benzyl, t-butyl ester, allyl ester, alkyi esters (e.g., methyl, ethyl), fluorenylmethoxycarbonyl groups, and carboxyiic and phosphorus acid protecting groups described in Greene's Protective Groups in Organic Synthesis, 4th Edition (the relevant parts of which are incorporated by reference).
  • Substituted benzyl groups include, but are not limited to, triphenyhnethyl (trityl), diphenylmethyl, o- itrobenzyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, p-nitrobenzyl, p-methoxybenzyl (PMB), 2,6-dimethoxybenzyl, 4-(methylsuifinyl)benzy3, 4-sulfobenzyl, 4-azidomethoxybenzyl, and piperonyl and benzyl protecting groups for carboxyiic and phosphorus acids disclosed in Greene's Protective Groups in Organic Synthesis (the relevant parts of which are incorporated by reference).
  • R is
  • R J is -F or - ;8 F; and R 2 is chloro or cyano
  • R is
  • R J is -F or - ; F; and R is chloro or cyano
  • R is
  • R" is -F or - 1 F; and R ' is cb!oro or cyano.
  • R is w /herein R J is --F or ⁇ - F: and R is chloro or cyano. 8040] in an embodiment of formula (I), R is R 1 , wherein R is -F or - F; and R ⁇ is chloro or cvano.
  • R is N R , wherein R' is ⁇ F or - ' F; and R 2 is chloro or cyano,
  • R is , wherein R" is -F or - ' F; and R 2 is chloro or cvano.
  • R' is -F or - :S F.
  • R J is -F.
  • R is
  • R 3 is -F or - ;8 F.
  • R is
  • R is - F.
  • R ⁇ is -F or - ;8 F.
  • R 1 is -F
  • R J is - 18 F.
  • R is Irs another embodiment of formula (I), R is
  • R is
  • R is 8 F
  • the invention comprises compounds of formula (1) of the formula (T*),
  • R and R are defined according to any one of the embodiments described above for formulae (T), and one, two, or three of the chiral centers 1 *, 2*, and 3* is enantiomericaliy enriched (defined herein as having >50% R or S stereochemistry) or enaniiomericaiiy pure (defined herein as having greater than 90, 91 , 92, 93, 94, 95, 96, 97, 98, or 99% R or S stereochemistry).
  • 1 *, 2*, and 3* are chiral centers that are independently racemic (rac) or in the S or R stereoeoniiguration.
  • compounds according to this aspect include those with the following combinations of stereoconfigurations, and mixtures thereof:
  • the compound can be of the formula (la),
  • the compound can be of the formula (lb),
  • the compound can be of the formula (Ic),
  • the compound can be of the formula (Id),
  • the compound can be of the formula (If),
  • R 1 is hydrogen
  • R 1 is a protecting group
  • R 1 is t-butyl or benzyl.
  • R 1 is t-butyl
  • R 1 is benzyl
  • R is phenyl or pyridyL each substituted with either one [ : S FJ-Fluoro group or one [ l9 F]-Fi oro group and optionaily substituted with a second group selected from the group consisting of chloro and cyano; and each R p is a protecting group (e.g., t-butyl or benzyl); under conditions suitable for removing each of the R P groups.
  • R p is a t-butyl group
  • the method can be maintained under anhydrous conditions to prevent degradation of the compounds as the phosphoramidate moiety is known to be unstable in aqueous acidic media
  • each of the following deprotection conditions can be utilized for removal of t-butyl groups: i) Contacting the compound with an acid selected from the groups consisting of, triiiuoroacetic acid, hydrochloric acid, formic acid, glacial acetic acid, chloroacetic acid, and mixtures thereof;
  • scavengers such as, but not limited to triethylsilane (TES); v) Contacting the compound as in any of the preceding at a temperatures between room temperature (e.g., 25 °C) and 180 °C;
  • TM8-I irimeihyisiiyl iodide
  • TMSOTt trimethylsilyl trifiate
  • TAA triethylamine
  • the conditions include contacting the compound with formic acid. In certain other embodiments, the conditions include contacting the compound with neat formic acid.
  • the conditions include contacting the compound with formic acid at a temperature between about room temperature (e.g., 25 °C) and 100°C. in certain embodiments, the conditions include contacting the compound with formic acid at a temperature between about room temperature (e.g., 25 °C) and 75°C, In certain embodiments, the conditions include contacting the compound with formic acid at a temperature between about 35 °C and 75°C. Tn certain embodiments, the conditions include contacting the compound with formic acid at a temperature between about 40 °C and 60°C. In certain embodiments, the conditions include contacting the compound with formic acid at a temperature between about 45 °C and 55 °C.
  • the conditions include contacting the compound with neat formic acid at a temperature between about room temperature (e.g., 25 °C) and 10Q°C. In certain embodiments, the conditions include contacting the compound with neat formic acid at a temperature between about room temperature (e.g., 25 °C) and 75°C, In certain embodiments, the conditions include contacting the compound with neat formic acid at a temperature between about 35 °C and 75°C, In certain embodiments, the conditions include contacting the compound with neat formic acid at a temperature between about 40 °C and 60°C. In certain embodiments, the conditions include contacting the compound with neat formic acid at a temperature between about 45 °C and 55 °C.
  • the compound can be heated at a desired temperature (e.g., between about 45 °C and 55 °C) for a period of time between about 15 seconds and 15 minutes. In certain embodiment, the heating is for between about 15 seconds and 10 minutes; or 15 seconds and 8 minutes; or 1 minute and 8 minutes; or 2. minutes and 8 minutes; or 3 minutes and 8 minutes; or 4 minutes and 6 minutes; or about 5 minutes.
  • a desired temperature e.g., between about 45 °C and 55 °C
  • the heating is for between about 15 seconds and 10 minutes; or 15 seconds and 8 minutes; or 1 minute and 8 minutes; or 2. minutes and 8 minutes; or 3 minutes and 8 minutes; or 4 minutes and 6 minutes; or about 5 minutes.
  • any solvents and/or acids can be removed from the reaction mixture by methods familiar to those skilled in the art, such as in vacuo removal or by purging the reaction mixture with an inert gas, such as Ar, He, or N 2 .
  • the conditions mclude contacting the compound with trifluoroacetic acid. In certain other embodiments, the conditions include contacting the compound with trifluoroacetic acid in a solvent. In certain embodiments, the solvent is 1 ,2- dichloroethane.
  • the conditions include contacting the compound with trifluoroacetic acid and a scavenger, such as triethylsilane. In certain other embodiments, the conditions include contacting the compound with trifluoroacetic acid and triethylsilane in a solvent. In certain embodiments, the solvent is 1,2-dichloroeihane. [8(587] In certain embodiments, the conditions include contacting the compound with udiluoroacetie acid and triethylsilane in 1 ,2-dichloroethatie ai a temperaiure between about room temperature (e.g., 25 °C) and 150°C.
  • room temperature e.g. 25 °C
  • the conditions include contacting the compound with trifiuoroacetic acid and triethylsilane in 1 ,2-dichforoethane at a temperaiure between about 50 °C and 150°C. In certain embodiments, the conditions include contacting the compound with trifiuoroacetic acid and triethylsilane in 1,2-dichloroethane ai a temperature between about 75 °C and 125°C. In certain embodiments, the conditions include contacting the compound with trifiuoroacetic acid and triethylsilane in 1 ,2-dichioroethane at a temperature between about 90 °C and 1 10°C.
  • the compound can be heated at a desired temperature (e.g., between about 90 °C and 10 °C) for a period of time between about 15 seconds and 15 minutes.
  • a desired temperature e.g., between about 90 °C and 10 °C
  • the heating is for between about 1 minute and 15 minutes: or about 1 minute and 12. minutes; or 5 minute and 15 minutes; or 5 minutes and 12. minutes; or 7 minutes and 12 minutes; or 9 minutes and I I minutes; or about 10 minutes.
  • any solvents and/or acids can be removed from the reaction mixture by methods familiar to those skilled in the art, such as in vacuo removal or by purging the reaction mixture with an inert gas, such as Ar or N 2 .
  • each p is an optionally substituted benzyl group.
  • each R p is a benzyl group.
  • each R ? is a substituted benzyl group.
  • suitable deprotection conditions include, but are not limited to, hydrogenoJysis conditions (e.g., 3 ⁇ 4 and Pd/C) or catalytic hydrogen transfer using ammonium formate and Pd/C. Other hydrogenation catalysis may be used as are familiar to those skilled in the art.
  • alternative hydrogen sources may be used including, but not limited to ammonium formate, sodium formate, or formic acid with triethyiamine. In certain embodiments, the hydrogen source is ammonium formate.
  • the hydrogenation may be undertake in a suitable solvent, selected from, but not limited to, ethanol, tetrahydrofuran, water, or phosphate buffered saline, or a mixture thereof.
  • a suitable solvent selected from, but not limited to, ethanol, tetrahydrofuran, water, or phosphate buffered saline, or a mixture thereof.
  • the deprotection can be setup in a cartridge where the Pd C catalyst is loaded in a layer or distributed in inert material, then, the halogenated or radiolabeled sample (e.g., containing -F or - J 8 F) dissolved in a solvent (such as ethanol), is further dissolved in ammonium formate and Hushed through the cartridge to yield deprotected material without the need for further purification.
  • a solvent such as ethanol
  • Pd/C as a catalyst for deprotection
  • 5 - 10 wt% Pd/C can be used.
  • 10 wt% Pd/C is used.
  • About 0.0.1 to about 0.40 moiar equivalents of Pd/C to the compound being deprotected can be used.
  • about 0.01 to about 0.30 moiar equivalents are used.
  • 8 F label is removed from the compound during the deprotection step (greater than about 90 % yield). In other embodiments, less than about 5 % of the l8 F label is removed from the compound during the deprotection step (greater than about 95 % yield). In other embodiments, less than about 3 % of the i 8 .F label is removed from the compound during the deprotection step (greater than about 97 % yield). In other embodiments, less than about 2 % of the lS F label is removed from the compound during the deprotection step (greater than about 98% yield).
  • less than about 1 % of the ' F label is removed from the compound during the deprotection step (greater than about 99 % yield). In other embodiments, essentially none of the 18 F label is removed from the compound during the deprotection step (essentially quantitative yield) .
  • the deprotection can be completed in less than about 30 minutes.
  • the deprotection step can be completed in less than about 20 minutes, ot about 15 minutes, or about 10 minifies.
  • the deprotection can be completed in between about 1 minute and about 30 minutes; or about 1 minute and about 20 minutes; or about I minute and about 15 minutes; or about 1 minute and about 10 minutes; or about 5 minutes and about 30 minutes; or about 5 minutes and about 20 minutes; or about 5 minutes and about 15 minutes; or about 5 minutes and about 10 minutes.
  • the compound is
  • R is phenyl or pyridyl, each substituted with one leaving group and optionally substituted with a second group selected from the group consisting of chloro and cyano; and each p is a protecting group (e.g., t-butyl or benzyl).
  • R and R p are as defined according to any one of the embodiments described above for formula (II), and the stereoconfiguration of
  • the compound of formula (II) can be of the formula
  • the compound of fonnula (II) can be of the formula
  • the compound of fonnula (II) can be of the formula
  • the compound of formula (II) can be of ihe formula
  • the compound of formula (II) can be of ihe formula
  • the compound of formula (IT) can be of the formula
  • R is
  • R 5 is a leaving group; and R 4 is chloro or cyano.
  • R is
  • R ⁇ is a leaving group; and R is chloro or cyano.
  • R is wherein is a leaving group; and R " is chloro or cyano.
  • R is wherein R 5 is a leaving group; and R *f is chloro or cyano.
  • R is
  • R J is a leaving group; and R 4 is chJoro or cyano.
  • R is , wherein R J is a leaving group; and R" is chloro or cyano.
  • R is , wherein R 3 is a leaving group; and R 4 is chloro or cyano.
  • R " ' is a leaving group
  • R J is a leaving group
  • R is wherein R is a leaving group.
  • a "leaving group” is a chemical entity that is capable of being displaced from a phenyl or pyridyi ring under SjsAr conditions are as familiar to those skilled in the art. For example, see March, J., Advanced Organic Chemistry, 4'" Ed. ( 1992), at pages
  • the leaving group is nitro, trimethyiammonium, trimethylstannyl, benzotriazol- l -yloxy, chloro, bromo, iodo, C-i- Cjoalkylsulfonate, Ci-Cjohaloalkylsulfonate, or phenylsulfonate, wherein the phenyl is optionally substituted with 1, 2, or 3 groups which are each independently halogen or C1 -C4 alkyl (e.g., besylate, tosylate, mesylate (CH3S(0) 2 0 " ) classroom triflate (CF3S(0) 2 0 " ), nonaflate (CF 3 CF 2 CF 2 CF 2 S(0) 2 0 " ), 2,4,6-trimethylbenzenesulfonate, or 2,4,6- triisopropylbenzenesulfonate).
  • 1, 2, or 3 groups which are each independently halogen or C1 -C4 alky
  • R D is trimethyiammonium
  • A- is a monovalent anion
  • a " is a monovalent anion
  • R is is an monovalent anion.
  • R is is an monovalent anion.
  • R is A " is triflate. [0 ⁇ 2 ⁇ Irs an embodiment of formulas (II) and (Ila-d), R is
  • R is
  • R p is t-butyl or benzyl.
  • R p is t-butyl
  • R p is benzyl
  • the monovalent anion is chloride, bromide, iodide, hydrogen sulfate, formate, trifluoromethanesulfonate (i.e., inflate), toluenesulfonate, methanesulfonate, methyl sulfonate, nitrate, benz founded, or acetate.
  • the monovalent anion is iodide, trifluoromethanesulfonate (i.e., triflate), methyl sulfonate, or acetate.
  • the monovalent anion is trifluoromethanesulfonate (i.e., triflate).
  • the fSuorinated compounds (e.g. , of formula (1)) can be prepared according to methods comprising contacting a compound of the formula (II), as defined in any of the preceding embodiments of formula (II) with a fluoride or radiofiuoride source.
  • the compounds can be prepared according to a method comprising contacting a compound of the formula.
  • R is phenyl or pyridyl, each substituted with one leaving group and optionally substituted with a second group selected from the group consisting of chloro and cyano: and each R p is a protecting group (e.g., t-butyl or benzyl);
  • the radiofiuoride source is Na l s F, K l d F, Cs l8 F, tetra(d- C6)alkylammonium 1 " F fluoride, or tetra(C] -C6)alkylphosphonium i8 F fluoride.
  • the fluoride source is NaF, KF, CsF, tetra(C] - C6)alkyiammonium fluoride, or tetraiCi-Celaikyipliosphonium fluoride.
  • a base may be used in combination with the fluoride or radiofiuoride source.
  • Suitable bases include, but are not limited to, potassium carbonate, potassium bicarbonate, potassium oxalate, potassium sulfonates, potassium tert-alkoxylates, cesium carbonate, cesium bicarbonate, tetrabutylammomum hydroxide (TBAOH), te rabutylammonium bicarbonate (TBAHC ( 3 ⁇ 4), and tetrabutylammonium mesylate (TBAOMs).
  • phase transfer catalyst such as an aminopolyether or crown ether, for example, 4,7,13,16,21,24 hexaoxa-1, 10- diazabicyclo[8,8,8]hexacosane (Kryptofix 2,2.2; K222) may be added and the reaction performed in a non protic solvent.
  • the treatment with fluoride or radiofluoride anion can be effected in the presence of a suitable organic solvent such as aeetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, 1 ,2 dimethoxyethane, ethanol, methanol, iso- propanol, n-butanol, t-butanol, amyl alcohol, sulfoiane, N-methylpyrrolidone, toluene, benzene, dichlorobenzenes, dichloromethane, xylenes, or mixtures thereof, at a non-extreme temperature, for example, 15 °C to 180 °C, preferably at ambient to elevated temperatures, such as 20 °C to 150 °C; or 20 °C to 120 °C; or 20 °C to 100 °C; 20 °C to 70 °C.
  • the base used in combination with the fluoride or radiofluoride source is cesium carbonate or tetrabutylammonium bicarbonate. In one embodiment, the base used in combination with the fluoride or radioiluoride source is cesium carbonate. In one embodiment, the base used in combination with the fluoride or radiofluoride source is tetrabutylammonium bicarbonate.
  • the base used in combination with the fluoride or radiofluoride source is cesium carbonate or tetrabutylammonium bicarbonate at a temperature between about 50 and 70°C. In one embodiment, the base used in combination with the fluoride or radiofluoride source is cesium carbonate at a temperatitre between about 50 and 70°C. In one embodiment, the base used in combination with the fluoride or radiofluoride source is tetrabutylammonium bicarbonate at a temperature between about 50 and 70°C.
  • the base used in combination with the fluoride or radiofluoride source is tetrabutylammonium hydroxide.
  • the base used in combination with the fluoride or radioiluoride source is tetrabutylammonium hydroxide at a temperature between about 90 °C and 110 °C (e.g., 100°C).
  • the base used in combination with the fluoride or radiofluoride source is tetrabutylammonium hydroxide at a temperature between about 90 °C and 1 10 °C (e.g., i00°C), where the iemperature is maintained for about 5 minuies to about 15 minutes (e.g., about 10 min.).
  • excess fluoride or radiofiuoride anion may optionally be removed from the solution of the fluoride-labeled or radiofluoride-labeled compound by any- suitable means, for example by distillation, chromatography such as by silica gel and C-18 reversed phase chromatography, or alternatively by ion- exchange chromatography or solid phase absorbents, for example by anionic exchange resin or a quaternary alkylated amino resin.
  • An anionic exchange resin is a resin containing a cation group, typically amino groups that are protonated to give ammonium salt or quaternary alkylated amino groups, which attract and retain anions present in the solution surrounding the said resin.
  • a resin is organic polymer or functionalized silica that is insoluble in most organic solvents, aqueous solutions and mixtures thereof.
  • a quaternary alkylated amino resin is a resin that it funetionalized with one or more amino groups and these amino groups are substituted independentl with three alkyl or alkyiaryl groups or mixture thereof to give an ammonium salt (N ' R ! R 2 R'R 4 ) where are R 1 is the resin R " , R' and R can be methyl, ethyl, propyl, butyl, benzyl, ethylphenyl.
  • a resin or solid, that allows trapping of 1 S F fluoride may be used, such as a QMA or PS-30 cartridge.
  • chromatography over SepPakTM cartridges (Waters Corp., Milford, MA: e.g., Cjg Silica, FlorisilTM, or Alumina A, B, N chemistries) may be used as are familiar to those skilled in the art.
  • Suitable ion-exchange resins include BIO-RAD AG 1 -X8 or Waters QMA and suitable solid phase absorbents include alumina.
  • the disclosure provides compounds that are
  • the compounds described in the examples herein comprise a radiolabeled pendant group connected to the parent structure (PMSA inhibitor or fragment thereof) via an amide bond.
  • a radiolabeled pendant group connected to the parent structure (PMSA inhibitor or fragment thereof) via an amide bond.
  • examples of structures of such pendant groups alone can be found in the literature as substrates for fluoride substitution ( l s F or 19 F)
  • few examples have an amide bond on the pendant group.
  • the reactivity of F with pendant groups alone or without an amide substituent on the pendant group does not allow one to predict if the same results would be obtamed when the amide group is present on the pendant groups.
  • the literature precedent for F reaction with a pendant group alone did not correlate to our results when that pendant group was attached through an amide bond to a model peptide mimic.
  • Protecting groups on the PSMA inhibitor can be later removed after the incorporation of the radiolabel ( 1S F) on a pendant group. Furthermore, once the radiolabel has been incorporated into a pendant group attached to a PSMA inhibitor precursor, a final deprotection step can remove all the protecting groups on the PSMA inhibitor in a single step (e.g., t-butyl or benzyl esters).
  • the deprotection reaction is preferably rapid, e.g., occurring within a fraction of the half-life of the radionuclide on the pendant group (e.g., t],? ⁇ 1 10 min. for 18 F); and (2) the conditions of deprotection should not result in the loss of the radiolabel on the pendant group.
  • the compounds herein can be deproteeted, for example, using catalytic hydrogen transfer. Conventional hydrogenolysis with H 2 gas and Pd/C is known to result in dehalogenation on aromatic rings. In fact we have observed this with pendant groups substituted with fluoride on model compounds. However, we have found conditions for catalytic hydrogen transfer in which defluorination is minimized and the reaction is complete within 20 min, and as little as 6 min without the loss of fluoride.
  • the present disclosure provides methods for detecting and/or identifying cells presenting PSMA comprising contacting a cell suspected of presenting PSMA with a compound as discussed above, or a composition comprising the compound.
  • the methods are suitable for imaging studies of PSMA inhibitors, for example, by studying competitive binding of non-radiolabeled inhibitors.
  • the methods are suitable for imaging of cancer, tumor or neoplasm.
  • the cancer is selected from eye or ocular cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer and bladder cancer, oral cancer, benign and malignant tumors, stomach cancer, liver cancer, pancreatic cancer, lung cancer, corpus uteri, ovary cancer, prostate cancer, testicular cancer, renal cancer, brain cancer (e.g., gliomas), throat cancer, skin melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma, basal cell carcinoma and squamous cell carcinoma, small ceil lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer, la
  • the methods are suitable for imaging any physiological process or feature in which PSMA is involved.
  • imaging methods are suitable for identification of areas of tissues or targets which express high concentrations of PSMA.
  • Typical applications include imaging glutamateric neurotransmission, presynaptic glutamatergic neurotransmission, malignant tumors or cancers that express PSMA, prostate cancer (including metastasized prostate cancer), and angiogenesis.
  • Essentially all solid tumors express PSMA in the neovasculture. Therefore, present methods can be used to image nearly all solid tumors including lung, renal cell, glioblastoma, pancreas, bladder, sarcoma, melanoma, breast, colon, germ cell, pheochromocytoma, esophageal and stomach.
  • certain benign lesions and tissues including endometrium, schwannoma and Barrett's esophagus can be imaged according to the present methods,
  • the radiolabeled compound is detected by positron emission tomography (PET).
  • PET positron emission tomography
  • the radiolabeled compound is detected by positron emission tomography - computed tomography (PET/CT).
  • PET/CT positron emission tomography - computed tomography
  • the subject of the methods may be a human, rat, mouse, cat, dog, horse, sheep, cow, monkey, avian, or amphibian.
  • the cell is in vivo or in vitro.
  • the cells being images or detected are in vivo.
  • Typical subjects to which compounds described herein may be administered will be mammals, particularly primates, especially humans.
  • mammals particularly primates, especially humans.
  • livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats.
  • rodents e.g. mice, rats, hamsters
  • rabbits primates, and swine such as inbred pigs and the like.
  • body fluids and ceil samples of the above subjects will be suitable for use such as mammalian, particularly primate such as human, blood, urine or tissue samples, or blood urine or tissue samples of the animals mentioned for veterinary applications.
  • a kit can be provided that contains from about 1 to about 30 mCi of the radionuclide-labeled imaging agent described above, in combination with a pharmaceutically acceptable carrier.
  • the imaging agent and carrier may be provided in solution or in lyophilized form.
  • the kit may optionally contain a sterile and physiologically acceptable reconstitution medium such as water, saline, buffered saline, and the like.
  • the kit may provide a compound, as discussed above, in solution or in lyophilized form, and these kit components may optionally contain stabilizers such as aCi, silicate, phosphate buffers, ascorbic acid, gentisic acid, and the like. Additional stabilization of kit components may be provided in this embodiment, for example, by providing the reducing agent in an oxidation- resistant form. Determination and optimization of such stabilizers and stabilization methods are well within the level of skill in the art.
  • a kit provides a non-radiolabeled precursor to be combined with a radiolabeled reagent on-site, such as Nai 1 & F] or K['*F].
  • the radiolabeled compounds herein may be used in accordance with the methods described herein by one of skill in the art. Images can be generated by virtue of differences in the spatial distribution of the imaging agents which accumulate at a site when contacted with PSMA.
  • the spatial distribution may be measured using any means suitable for the particular label, for example, a PET apparatus.
  • the extent of accumulation of the imaging agent may be quantified using known methods for quantifying radioactive emissions.
  • a particularly useful imaging approach employs more than one imaging agent to perform simultaneous studies.
  • a detectably effective amount of the imaging agent is administered to a subject.
  • a detectably effective amount is an amount sufficient to yield an acceptable image using equipment which is available for clinical use.
  • a detectably effective amount of an imaging agent may be administered in more than one injection.
  • the detectably effective amount of the imaging agent can var according to factors such as the degree of susceptibility of the individual, the age, sex, and weight of the individual, idiosyncratic responses of the individual, and the dosimetry . Detectably effective amounts of the imaging agent can also vary according to instrument and film-related factors. Optimization of such factors is well within the level of skill in the art.
  • the amount of imaging agent used for diagnostic purposes and the duration of the imaging s tudy will depend upon the radionuclide used to label the agent, the body mass of the patient, the nature and severity of the condition being treated, the nature of therapeutic treatments which the patient has undergone, and on the idiosyncratic responses of the patient. Ultimately, the attending physician will decide the amount of imaging agent to administer to each individual patient and the duration of the imaging study. In certain embodiments, a safe and sufficient amount of the compounds herein can be in the range of from about 0,01 mg to about 200 mg per dose.
  • the compounds herein described may have one or more charged atoms.
  • the compounds may be zwitterionic, but may be neutral overall.
  • Other embodiments may have one or more charged groups, depending on the pH and other factors.
  • the compound may be associated with a suitable counter- ion.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as a, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • Counter-ions may be changed, for example, by ion-exchange techniques such as ion-exchange chromatography. All zwitterions, salts and counter-ions are intended, unless the counter-ion or salt is specifically indicated.
  • the salt or counter-ion may be pharmaceutically acceptable, for administration to a subject. Pharmaceutically acceptable salts are discussed later.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyi, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpenty], 2,3-dimethylpentyl, n-heptyl, n-oetyi, n-nonyl, and n-decyl.
  • haloalkyl as used herein, means an alkyl group, as defined herein, substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) halogen groups (i.e., F, CI, Br, and/or I).
  • haloalkyl groups include, but are not limited to fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, and n- nonafluorobutyl.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a ceil in a ceil culture.
  • an in vivo cell is a ceil living in an organism such as a mammal.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting PSMA with a compound includes the administration of a compound described herein to an individual or patient, such as a human, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing PSMA.
  • pharmaceutically acceptable salt refers to both pharmaceutically acceptable acid and base addition salts and solvates.
  • Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfuric, formic, trifluoromethanesulfonic (i.e., triflic), toluenesulfonic, methanesuifonic, methyl sulfonate, nitric, benzoic, citric, tartaric, maJeic, hydroiodic, alkanoic such as acetic, HOOC-(CH 2 ) n -COOH where n is 0-4, and the like.
  • “Pharmaceutically acceptable salts” also include, for example, salts formed by the quaternization (e.g., alkylation) of a suitable site in the compound itself, such as methylation of a dimethylamine to form a trimethyianimonium group.
  • the counterion can be, for example, but not limited to, chloride, phosphate, hydrogen phosphate, bromide, sulfate, hydrogen sulfate, sulfmaie, formate, trifluoromethanesulfonate (i.e., triflate), toiuenesulfonate, methanesulfonate, methyl sulfonate, nitrate, benzoate, citrate, tartarate, maleate, iodide, acetate, and the like.
  • Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like.
  • the pharmaceutically acceptable salt is a potassium salt.
  • compositions suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bactenostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intra vesically or intrathecally.
  • a "pharmaceutically acceptable carrier” refers to a biocompatible solution, having due regard to sterility, piEta], isotonicity, stability, and the like and can include any and all solvents, diluents (including sterile saline, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection and other aqueous buffer solutions), dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and the like.
  • the pharmaceutically acceptable carrier may also contain stabilizers, preservatives, antioxidants, or other additives, which are well known to one of skill in the art, or other vehicle as known in the art.
  • the collected fraction was diluted with 25 mL water, passed through a CI 8 light (SepPak CI 8 light (Waters), preconditioned with 5 mL Ethanol and 10 mL water), the SPE was washed with 5 mL water, and then eiuted with 1 mL acetonitrile. The acetonitrile eluent was passed the solution through a dry SPE (255.4 MBq).
  • This vial was heated under gentle N 2 stream for 10 min at 140°C (heating block temperature) and 1 mL acetonitnle was added to the vial. The vial was then heated under gentle N 2 stream for 5 min at 140 °C (heating block temperature) and to cooled at room temperature over 5 min. in a lead pig
  • the PBS solution was diluted with 4 mL PBS and purified by prep FiPLC, collecting the main peak (62.25 MBq).
  • the collected fraction was diluted with 15 mL 0.02M K2CO 3 and loaded on QMA (preconditioned with 5 mL Methanol and 10 mL 0.02M K 2 C(3 ⁇ 4), the QMA washed with 2 mL water (load: 19.42 MBq, wash: 1.035 MBq, QMA: 32.84 MBq) and product eluted with 0.3 mL of 0.5 M NaCl into 0.2 mL PBS buffer (32.24 MBq).
  • the PBS solution was diluied with 4 mL PBS and purified by prep HPLC, collecting the main peak (54.50 MBq). diluted the fraction with 15 ml. 0.02. M K ⁇ ( ' () ; and loaded on QMA (preconditioned with 5 mL methanol and 10 mL 0.02 M K 2 C0 3 ) washed with 2 mL water (load: 19.83 MBq, wash: 0.85 MBq) and product eluted with 0.3 mL 0.5M NaCl into 0.2 mL PBS buffer (32.04 MBq).
  • the ethanol solution was concentrated under gentle N 2 -stream for 10 min. at 6()°C. 100 ⁇ trifluoroacetic acid, 100 ⁇ 1 ,2-dichloroethane, and 50 ⁇ , triethylsilane were added and the solution maintained for 10 min at 10Q°C. The solution was concentrated under gentle N 2 -stream for 10 min. at 80°C, and redissolved in 250 ⁇ PBS. The PBS solution was diluted with 4 mL PBS and purified by prep HPLC, collecting the main peak (60.83 MBq).
  • the collected fraction was diluted the fraction with 15 mL 0.02 M K >( O - and loaded on QMA (preconditioned with 5 mL methanol and 10 mL 0.02 M K2CO3).
  • the QMA was washed with 2 mL water (QMA: 41 .1 1 MBq) and product eluted with 0.3 mL of 0.5M NaCi into 0.2 mL PBS buffer (38.52 MBq).
  • the tBu protecting group was examined. Due to the acidic pH stability noted above, the tBu protecting group was considered a viable protecting group. It was noted that the hCTT54 scaffold was stable when treated to labeling conditions with tBu protecting groups suggesting a sterie block to the decomposition mechanism at work with the benzyl protecting groups.
  • the IC 5 o for CTT-54 was 12 iiM using PSMA isolated from LNCaP cells as a membrane fraction. This was consistent with the IC 50 value of 14 nM that was obtained using purified PSMA. Methods for IC1 ⁇ 2o determinations with purified PSMA or PSMA from the cell membrane fraction of LNCaP cells are described below.
  • a typical incubation mixture (final volume 250 was prepared by the addition of either 25 of an inhibitor solution or 25 TRIS buffer (50 mM, pH 7.4) to 175 ⁇ _ TRIS buffer (50 mM, pH 7.4 containing 1% Triton X-100) in a test tube.
  • PABGgG 25 , nL, 10 ⁇
  • the enzymatic reaction was initiated by the addition of 25 ⁇ _ of the PSMA working solution.
  • the final concentration of PABGgG was 1 ⁇ while the enzyme was incubated with five serially diluted inhibitor concentrations providing a range of inhibition from 10% to 90%.
  • the goal of the study was to demonstrate proof of concept for the novel homoserine class of 1S F labeled phosphoramidate molecules in vivo.
  • three compounds of the homoserine class (SFB-hCTT54, SFN-hCTT54, and SCLFN-hCTT54) were tested in nude mice bearing human tumor xenografts (LNCaP, 22RV 1) and compared to SFB-CTT54. All compounds tested were produced by indirect radiolabeling procedures described above.
  • LNCaP LNCaP. Mice (BALB/c nu/nu, provided by Taconic or Janvier, male, 7-8 weeks), were inoculated ⁇ weeks before the PET study by s.c. injection of 1x107 LNCaP cells (human prostate cancer) in a volume of 1 ⁇ Matrigei into the right shoulder and allowed to grow for approximately four weeks. 2-4 days before inoculation of the tumor cells, a testosterone pellet (Innovative Research of America, Cat.# NA-151) was implanted.
  • 1x107 LNCaP cells human prostate cancer
  • PET/CT images were analyzed by defining regions of interest (ROI) and quantifiying (racer uptake (%ID/g, mean averaged over time) by the instrument software.
  • ROI regions of interest
  • racer uptake %ID/g, mean averaged over time
  • SFN-hCTT54 which showed good tumor uptake (mean 2.8 ⁇ 1.0 %ID/g), excellent tumor to blood ratios (mean 52.9 ⁇ 15.5), and low uptake into bone (mean 0.1 ⁇ 0.090 %ID/g) pointing to little defluorination and high stability of the compound.
  • SFN-hCTT54 and SClFN-hCTT54 were tesied in 22RV1 xenografts ( 1 1 168, 1 1215). PSMA expression in 22RV1 xenografts was reported to be considerably lower compared to LNCaP xenografts (Regino et al. Curr Radiopharm. 2009 Jan;2(l):9-17). Nevertheless, imaging of 22RV1 tumors was possible with both compounds, although, as expected, tumor uptake values were lower compared to LNCaP xenografts.
  • Table 1 Summary of microPET/CT studies in tumor bearing nude mice.

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Abstract

La présente invention concerne des composés tels que définis dans la description qui sont utiles dans (1) des méthodes de diagnostic permettant la détection et/ou l'identification de cellules présentant l'antigène prostatique spécifique membranaire (PSMA) ; et (2) des procédés de préparation desdits composés.
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WO2014143736A1 (fr) * 2013-03-15 2014-09-18 Cancer Targeted Technology Llc Agents d'imagerie par tep ciblés sur le psma marqués au 18f
CN105308056A (zh) * 2013-03-15 2016-02-03 癌靶技术有限责任公司 18f-标记的靶向psma的pet成像剂
CN105308056B (zh) * 2013-03-15 2018-03-20 癌靶技术有限责任公司 18f‑标记的靶向psma的pet成像剂
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CN109803973A (zh) * 2016-08-10 2019-05-24 癌靶技术有限责任公司 螯合psma抑制剂
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CN109369432B (zh) * 2018-11-02 2021-06-25 永农生物科学有限公司 (s)-4-氯-2-氨基丁酸酯的制备方法
WO2022207906A1 (fr) 2021-04-02 2022-10-06 Advanced Accelerator Applications Procédés de diagnostic du cancer de la prostate

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