WO2000071171A2 - Ligands sigma-1 utiles pour determiner l'etat de proliferation de cellules cancereuses - Google Patents

Ligands sigma-1 utiles pour determiner l'etat de proliferation de cellules cancereuses Download PDF

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WO2000071171A2
WO2000071171A2 PCT/US2000/013834 US0013834W WO0071171A2 WO 2000071171 A2 WO2000071171 A2 WO 2000071171A2 US 0013834 W US0013834 W US 0013834W WO 0071171 A2 WO0071171 A2 WO 0071171A2
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compound
alkyl
sigma
aryl
alkoxy
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PCT/US2000/013834
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WO2000071171A3 (fr
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Robert H. Mach
Yunsheng Huang
Steven R. Childers
Kenneth T. Wheeler
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Wake Forest University
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Publication of WO2000071171A3 publication Critical patent/WO2000071171A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Definitions

  • S-phase fraction is an objective method for measuring the proliferative status of tumors
  • 30-40% of biopsy samples are unevaluable for flow cytometric analysis.
  • tissue sampling by biopsy can be problematic since most tumors are heterogeneous, and consist of both proliferative and nonproliferative cells. Therefore, tissue samples obtained from a tumor biopsy may not be representative of the entire tumor cell population.
  • Imaging procedures that avoid many of the problems associated with traditional procedures include single photon emission computed tomography (SPECT) and positron emission tomography (PET). Unlike flow cytometry of biopsy samples, which sample only a fraction of the tumor, SPECT and PET can image and provide information about an entire tumor.
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • Another alternate approach for imaging tumors is the use of radiolabeled small molecules that possess a high affinity for receptors that are abnormally expressed in tumor cells.
  • a number of studies have reported an overexpression of sigma receptors in a variety of human and murine tumors.
  • BJ. Nilner, et al. Cancer Research, 1995, 408-413 disclose that tumor cell lines of various tissue origins and species express sigma- 1 and sigma-2 receptors in high density.
  • sigma- 1 sites were disclosed to be expressed in numerous cell lines, including T47D breast ductal carcinoma cells, MCF-7 breast adenocarcinoma cells showed little or no binding of [ 3 H](+)-pentazocine, indicating the absence of sigma- 1 receptors in these cells.
  • R ] is hydrogen, (C,-C 6 )alkyl, aryl, or aryl(C C 6 )alkyl;
  • R 2 is aryl or heteroaryl
  • A is NE ⁇ , -O-, CR b R c , or -S-;
  • B is NR a , -O-, CR b R c , or -S-;
  • each R a is independently hydrogen, or (C,-C 6 )alkyl;
  • each R b is independently hydrogen, hydroxy, (C,-C 6 )alkyl, or (C,- C 6 )alkoxy;
  • each R c is independently hydrogen, or (C C 6 )alkyl; wherein any aryl or heteroaryl is optionally substituted with 1, 2,
  • R is not benzyl, when A is NH, B is CH 2 , C is oxo, and R 2 is phenyl, 1-naphthyl, 2-naphthyl, 2-thiophenyl, 3-thiophenyl, 2-pyridinyl, 3-, pyridinyl, 4-pyridinyl, 4-imidazolyl, 2-nitrophenyl, 3 nitrophenyl, 4-nitrophenyl, 4-(l-NO 2 , 3-NO 2 -P
  • the present invention also provides for a compound of formula I:
  • R j is hydrogen, (C,-C 6 )alkyl, aryl, or aryl(C r C 6 )alkyl;
  • R 2 is aryl or heteroaryl;
  • A is NR,, -O-, CR b R c , or -S-;
  • B is NR,, -O-, CR b R c , or -S-;
  • each R- j is independently hydrogen, or (C r C 6 )alkyl;
  • each R b is independently hydrogen, hydroxy, (C r C 6 )alkyl, or (C r C 6 )alkoxy;
  • each R c is independently hydrogen, or (C r C 6 )alkyl; wherein any aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, (C C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkanoyl, (C,-C 6 )alkanoyloxy, (C r C 6
  • the present invention also provides for a compound of formula I:
  • R is hydrogen, (C r C 6 )alkyl, aryl, or aryl(C r C 6 )alkyl;
  • R 2 is aryl or heteroaryl;
  • A is NR a , -O-, CR b R c , or -S-;
  • B is NR a , -O-, CR b R c , or -S-;
  • any aryl or heteroaryl of R 2 or heteroaryl of R is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, (C r C 6 )alkyl, (C,-C 6 )alkoxy, (C,-C 6 )alkanoyl, (C,- C 6 )alkanoyloxy, (C ⁇ C ⁇ alkoxycarbonyl, and methylenedioxy; and wherein any aryl or heteroaryl of R 2 or heteroaryl of R, is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, (C r C 6 )alkyl, (C,-C 6 )alkoxy, (C,-C 6 )alkanoyl, (C,- C 6 )
  • the present invention also provides for a compound of formula I:
  • R [ is hydrogen, (C,-C 6 )alkyl, aryl, or aryl(C,-C 6 )alkyl;
  • R 2 is aryl or heteroaryl;
  • A is-O-, CR b R c , or -S-;
  • B is NR a , -O-, CR b R c , or -S-;
  • each R a is independently hydrogen, or ( -C ⁇ alkyl;
  • each R b is independently hydrogen, hydroxy, (C,-C 6 )alkyl, or (C,- C 6 )alkoxy;
  • each R c is independently hydrogen, or (C,-C 6 )alkyl; wherein any aryl or heteroaryl is optionally substituted with 1, 2,
  • substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, ( -C ⁇ alkyl, (C C 6 )alkoxy, (C r C 6 )alkanoyl, ( -C ⁇ alkanoyloxy, (C,-C 6 )alkoxycarbonyl, and methylenedioxy; or a pharmaceutically acceptable salt thereof.
  • the present invention also provides for a compound of formula I:
  • R is hydrogen, (C,-C 6 )alkyl, aryl, or aryl(C r C 6 )alkyl;
  • R 2 is aryl or heteroaryl;
  • A is NR a , -O-, CR ⁇ , or -S-;
  • B is -O- or -S-;
  • the present invention also provides for the compound N-(l- benzylpiperidin-4-yl)-2-fluorophenylacetamide, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides for the compound 18 F-N-(1- Benzylpiperidin-4-yl)-2-fluorophenylacetamide, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a detectably labeled compound of the present invention (e.g., sigma-1 ligand), and a pharmaceutically acceptable diluent or carrier.
  • the present invention also provides for a compound of the present invention that is useful in medical therapy.
  • the present invention also provides for a detectablt labeled compound of the present invention that is useful in medical imaging.
  • the present invention also provides for a detectablt labeled compound of the present invention that is useful to determine the proliferative status of a tumor (e.g., solid tumor) that comprises cells that express sigma-1 receptors.
  • the proliferative status of a tumor is determined by: (a) contacting (e.g., in vivo or in vitro) the cells with the compound , and (b) determining the extent to which the compound binds to the cells, wherein the extent provides a measure of the proliferative status of the tumor.
  • the compound can be contacting is.
  • the invention also provides a method for determining the proliferative status of cancer cells that express sigma-1 receptors, comprising:
  • the invention also provides novel compounds of formula (I), as described herein, both labeled and unlabeled.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a detectably labeled sigma-1 ligand, and a pharmaceutically acceptable carrier.
  • the invention also provides a method for determining the proliferative status of cancer cells that express sigma-1 receptors and sigma-2 receptors, comprising:
  • the invention also provides a method for determining the proliferative status of cancer cells that express sigma-1 receptors and sigma-2 receptors, comprising:
  • the invention also provides a method for inhibiting the growth of cancer cells (e.g., breast cancer cells, prostate cancer cells, and/or bladder cancer cells) that express sigma-1 receptors comprising administering to a mammal in need of such treatment an effective inhibitory amount of a sigma-1 ligand labeled with a therapeutic radionuclide (e.g. Rhenium- 186 or Yttrium-90), or a pharmaceutically acceptable salt thereof.
  • a therapeutic radionuclide e.g. Rhenium- 186 or Yttrium-90
  • the invention also provides the use of a detectably labeled sigma- 1 ligand (preferably a selective sigma-1 ligand or a compound of formula I) to prepare a medicament useful for determining the proliferative status of cancer (e.g., breast cancer, prostate cancer, and/or bladder cancer) cells.
  • a detectably labeled sigma- 1 ligand preferably a selective sigma-1 ligand or a compound of formula I
  • cancer e.g., breast cancer, prostate cancer, and/or bladder cancer
  • the invention also provides the use of a combination of 1) a detectably labeled sigma-1 ligand (preferably a selective sigma-1 ligand or a compound of formula I), and 2) a sigma-2 ligand, to prepare a medicament useful for determining the proliferative status of cancer (e.g., breast cancer, prostate cancer, and/or bladder cancer) cells.
  • a detectably labeled sigma-1 ligand preferably a selective sigma-1 ligand or a compound of formula I
  • a sigma-2 ligand to prepare a medicament useful for determining the proliferative status of cancer (e.g., breast cancer, prostate cancer, and/or bladder cancer) cells.
  • the invention also provides the use of a detectably labeled sigma- 1 and sigma-2 ligand to prepare a medicament useful for determining the proliferative status of cancer (e.g., breast cancer, prostate cancer, and/or bladder cancer) cells.
  • cancer e.g., breast cancer, prostate cancer, and/or bladder cancer
  • Figure 1 illustrates the results of a tissue culture sigma-1 receptor binding test.
  • Figure 2 shows the relative density of sigma-1 and sigma-2 receptors from blocking studies in mouse brain and mouse mammary adenocarcinoma tumors in nude mice.
  • Figure 3 shows F-l 8 labeled tumor uptake of a specific compound of the present invention
  • Figure 4 illustrates specific compounds of the present invention which are compounds of formula I labeled with a metal chelating group comprising a radionuclide M.
  • sigma-1 receptor density is a biomarker of cancer cell proliferation, and herein discloses a method to assess the proliferative status of cancer cells using a detectably labeled sigma-1 ligand.
  • previous studies suggest that sigma-1 receptors are not expressed by MCF-7 breast cancer cells, it has been determined that sigma-1 receptors on breast cancer cells are unstable under the isolation and storage conditions typically used for such cells.
  • sigma-1 selective ligands are useful for assessing the proliferative status of breast cancer cells as well as other sigma-1 expressing cancer cells.
  • sigma-1 ligand comprises any compound that is capable of binding to sigma-1 receptors to a measurable degree. Suitable sigma-1 ligands are known in the art, for example, see Y. Huang et al., Poster Number MEDI 055, presented at the 213th American
  • the compound binds selectively to sigma-1 receptors over sigma-2 receptors.
  • a compound's ability to bind to sigma-1 and sigma-2 receptors can be determined using binding assays that are known in the art (see for example, Y. Huang, et al., J. Med. Chem., 1998, 41, 13, 2361-2370) or can be determined using binding assays similar to those described hereinbelow.
  • Preferred sigma-1 ligands bind at least 2, at least 3, at least 5, at least 10, or at least 25 times more readily to a sigma-1 receptor than to a sigma-2 receptor.
  • a specific sigma-1 ligand that can be detectably labeled and used in the methods of the invention is a compound of formula I:
  • R j is hydrogen, (C,-C 6 )alkyl, aryl, or ary ⁇ C j -C ⁇ alkyl;
  • R 2 is aryl or heteroaryl;
  • A is NR a , -O-, CR b R c , or -S-;
  • B is NR a , -O-, CR b R c , or -S-;
  • Radioisotope can be incorporated into said compound or appended to said compound of formula I using techniques well known in the art, for example, techniques analogous to those described in Arthur Murry III, D. Lloyd Williams; Organic Synthesis with Isotopes, vol. I and II, Interscience Publishers Inc., N.Y. (1958) and Melvin Calvin et al. Isotopic Carbon John Wiley and Sons Inc., N.Y. (1949). Any radioisotope capable of being detected in a diagnostic procedure can be employed as a label.
  • suitable radioisotopes include: carbon-11, fluorine-18, fluorine-19, iodine-123 and iodine-125.
  • a compound of formula I may be labeled by appending one or more radioisotopes of a halogen (e.g. iodine-123) to an aromatic ring.
  • a compound of formula I can be labeled with a metal chelating group optionally comprising a radionuclide, such as a metallic radioisotope.
  • Such chelating groups are well known in the art and include polycarboxylic acids such as for example diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, and the like, or analogs or homologs thereof, as well as the chelating groups disclosed in S. Meegalla et al. J. Am. Chem. Soc. 117 11037-11038, 1995 and in S. Meegalla et al. Bioconjugate Chem. 7:421- 429, 1996.
  • the chelating group or the radionuclide therein may be attached directly to a compound of formula I, or may be attached to a compound of formula I by means of a divalent or bifunctional organic linker group.
  • Such bifunctional linker groups are well known in the art and are preferably less than about 50 angstroms in length.
  • suitable linker groups include 2- aminoethyl, 2-mercaptoethyl, 2-aminopropyl, 2-mercaptopropyl, e-amino caproic acid, 1 ,4-diaminobutane, and the like.
  • the linker group may be attached at any synthetically feasible position on the compound of formula I.
  • the linker group is attached to the piperidine nitrogen of a compound of formula I by replacement of the R, substituent.
  • a compound of formula I bearing a linker group in place of R can conveniently be prepared from a corresponding compound of formula I wherein R, is hydrogen by alkylation or acylation of the piperidine nitrogen. Suitable conditions for the acylation or alkylation of secondary amines are known in the art.
  • Figure 4 shows four compounds of the invention (II, III, IV, and N) which are compounds of formula I labeled with a metal chelating group comprising a radionuclide M. Any metallic radioisotope capable of being detected in a diagnostic procedure can be employed as a radionuclide.
  • radioisotopes include: Antimony-124, Antimony-125, Arsenic-74, Barium-103, Barium-140, Beryllium-7, Bismuth-206, Bismuth-207, Cadmium-109, Cadmium-115m, Calcium-45, Cerium-139, Cerium-141, Cerium-144, Cesium- 137, Chromium-51, Cobalt-56, Cobalt-57, Cobalt-58, Cobalt-60, Cobalt-64, Erbium-169, Europium-152, Gadolinium- 153, Gold-195, Gold-199, Hafnium- 175, Hafhium-175-181, Indium-I l l, Iridium-192, Iron-55, Iron-59, Krypton-85, Lead-210, Manganese-54, Mercury-197, Mercury-203, Molybdenum-99, ⁇ eodymium-147, Neptunium-237, Nickel-63, Niobium-95, O
  • Suitable nuclear medicine imaging techniques include Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), Planar scintigraphy, and magnetic resonance imaging (see E. Bombardieri, et al. eur. J. Nuc. Med., 1997, 24, 809-824).
  • Preferred imaging techniques include SPECT and PET, which can image and provide information about an entire tumor. The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and ⁇ (X) wherein each X is absent or is H, O, ( -C ⁇ alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • (C r C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C,-C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • ( -C ⁇ alkanoyl can be acetyl, propanoyl or butanoyl;
  • (C ⁇ C ⁇ alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
  • the invention provides novel compounds of formula I as well as novel detectably labeled compounds of formula I.
  • Unlabeled compounds of formula I are useful as intermediates for preparing labeled compounds of formula I.
  • Certain compounds of formula I were disclosed as potential imaging agents by Y. Huang et al, Poster Number MEDI 055, presented at the 213th American Chemical Society Meeting, April 13-17, 1997, San Francisco, California.
  • R ⁇ is benzyl, when A is NH, B is CH 2 , C is oxo, and R 2 is phenyl, 1-naphthyl, 2-naphthyl, 2-thiophenyl, 3-thiophenyl, 2-pyridinyl, 3-, pyridinyl, 4-pyridinyl, 4-imidazolyl, 2-nitrophenyl, 3 nitrophenyl, 4-nitrophenyl, 4-(l-NO 2 , 3-NO 2 -Ph), 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-tromethoxyphenyl, 4-methylthiophenyl, 2- hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3- chlor
  • R t is benzyl, when A is NH, B is CH 2 , C is oxo, and R 2 is 2-chlorophenyl, 3-chlorophenyl, 4- chlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2- bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4- difluorophenyl, 3,5-difluorophenyl, 2-trifluoromethylphenyl
  • R is hydrogen, (C,-C 6 )alkyl, aryl, or aryl(C,-C 6 )alkyl;
  • R 2 is aryl or heteroaryl;
  • A is NR a , -O-, CR b R c , or -S-;
  • B is NR,, -O-, CR ⁇ , or -S-;
  • each R ⁇ is independently hydrogen, or (C C 6 )alkyl;
  • each R b is independently hydrogen, hydroxy, (C 1 -C 6 )alkyl, or ( -C ⁇ alkoxy;
  • each R c is independently hydrogen, or (C,-C 6 )alkyl; wherein any aryl of R, is substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoro
  • R ) is benzyl, which is substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, (C,-C 6 )alkyl, (C,-C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C,-C 6 )alkanoyloxy, (C j -C ⁇ alkoxycarbonyl, and methylenedioxy; or a pharmaceutically acceptable salt thereof.
  • R is benzyl, which is substituted with 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, (C r C 6 )alkyl, ( -C ⁇ alkoxy, (C,-C 6 )alkanoyl, (C r C 6 )alkanoyloxy, (C,-C 6 )alkoxycarbonyl, and methylenedioxy.
  • R is hydrogen, (C,-C 6 )alkyl, aryl, or aryl(C r C 6 )alkyl
  • R 2 is aryl or heteroaryl
  • A is-O-, CR b R c , or -S-
  • B is NR a , -O-, CR b R c , or -S-
  • each R a is independently hydrogen, or (C j -C 6 )alkyl
  • each R b is independently hydrogen, hydroxy, (C r C 6 )alkyl, or (C C 6 )alkoxy
  • each R c is independently hydrogen, or (C,-C 6 )alkyl
  • any aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy
  • R is hydrogen, (C C 6 )alkyl, aryl, or aryl(C r C 6 )alkyl
  • R 2 is aryl or heteroaryl
  • A is NR a , -O-, CR b R c , or -S-
  • B is -O- or -S-
  • each R- is independently hydrogen, or (C,-C 6 )alkyl
  • each R b is independently hydrogen, hydroxy, (C,-C 6 )alkyl, or (C,-C 6 )alkoxy
  • each R c is independently hydrogen, or (C,-C 6 )alkyl
  • any aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, tri
  • R is benzyl, which is substituted with 1, 2, 3, or 4 independent halo substituents.
  • R is phenethyl
  • R is phenethyl, which is substituted with 1, 2, 3, or 4 independent halo substituents.
  • R x is phenethyl, which is substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, (C,-C 6 )alkyl, (C r C 6 )alkoxy, (C,-C 6 )alkanoyl, (C,-C 6 )alkanoyloxy, (C,-C 6 )alkoxycarbonyl, and methylenedioxy.
  • R 2 is phenyl or naphthyl, optionally substituted with 1, 2, or 3, substituents independently selected from the group consisting of halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C ] - C 6 )alkyl, (C,-C 6 )alkoxy, (C r C 6 )alkanoyl, (C r C 6 )alkanoyloxy, and (C,- C 6 )alkoxycarbonyl .
  • R 2 is pyridinyl, imidazolyl, indolyl or pyrimidinyl, optionally substituted with 1, 2, or 3, substituents independently selected from the group consisting of halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C,-C 6 )alkyl, (C r C 6 )alkoxy, (C,-C 6 )alkanoyl, (C,- C 6 )alkanoyloxy, and (C,-C 6 )alkoxycarbonyl.
  • R 2 is thiophenyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C,-C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkanoyl, (C r C 6 )alkanoyloxy, and (C,-C 6 )alkoxycarbonyl.
  • substituents independently selected from the group consisting of halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C,-C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkanoyl, (C r C 6 )alkanoyloxy, and (C,-C 6 )alkoxycarbonyl.
  • a specific value for A is NH.
  • a specific value for B is NH, CH 2 ⁇ or CH(OH).
  • salts of a detectably labeled sigma-1 ligand may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the detectably labeled sigma-1 ligands may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of the compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of compound in such therapeutically useful compositions is such that an
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the compound may be incorporated into sustained-release preparations and devices.
  • the detectably labeled sigma-1 ligands may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of a compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating a compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder.
  • the detectably labeled sigma-1 ligands may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful dosages of the detectably labeled sigma-1 ligands can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the concentration of the compound(s) in a liquid composition, such as a lotion will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%.
  • the concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
  • Single dosages for injection, infusion or ingestion will generally vary between 50-1500 mg, and may be administered, i.e., 1-3 times daily, to yield levels of about 0.5 - 50 mg/kg, for adults.
  • Example 1 Stability of sigma-1 receptors on 67P cells.
  • the mouse mammary adenocarcinoma line 66 is known to be an appropriate in vitro model system for studying biomarkers of cell proliferation.
  • the expression of sigma-1 receptors on proliferative (P) and quiescent (Q) 66 cells was examined. Scatchard analyses of sigma-1 receptors were performed on 66P and 66Q cell membranes stored overnight at -80°C (Table 1). See Y.C. Cheng, et al, Biochem. Pharmacol, 1973, 22, 3099-4022. Table 1. Sigma-1 receptor binding studies in 3-day 66P cells and either 7- day, 10-day, or 12 day 66 Q cells
  • sigma-1 receptors can be used as a biomarker for tumor cell proliferation, and may be used for noninvasively assessing the proliferative status of tumors (e.g., breast tumors, prostate tumors, and/or bladder tumors). Additionally, because sigma-1 receptors were found to have a higher P:Q ratio than sigma-2 receptors, the methods of the instant invention may possess an advantage over previous methods that use sigma-2 ligands to determine the proliferative status of cancer cells.
  • Example 3 In vivo labeling of sigma-1 receptors in vivo with an 18 F-Iabeled mixed sigma-l/sigma-2 receptor imaging agent.
  • IC sigma- 1 -selective ' 8 F-N-( 1 -benzylpiperidin-4-yl)-2-fluorophenylacetamide
  • mice were sacrificed at 2 hours post-i.v. injection. The tumor and other organs of interest were removed, weighed and counted. Sigma-1 and sigma-2 biodistribution was calculated by measuring %I.D./c.c. tissue sample, as well as by tissue:blood ratio. Results are shown in Table 2.
  • Results indicate that it is possible to label both sigma-1 and sigma-2 receptors in vivo.
  • tissue uptake and a high tissue:blood ratio in all organs known to have a high density of sigma- receptors.
  • the tumor uptake of compound 143 was also high, resulting in a tumo ⁇ blood ratio of 25 at 2 hours post-injection of the radiotracer.
  • the relative density of sigma-1 and sigma-2 receptors was analyzed by comparing the uptake of the radiotracer alone and when co-injected with the blocking agents ( Figures 2).
  • the sigma-1 blocking study reduced both the % I.D./c.c. and tumor:blood ratio of compound 143, suggesting that there is a high density of sigma-1 receptors in these mouse tumors.
  • 66Q cells demonstrates that sigma-1 receptors are a biomarker of cell proliferation in breast cancer cells, prostate cancer cells, and/or bladder cancer cells. More specifically, these data, in concert with in vitro binding data from 66P and 66Q cells, demonstrates that sigma-1 receptors are a biomarker of cell proliferation in breast cancer cells.
  • Labeled compounds of formula I were also prepared as desc ⁇ bed in Examples 5-20.
  • Labeled compounds of formula I can convemently be prepared using procedures similar to those described below by substituting a labeled starting material (e.g. a starting material that includes a radionuclide) for the corresponding starting material described below.
  • a labeled starting material e.g. a starting material that includes a radionuclide
  • the intermediate 4-phenylacetamidopiperidine was prepared as follows.
  • N-(l-benzylpiperidin-4-yl)phenylacetamide To an ice-cold solution of phenylacetic acid (3.4 g, 25 mmol) in dry THF (100 mL) was added DCC (5.2 g, 25 mmol). After stirring for 15 minutes, 4-amino-l-benzylpiperidine (4.8 g, 25 mmol) was added. The reaction was continued at room temperature overnight. The solid was removed by filtration, the solvent was removed, and the resulting residue was extracted with CH 2 C1 2 (3 x 30 mL). The combined organic layers were washed with IN NaOH, saturated aqueous NaCI, dried over Na-.SO 4 , and concentrated in vacuo.
  • Example 10 N-(l-(4-iodobenzyl)piperidin-4-yl)phenylacetamide (100). Using a procedure similar to that described in Example 5, except replacing the 2-fluorobenzyl bromide with 4-iodobenzyl bromide, the title compound was prepared; yield 41%; mp 136-138 °C.
  • the intermediate 4-(2-fluorophenyl)acetamidopiperidine was prepared as follows. a. l-Benzyl-4-trifluoroacetamidopiperidine. To a solution of 4-amino-l- benzylpiperidine (9.5 g, 50 mmol) in dry dichloromethane (200 mL) was added trifluoroacetic anhydride (12.6 g, 60 mmol) and triethylamine (5 mL) under ice and stirring.
  • the catalyst was removed by filtration and the solution was concentrated in vacuo to give an oil which was reacted with di-tert-butyl-di-carbonate (11.0 g, 50 mmol) in dicholoromethane (200 mL) for 6 hours.
  • the reaction mixture was transfe ⁇ ed into a separatory funnel and washed with aqueous NaHCO 3 , water and dried over Na ⁇ O ⁇
  • the residue was dissolved in methanol (100 mL) and of 30% ammonium hydroxide (50 mL) and refluxed for 6 hours.
  • the solvent was removed and the residue was dissolved in dichloromethane (100 mL), washed with 1 N NaOH, water and dried over Na ⁇ O,,.
  • the solvent was removed and the product was recrystallized from ethyl acetate-hexane to give 4-amino-l-(tert-butoxycarbonyl)piperidine (5.75 g, 58%).

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Abstract

L'invention concerne une méthode permettant de déterminer l'état de prolifération de cellules cancéreuses exprimant des récepteurs sigma-1, ainsi que des composés marqués de façon à pouvoir être identifiés et des compositions pharmaceutiques utiles pour mettre en oeuvre de telles méthodes.
PCT/US2000/013834 1999-05-21 2000-05-19 Ligands sigma-1 utiles pour determiner l'etat de proliferation de cellules cancereuses WO2000071171A2 (fr)

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US7514562B2 (en) 2003-03-07 2009-04-07 Glaxo Group Limited Urea derivatives and their use as vanilloid receptor antagonists in the treatment of pain
US7528151B2 (en) 2003-03-06 2009-05-05 Glaxo Group Limited Heterocyclic urea derivatives for the treatment of pain
JP2017522366A (ja) * 2014-05-30 2017-08-10 スプハエラ ファーマ ピーヴィーティー リミテッド 抗結核薬としての新規な化合物
JP2017538677A (ja) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． 免疫調節剤

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7528151B2 (en) 2003-03-06 2009-05-05 Glaxo Group Limited Heterocyclic urea derivatives for the treatment of pain
US7514562B2 (en) 2003-03-07 2009-04-07 Glaxo Group Limited Urea derivatives and their use as vanilloid receptor antagonists in the treatment of pain
WO2004078101A2 (fr) * 2003-03-08 2004-09-16 Glaxo Group Limited Derives d'uree
WO2004078101A3 (fr) * 2003-03-08 2005-02-17 Glaxo Group Ltd Derives d'uree
JP2006519805A (ja) * 2003-03-08 2006-08-31 グラクソ　グループ　リミテッド バニロイド受容体拮抗活性を有する尿素誘導体
US7528150B2 (en) 2003-03-08 2009-05-05 Glaxo Group Limited Urea derivatives having vanilloid receptor antagonist activity
JP2017522366A (ja) * 2014-05-30 2017-08-10 スプハエラ ファーマ ピーヴィーティー リミテッド 抗結核薬としての新規な化合物
JP2017538677A (ja) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． 免疫調節剤
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