Nothing Special   »   [go: up one dir, main page]

WO1994026314A1 - Composes destines a la visualisation et a la therapie du cancer - Google Patents

Composes destines a la visualisation et a la therapie du cancer Download PDF

Info

Publication number
WO1994026314A1
WO1994026314A1 PCT/US1993/004309 US9304309W WO9426314A1 WO 1994026314 A1 WO1994026314 A1 WO 1994026314A1 US 9304309 W US9304309 W US 9304309W WO 9426314 A1 WO9426314 A1 WO 9426314A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
independently
lower alkyl
halo
radionuclide
Prior art date
Application number
PCT/US1993/004309
Other languages
English (en)
Inventor
Christy S. John
Jesse Baumgold
John G. Mcafee
Terry W. Moody
Original Assignee
John Christy S
Jesse Baumgold
Mcafee John G
Moody Terry W
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by John Christy S, Jesse Baumgold, Mcafee John G, Moody Terry W filed Critical John Christy S
Priority to CA002139503A priority Critical patent/CA2139503A1/fr
Priority to PCT/US1993/004309 priority patent/WO1994026314A1/fr
Priority to JP6525353A priority patent/JPH08510235A/ja
Priority to EP94930839A priority patent/EP0650372A4/fr
Publication of WO1994026314A1 publication Critical patent/WO1994026314A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/0412—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K51/0419—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to a class of compounds having particular affinity for a specific cell surface receptor prevalent on certain cancer cells, e.g. lung carcinomas, malignant melanomas, gliomas,
  • the present invention provides such compounds as agents for detecting and treating tumors, particularly tumors having cancer cells which possess a cell surface sigma receptor.
  • Lung carcinomas, malignant melanomas, gliomas, neuroblastomas, pheochromocytomas, colon carcinomas and renal carcinomas are aggressive forms of cancer, the early detection and treatment of which are of paramount importance. If left undetected or untreated for several years or even months the median survival time of
  • lung cancer has lead to the highest number of fatalities. In 1992 alone, lung cancer caused about 165,000 deaths within the United States. Two major types of lung carcinomas are
  • SCLC small cell lung carcinoma
  • SCLC is a neuroendocrine tumor that secretes several peptide growth factors including bombesin/gastrin releasing peptide (BN/GRP). SCLC is responsive to chemotherapy and radiation therapy, but relapse occurs frequently, and the median survival time is only about one year.
  • BN/GRP bombesin/gastrin releasing peptide
  • NSCLC accounts for about 75% of all lung cancer cases and encompasses a variety carcinomas including adenocarcinomas, large cell carcinomas and squamous cell carcinomas. NSCLC tumors secrete
  • TGF- ⁇ transforming growth factor-alpha
  • Melanomas are among the most serious manifestations of skin cancer and lead to a greater number of fatalities than any other form of skin cancer. Melanomas can metastasize through the lymphatic system to regional nodes and then via the blood to secondary sites on the skin or in the liver, lungs and brain.
  • radiopharmaceuticals A variety of radiopharmaceuticals have been evaluated for diagnostic imaging. For example,
  • IDAB N-(diethylaminoethyl)4-iodobenzamide
  • IDAB is taken up in high concentrations by non-melanoma cells in the liver and lung.
  • IDAB does not have optimal specificity for melanoma cells and its uptake by non-tumor cells
  • the present invention provides compounds which bind with high specificity and affinity to the cell surface of cancer cells. These compounds bind, for example, to receptors on the cancer cell surface.
  • receptors on the cancer cell surface One such receptor is a sigma receptor.
  • Sigma receptors are known to be present on neural tissues and certain immortalized neuroblastoma and glioma cell lines (Walker et al. 1990 Pharmacol. Reviews 42: 355-400; and Villner et al. 1992 in Multiple Sigma and PCP Receptor Ligands: Mechanisms for Neuromodulation and Neuroprotection?
  • sigma receptors are prevalent on some types of cancer cells, e.g. neuroblastoma, melanoma, glioma, pheochromocytoma, colon, renal and lung carcinoma cells. Therefore the compounds of the present invention are useful for detecting and treating tumors, e.g. those containing cells with sigma receptors.
  • the present compounds are also useful for diagnostic imaging any tissue having a sigma receptor, e.g. a neural tissue such as the brain or spinal cord.
  • the present invention provides a method for diagnosing a mammal for the presence of a mammalian tumor which includes administering to a mammal a
  • the compounds of the present invention are of the general formula I.
  • X is a radionuclide
  • Z 0 or two -H
  • each R 1 is independently H, halo, lower alkyl or lower alkoxy
  • R a and R b are independently H, halo, lower alkyl, lower alkoxy or R a and R b together with the carbon atoms to which they are attached form a cycloalkenyl or heterocylic ring;
  • R 2 is —N(R 3 ) 2 or a 5 to 6 membered nitrogen containing heterocyclic ring which is unsubstituted or substituted with at least one alkyl substituent;
  • each R 3 is independently hydrogen or lower alkyl
  • j and y each are independently an integer from
  • q is an integer from 0 to 2;
  • the compound is not an iodine radioisotope of (N-diethylaminoethyl)-4-iodobenzamide.
  • the present invention also provides a method for treating a mammalian tumor which includes
  • composition including a tumor-inhibiting amount of a compound of formula I.
  • the present invention further provides a method for diagnostic imaging of a mammalian tissue which has cell surface sigma receptors which includes administering to a mammal a diagnostic imaging amount of a compound of the present invention and detecting an image of a tissue having an abundance of cells with sigma receptors.
  • a further aspect of the present invention provides a method for in vitro detection of a cancer cell in a mammalian tissue sample which includes
  • Another aspect of the present invention provides a preferred compound of formula I, e.g. a compound of any one of formulae II, III or IV.
  • Q is a radionuclide, halide or an activating group
  • R 4 is —N(R 3 ) 2 or an N-linked 5 to 6 membered nitrogen containing heterocyclic ring which can have at least one alkyl substituent, wherein each R 3 is
  • R 5 is a 5 or 6 membered nitrogen containing heterocyclic ring which can have at least one alkyl substituent
  • n is an integer from 2 to 6;
  • n is an integer from 3 to 6.
  • Such preferred compounds can also be used in the methods of the present invention.
  • compositions and kits containing the present compounds are also provided herein.
  • Fig. 1 illustrates the log molar amount of nonradioactive IPAB needed to competitively inhibit binding of radioactive IPAB to malignant melanoma cells.
  • the K i obtained from these data was 6.8 nM.
  • Fig. 2A provides a scintigraphic image
  • Fig. 2B provides a scintigraphic image
  • Fig. 3A provides a scintigraphic image
  • Fig. 3B provides a scintigraphic image
  • Fig. 4 provides a scintigraphic image obtained at 30 hrs. after a nude mouse bearing a human lung adenocarcinoma tumor received [ 131 I]PAB.
  • the arrow indicates the implanted tumor.
  • the present invention provides novel compounds and methods for detecting and treating certain types of cancer, e.g. neuroblastomas, gliomas, pheochromocytomas, melanomas, colon, renal and lung carcinomas.
  • the compounds of the present invention bind to a cell surface sigma receptor and exhibit vibrant cell specificity and affinity for the above cancerous cells and for cells having sigma receptors.
  • the present invention is directed to a method for detecting a mammalian tumor which includes administering to a mammal a diagnostic imaging amount of a compound of the present invention, and observing retention of the compound in a tissue of the mammal; wherein the compound is of any one of formulae I, II, III or IV:
  • X is a radionuclide
  • Q is a radionuclide, halide or an activating group
  • Z 0 or two -H
  • each R 1 is independently H, halo, lower alkyl or lower alkoxy
  • R a and R b are independently H, halo, lower alkyl, lower alkoxy or R a and R b together with the carbon atoms to which they are attached form a cycloalkenyl or heterocylic ring;
  • R 2 is —N(R 3 ) 2 or a 5 to 6 membered nitrogen containing heterocyclic ring which is unsubstituted or substituted with at least one alkyl substituent; each R 3 is independently hydrogen or lower alkyl;
  • R 4 is —N(R 3 ) 2 or an N-linked 5 to 6 membered nitrogen containing heterocyclic ring which can have at least one alkyl substituent, wherein each R 3 is
  • R 5 is a 5 or 6 membered nitrogen containing heterocyclic ring which can have at least one alkyl substituent
  • j and y are independently an integer from 0 to 6;
  • q is an integer from 0 to 2;
  • n is an integer from 2 to 6;
  • n is an integer from 3 to 6;
  • the compound is not an iodine radioisotope of (N-diethylaminoethyl)-4-iodobenzamide.
  • the present invention also provides a method for treating a mammalian tumor which includes
  • composition including a tumor-inhibiting amount of a compound of formula I, II, III or IV.
  • the present invention further provides a method for diagnostic imaging of a mammalian tissue which has cell surface sigma receptors which includes administering to a mammal a diagnostic imaging amount of a compound of the present invention and detecting an image of a tissue having an abundance of cells with sigma receptors.
  • the present invention further provides a method for in vitro detection of a cancer cell in a mammalian tissue sample which includes contacting a mammalian tissue sample with an in vitro diagnostic imaging amount of a compound of formula I for a time and under conditions sufficient for binding of the compound to the cancer cell and detecting such binding.
  • radionuclide When used for diagnostic imaging X or Q as a radionuclide is used. Moreover X or Q radionuclide groups which are preferably used for diagnostic imaging are ⁇ -emitting radionuclides which can be detected by radioimaging procedures, e.g. by scintigraphic imaging. Such ⁇ -emitting radionuclides emit radiation which is sufficently penetrating to be detected through tissues. Moreover, for diagnostic imaging preferred radionuclides do not emit a particle, e.g. an ⁇ or ß particle.
  • Preferred X and Q groups for diagnostic imaging include
  • More prefeerred X and Q groups for diagnostic imaging include 123 I, I and F. I is especially preferred for diagnostic imaging.
  • X or Q as a radionuclide is used.
  • X and Q radionuclides employed for therapy are ß-emitting or an ⁇ -emitting radionuclides.
  • any cytotoxin which exhibits a localized cell killing activity can be used in place of a X or Q radionuclide.
  • the preferred X and Q groups for treating cancers include 131 I, 211 At, 212 Pb, 212 Bi, 76 Br, 77 Br and the like.
  • compounds for treating cancer more preferably have X or Q as 131 I .
  • Q is a radionuclide, a halide or an activating group.
  • Compounds having Q as a halide or an activating group are provided as non-radioactive compounds of the present invention which can be readily converted into the corresponding radioactive compound. Since the utility of a radioactive compound relates to the specific activity of such a radioactive compound, it is often preferred to add the radionuclide just before use. Accordingly compounds having Q as halide or as an activating group are provided, for example, in a form useful for storage or transport.
  • Q is a halide
  • such a halide is preferably Br or I.
  • an activating group is a group which is easily displaced by a radionuclide via electrophilic aromatic substitution.
  • activating groups include tributyl-tin, trimethylsilyl, t-butyldimethylsilyl, iodide and the like.
  • Z 0, i.e. the -CZ- group forms a carbonyl.
  • R 3 is preferably an alkyl.
  • lower alkyl when used singly or in combination, refers to alkyl groups containing one to six carbon atoms.
  • Lower alkyls may be straight chain or branched and include such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
  • the preferred alkyl groups contain one to four carbon atoms.
  • a lower alkylene singly or in combination with other groups, contains up to six carbon atoms in the main chain and a total of 10 carbon atoms if the alkylene is branched.
  • Lower alkylene groups include methylene, ethylene, propylene, isopropylene, butylene, t-butylene, sec-butylene, isobutylene, amylene, isoamylene, pentylene, isopentylene, hexylene and the like.
  • the preferred lower alkylene groups contain one to four carbon atoms.
  • cycloalkenyl refers to a partially saturated cyclic structure, i.e. a ring, having 3-7 ring carbon atoms which can have one or two unsaturations. Since the cycloalkenyl groups of the present invention are fused to a phenyl moiety such cycloalkenyls are partially unsaturated.
  • the subject cycloalkenyls groups include such groups as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl rings.
  • lower alkoxy refers to a lower alkyl group attached to the main chain via an oxygen atom.
  • Halo refers to a halogen, especially bromine, iodine, chlorine and fluorine.
  • a halo group is a commonly available, non-radioactive halogen isotope.
  • Preferred halo groups include iodide,
  • a heterocylic ring means a saturated, partially saturated or aromatic heterocyclic ring having at least one nitrogen or oxygen ring atom. As is known to the skilled artisan a saturated
  • heterocyclic ring has no double bonds.
  • a partially saturated heterocyclic ring can has at least one double bond.
  • the present heterocyclic rings can have up to three heteroatoms and up to a total of six ring atoms. Accordingly heterocyclic rings of the present invention can have about 2 to about 5 ring carbon atoms,
  • heterocyclic ring has only one nitrogen or one oxygen heteroatom, or one nitrogen atom and one oxygen heteroatom.
  • Heterocyclic rings can also have a mixture of nitrogen or oxygen heteroatoms, e.g.
  • heterocylic ring contain one or two ring heteroatoms, most preferred is one ring nitrogen or oxygen heteroatom.
  • Heterocyclic rings of the present invention are monocyclic; such monocyclic rings can be fused to a phenyl ring to form a bicyclic ring.
  • Representative partially saturated and heteroaromatic heterocyclic rings include furan, pyran, oxazine, isoxazine, pyrrole, pyrazole, pyridine, pyrazine, triazole, tetrazole, triazine, pyrimidine, pyridazine, furazan and the like.
  • heteroaromatic groups include pyridine and the like.
  • saturated heterocyclic rings include tetrahydrofuran, pyrazolidine, imadazolidine, pyrrolidine, azetidine, piperidine, piperazine and morpholine.
  • R a and R b are independently H, halo, lower alkyl, lower alkoxy or R a and R b together with the carbon atoms to which they are attached form a cycloalkenyl or heterocylic ring.
  • R a and R b together form a cycloalkenyl or heterocylic ring, such a ring is fused to the phenyl.
  • Such a cycloalkenyl ring formed from R a and R b has only one unsaturation in the cycloalkenyl ring and that unsaturation is contributed by the phenyl ring to which the cycloalkenyl is fused.
  • a cycloalkenyl formed by R a and R b can be a 5 or 6 membered ring, such rings are preferably 5-membered rings, e.g.
  • cyclopentenyl examples include indanyl and tetrahydronaphthyl, e.g., 5,6,7,8-tetrahydronaphthyl, and the like.
  • the heterocyclic ring preferably has one nitrogen or oxygen heteroatom and 5 or 6 ring atoms.
  • heterocyclic is as defined hereinabove.
  • the heterocyclic ring contains at least two ring carbon atoms when the heterocyclic ring is a 5-membered ring, and the number of ring carbon atoms present can range from 2-4 carbon ring atoms.
  • the number of ring carbon atoms can range from 2-5 ring carbon atoms.
  • the total number of ring carbon atoms will range from 6-8 ring carbon atoms when the phenyl ring is fused to a 5-membered heterocyclic ring and 6-9 ring carbon atoms when the phenyl ring is fused to a 6-membered
  • heterocyclic ring can contain up to 3 ring heteroatoms.
  • the preferred ring heteroatoms are oxygen and nitrogen, especially oxygen.
  • Preferred heterocyclic rings formed by R a and R b include
  • each R 1 is independently H, halo, lower alkyl or lower alkoxy.
  • R 1 is H, halo or lower alkoxy. More preferred R 1 groups include H and halo. However, in one embodiment R 1 is preferably alkoxy.
  • variable q is defined herein as an integer ranging from 0 to 2 which describes the number of R 1
  • q can maximally be 2.
  • q is less than 2 some positions on the phenyl group are unsubstituted; in this case a hydrogen is present at the positions having no R 1 group.
  • Preferred values for q are 0 to 1.
  • R 1 is as described hereinabove and Q is a radionuclide (e.g. X), a halide or an activating group.
  • Q is a radionuclide (e.g. X), a halide or an activating group.
  • R 2 is —N(R 3 ) 2 or a 5 to 6 membered nitrogen containing heterocyclic ring which is unsubstituted or substituted with at least one alkyl substituent; wherein each R 3 is independently hydrogen or lower alkyl.
  • R 3 is lower alkyl in the —N(R 3 ) 2 groups of the present invention.
  • Preferred R 2 heterocyclic rings include N-piperidinyl, N-pyrrolidinyl, N-pyridinyl, N-morpholinyl, N-pyrrolyl, piperidinyl, pyrrolidinyl, pyridinyl, morpholinyl or pyrrolyl, which can be substituted with an R 6 lower alkyl.
  • R 6 is preferably attached to the nitrogen of the piperidinyl, pyrrolidinyl or morpholinyl rings.
  • R 2 can be R 4 as defined herein.
  • R 2 can be R 5 as defined herein.
  • R 2 can be —N(R 3 ) 2 as defined herein,
  • R 4 is —N(R 3 ) 2 or an N-linked 5 to 6 membered nitrogen containing heterocyclic ring which can have at least one alkyl substituent.
  • N-linked means that the nitrogen
  • R 4 is used in formula II to indicate a preference for attachment of the nitrogen present within the heterocyclic ring to the main chain.
  • Preferred R 4 heterocyclic rings include rings of the formulae:
  • R 6 is hydrogen or lower alkyl and each i is independently an integer from 0 to 1.
  • Preferred R 4 heterocyclic rings include N-piperidinyl, N-pyrrolidinyl, N-pyridine and the like.
  • preferred compounds have heterocyclic rings that are not attached via the ring nitrogen.
  • R 5 is used in formula III to describe such compounds, wherein R 5 is a 5 or 6 membered nitrogen containing heterocyclic ring which can have at least one alkyl substituent.
  • R 5 is any one of the following:
  • each i is independently an integer from 0 to 1 and R 6 is hydrogen or lower alkyl.
  • More preferred R 5 heterocyclic rings include piperidinyl, pyrrolidinyl or which are N-substituted with an R 6 lower alkyl, or pyridinyl which can have an R 6 lower alkyl.
  • Such an R 6 lower alkyl is preferably methyl, ethyl, propyl or butyl.
  • the compounds of formula IV have an -N(R 3 ) 2 group which is hydrogen or lower alkyl.
  • R 3 is lower alkyl, e.g. methyl, ethyl, propyl or butyl.
  • variable j refers to an integer ranging from 0 to 6 which defines the length of the alkylene chain separating the phenyl and -CZ-moieties of the present compounds.
  • j is an integer from 0 to 3. More preferably, j is an integer from 0 to 2.
  • j is preferably 0.
  • y is 0 to 6.
  • the variable y defines the length of the alkylene chain separating the -CZ-NR 3 - and R 2 groups in the -CZ-NR 3 —(CH2) y —R 2 moiety of formula I.
  • y is 1 to 3; more preferably y is 1 to 2.
  • variable m defines the length of the alkylene chain separating the -CZ-NR 3 - and the R 5 group in the -CZ-NR 3 —(CH2) m —R 5 moiety of formula III.
  • the variable m is an integer ranging from 2 to 6.
  • m is preferably 2 to 4 and more preferably 2 to 3.
  • n is an integer ranging from 3 to 6. In a preferred embodiment n is 3.
  • Preferred compounds of the present invention include the following. ,
  • the present compounds and compositions contain one or more elements of each of the Markush groupings in X, Q, Z, R a , R b , R 1 , R 2 , R 3 , R 4 and R 5 and the various combinations thereof.
  • R 2 may be one or more of the substituents listed hereinabove or any and all of the substituents of N(R 3 ) 2 , R 4 and R 5 .
  • the present compounds can bind to a specific cell receptor prevalent on certain types of cancer cells.
  • cancer cells include lung carcinoma, colon carcinoma, renal carcinoma, melanoma, glioma,
  • cell receptor to which the present compounds bind is a cell surface sigma receptor.
  • the binding characteristics of the present compounds were determined by observing whether binding was inhibited by known sigma receptor antagonists. Many antagonists are known which have demonstrated binding specificities for a given cell surface receptor. Such antagonists can be tested as competitive inhibitors for cellular binding by compounds of the present invention. If a given antagonist is a competitive inhibitor the receptor to which the antagonist binds must also bind the subject compounds.
  • a malignant melanoma cell line binds the present compounds with strong specificity and affinity. Only antagonists which bind to the same site as the present compounds can inhibit binding of the subject compounds.
  • Antagonists which can be tested include antagonists specific for cell receptors such as sigma (e.g. using SE2466-2), sigma-1 (e.g. fluphenazine at low concentrations), sigma-2 (e.g. fluphenazine at high concentrations), dopamine-1 (e.g. SCH23390), dopamine-2 (e.g. raclopride), melanocyte secreting hormone receptor (e.g. melanocyte secreting hormone peptide), 5-hydroxytryptamine-1 (e.g. mianserin), 5-hydroxytryptamine-la (e.g. NAN-190), 5-hydroxytryptamine-lc (e.g. ketanserine), 5-hydroxytryptamine-2 (e.g.
  • ketanserine and mianserin and 5-hydroxytryptamine-3 (e.g. 3-tropanyl-dichloroben) cell receptors and the like.
  • antagonists with demonstrated binding specificity for cell surface sigma receptors e.g. fluphenazine
  • Cell types which have sigma receptors include normal neural tissues (e.g., brain, spinal cord and the like) as well as lung carcinoma, colon carcinoma, renal carcinoma, melanoma, pheochromocytoma, glioma,
  • NSCLC melanomas and non-small cell lung carcinoma
  • NSCLC cancers include lung adenocarcinoma, lung squamous cell carcinoma, large cell lung carcinoma and the like.
  • a method for detecting a mammalian tumor or a tissue containing cell surface sigma receptor includes administering to a mammal a composition including a diagnostic imaging amount of at least one of the present compounds.
  • a diagnostic imaging amount is a dosage of at least one of the subject compounds which permits sufficient tumor or tissue localization of the compound to allow detection of the tumor or tissue.
  • This dosage can range from about about 1 ⁇ g to about 1 g of the compound per liter which can be administered in doses of about 1 ng/kg body weight to about 10 ug/kg body weight.
  • Preferred dosages of the present compounds are in the range of about 10 ng to about 2 ug/kg for diagnostic imaging.
  • the amount of radioactvity is administered to a mammal a composition including a diagnostic imaging amount of at least one of the present compounds.
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • the present invention is directed to a method for treating a mammalian tumor which includes administering to a mammal a composition including a tumor-inhibiting amount of at least one compound of the present invention.
  • a tumor-inhibiting amount is an amount of at least one of the subject compounds which permits sufficient tumor
  • tumor growth or size can be monitored by any known diagnostic imaging procedure, e.g. by using the present methods.
  • This dosage can range from about 0.1 mmole/kg body weight to about 500 mmole/kg body weight.
  • a preferred dosage is about 5 to about 50 mmole/kg body weight.
  • the amount of radioactivity administered can vary depending on the type of radionuclide. However, with this in mind the amount of radioactivity which is administered can vary from about 1 mCi to about 800 mCi. Preferably, about 10 mCi to about 600 mCi is
  • Such a specific activity is preferably very high, e.g. for 123 I-labeled compounds the specific activity should be at least about 1,000 Ci/mM to about 50,000 Ci/mM. More preferably the specific activity for 123 I-labeled compounds is, e.g. about 10,000 Ci/mM to about 22,000 Ci/mM.
  • the present invention provides a method for in vitro detection of a cancer cell in a mammalian tissue sample which includes
  • Samples can be collected by procedures known to the skilled artisan, e.g. by collecting a tissue biopsy or a body fluid, by aspirating for tracheal or pulmonary samples and the like.
  • any mammalian tissue can be tested in vitro.
  • Preferred tissues for in vitro testing include lung, bronchial, lymph, skin, brain, liver, any tissue of nervous origin and the like. Samples can be sectioned, e.g. with a microtome, to facilitate
  • Samples can also be fixed with an appropriate fixative either before or after incubation with one of the present compounds to improve the histological quality of sample tissues.
  • Conditions sufficient for binding of the compound to a cell surface sigma receptor on the cancer cell include standard tissue culture conditions, i.e. samples can be cultured in vitro and incubated with one of the present compounds in physiological media. Such conditions are well known to the skilled artisan.
  • samples can be fixed and then incubated with a compound of the present invention in an isotonic or physiological buffer.
  • An amount of at least one of the present compounds for in vitro detection of a cancer cell can range from about 1 ng/l to about 1000 ⁇ g/l .
  • a preferred amount is about 1 ⁇ g/l to about 100 ⁇ g/l.
  • X and Q radionuclides for in vitro diagnosis of cancer include 125 I, 18 F, - 35 S-alkyl,
  • samples can be incubated in the presence of a selected compound, then washed and counted in a standard scintillation counter.
  • samples can be dipped in photoemulsion and the signal detected under light microscopy after several days, as exposed silver grains.
  • Compounds of the present invention can be prepared by any procedure available to the skilled artisan using protecting groups, leaving groups, activating groups and the like as needed. Starting compounds can be chosen which have the desired R 1 , R 2 , R 3 , R 4 , R 5 and R 6 groups at the requisite positions.
  • a leaving group may be used in place of the desired R 1 , R 2 , R 3 , R 4 , R 5 or R 6 group, and the appropriate group may replace the leaving group in a later synthetic step.
  • a protecting group on a reactive group which may be present on starting materials, e.g., an amine or similar reactive group on the chosen starting material.
  • the use of leaving or protecting groups prevents undesirable side reactions from occurring, while permitting desired reactions to take place.
  • a leaving group is defined as a group which is readily broken away from its union with a carbon atom. These groups are readily recognizable by one skilled in the art.
  • Suitable leaving groups are generally electron attracting groups, either because of their electronegativity or because they have an inductive effect, and may include groups such as halides, N 3 , HO-Aryl, or HSO 3 -Aryl groups, and the like.
  • a leaving group can be present at the position of X or Q on a starting material for the present compounds; such a leaving group is preferably a halide, e.g. Br or I.
  • a protecting group is covalently bound to a reactive group to render the reactive group unreactive while allowing desired reactions to take place.
  • a protecting group must in addition be easily removed without chemically altering the remainder of the molecule, and must regenerate the correct structure of the reactive group.
  • Examples of protecting groups effective with, for example, primary and secondary amino groups include acetyl, carbobenzoxy (cleaved by acid hydrolysis), benzyl (cleaved by catalytic
  • an activating group is a group which is easily displaced by a radionuclide via electrophilic aromatic substitution.
  • the activating group is used to facilitate substitution of a
  • Radionuclide onto the present compounds Activating groups contemplated by the present invention include tributyl-tin, trimethylsilyl t-butyldimethylsilyl iodide and the like.
  • the present compounds can be prepared from readily available starting materials, for example, by amidation of a substituted phenyl alkylcarboxylate or a substituted benzoic acid with an appropriate amine.
  • phenylcarboxyalkyl can be used as a starting material.
  • a phenylcarboxyalkyl (V) having a leaving group (Y) at the desired X (or Q) position can be amidated in the presence of a halogenating reagent with an amine of formula VI, as depicted below.
  • Y is a leaving group and R 1 , R a , R b q, j, y and R 2 are as described hereinabove.
  • Y is a halo group, e.g. Cl, Br or I. More preferred Y groups are Br in a meta position and I in a para position relative to the carboxyl group, when the X or Q is to be placed in such a respective meta or para position.
  • Halogenating reagents for the above described reaction include those which can convert the carboxylate to an acid halide, e.g. thionyl halide such as SOCl 2 , PCl 5 , PCl 3 and the like.
  • a preferred halogenating reagent is SOCl 2 in the presence of dimethylformamide.
  • reaction can be heated to reflux
  • a preferred solvent for this reaction is a nonpolar volatile solvent, e.g. chloroform.
  • the acid chloride so formed is sufficiently stable to be
  • the amine e.g. VI
  • the solvent for this reaction is also preferably a nonpolar solvent, e.g. chloroform.
  • a reducing agent can be used, e.g. boron hydride, sodium borohydrate, lithium aluminium hydride and the like,
  • a preferred reducing agent is boron hydride (BH 3 ) in the presence of
  • tetrahydrofuran THF
  • the carbonyl of a compound of formula VII can be converted to a methylene by the following reaction.
  • R 3 of -CZ-NR 3 - is lower alkyl
  • such a lower alkyl is added, e.g. by alkylation, after
  • Alkylation can be done by any available procedure, e.g. using an alkyl halide with a sodium salt in dimethylformamide or ethanol.
  • an alkyl halide e.g. iodomethane
  • a compound of formula VIII in the presence of sodium bicarbonate or sodium carbonate using dimethylformamide as solvent.
  • a Q group can replace the Y leaving group, e.g. on VII or VIII.
  • Q is a radionuclide, a halide or an activating group.
  • Q is a halide a starting material having the desired halide at the position of Q can be utilized, e.g. V can be bromophenyl carboxyalkyl, iodophenyl carboxyalkyl iodobenzoic acid, and the like.
  • An activating group can be placed at the position of Y by available
  • the activating group (Q) can in turn be readily replaced by a radionuclide (i.e. X) to generate compounds of formulae I, II, III or IV, wherein X is the desired radionuclide.
  • a radionuclide i.e. X
  • activation can be achieved using palladium catalyzed stannylation with bis(tributyltin), as depicted below.
  • a protecting group (R 7 ) is first placed on the -CZ-NR 3 - amine, if R 3 is hydrogen.
  • R 3 of the -CZ-NR 3 - is lower alkyl, no such protecting group is needed.
  • Protecting groups used for a -CZ-NR 3 - amine can be any protecting group for a secondary amine, e.g. carbobenzoxy (i.e. CBz, cleaved by acid hydrolysis), benzyl (cleaved by catalytic
  • tert-butoxycarbonyl i.e. t-BOC, cleaved by mild acid treatment
  • the silylation reaction can then be performed as depicted below, e.g. using an amine protected compound of formula VIII.
  • Q is trimethylsilane (Me 3 Si).
  • the R 7 group can be removed by standard techniques, e.g. when R 7 is CBz or t-BOC acid hydrolysis can remove R 7 and restore the secondary amine (-NH-). Silylation is preferred for compounds wherein Z is two - H.
  • the radioactively labeled compounds of the present invention can be produced with high specific activity and high yield by reacting a radioisotope (e.g. 123 I, 125 I or 131 I) with an activated intermediate (e.g. a compound of formula IX or X) in the presence of an oxidizing agent.
  • a radioisotope e.g. 123 I, 125 I or 131 I
  • an activated intermediate e.g. a compound of formula IX or X
  • an oxidizing agent Any oxidizing reagent which can convert the negatively charged radionuclide to a
  • oxidizing reagents include iodogen beads, peroxides such as peracetic acid, hydrogen peroxide and the like, as well as N-chloro-4-toluene-sulfonamide (i.e. chloramine- T).
  • a more preferred oxidizing reagent is chloramine-T.
  • An acid e.g. HCl, can also be added.
  • radionuclide replaces the activating group is depicted below using, e.g. a compound of formula IX.
  • heterocyclic ring can be in place on the starting material.
  • R a and R b of formula V together with the carbon atoms to which they are
  • Another embodiment of the present invention provides a compartmentalized kit for detection of a mammalian tumor which includes a first container adapted to contain at least one of the compounds of the present invention.
  • mammalian tumor which includes a first container adapted to contain at least one of the compounds of the present invention.
  • kits for detecting or treating a mammalian tumor can have any one of formulae I, II, III, IV, VII, VIII, IX or X.
  • preferred compounds for the present kits are of any one of formuale II, III, IV,
  • kits include compounds of formula IX.
  • Compounds provided in the present kits preferably have a Q rather than an X group and such a Q group is preferably an activating group.
  • Activating groups presnt on compounds provided in the subject kits include tributyl-tin, trimethylsilyl or t-butyldimethylsilyl. Tributyl-tin is an especially preferred activating group for compounds provided in the present kits.
  • kits of the present invention can be adapted to contain another container having a reagent for replacing a activating group with a radionuclide.
  • a reagent can be an oxidizing reagent, e.g. chloramine-T.
  • kits of the present invention can be adapted to contain another container having a material for separating unattached radionuclide from the radiolabeled compounds of the present invention having an attached X group.
  • a material can be any chromatographic material including a thin layer chromatography plate, a molecular exclusion resin, a silica gel, a reverse phase resin and the like.
  • resins can also be provided in the form of a prepacked column.
  • the present compounds can be administered to a mammal as a pharmaceutical composition.
  • compositions contain a diagnostic imaging or an anti-tumor amount of at least one of the present compounds together with a pharmaceutically acceptable carrier.
  • compositions can be administered by well-known routes including oral, intravenous, intramuscular, intranasal, intradermal, subcutaneous, parenteral, enteral, topical and the like.
  • routes of administration the pharmaceutical composition may require protective coatings.
  • the subject compounds may be incorporated into a cream, solution or suspension for topical
  • the pharmaceutical forms suitable for injection include sterile aqueous solutions or
  • Typical carriers include a solvent or dispersion medium containing, for example, water, buffered aqueous solutions (i.e., biocompatible buffers), ethanol, polyol (glycerol, propylene glycol, polyethylene glycol and the like), suitable mixtures thereof, surfactants or vegetable oils. Sterilization can be accomplished by any art recognized technique, including but not limited to, addition of antibacterial or antifungal agents, for example, paraben,
  • chlorobutanol phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents such as sugars or sodium chloride may be incorporated in the subject compositions.
  • sterile injectable solutions containing at least one of the present compounds is accomplished by incorporating these compounds in the required amount in the appropriate solvent with various ingredients enumerated above, as required, followed by sterilization, preferably filter sterilization. To obtain a sterile powder, the above solutions are vacuum-dried or freeze-dried as necessary.
  • the pharmaceutical compositions containing an effective dosage of the compound can also contain an inert diluent, an assimilable edible carrier and the like.
  • Orally administered compositions can be provided in hard or soft shell gelatin capsules, tablets, elixirs, suspensions, syrups and the like.
  • compositions provide effective dosages of the present compounds in the range of about 10 ng to about 2 ug/kg for diagnostics and preferably about 5 to about 50 mmole/kg body weight for therapy.
  • Such a specific activity is preferably very high, e.g. for 123 I-labeled compounds the specific activity should be at least about 1,000 Ci/mM to about 50,000 Ci/mM. More preferably the specific activity for 123 I-labeled compounds is, e.g. about 10,000 Ci/mM to about 30,000 Ci/mM.
  • a pharmaceutically acceptable carrier includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and the like which are physiologically acceptable.
  • solvents dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and the like which are physiologically acceptable.
  • the use of such media and agents are well-known in the art. The following Examples further illustrate the invention.
  • TLC thin layer chromatography
  • the residue (D) was dissolved in 90% ethanol, and 10% 0.01 M
  • TLC thin layer chromatography
  • the acid chloride was used without further purification for the condensation with amine.
  • the mixture was stirred for 3 hours at room temperature.
  • the organic layer was separated, dried over anhyd Na 2 SO 4 , and the volatiles removed in vacuo to give a light yellow oil.
  • the oil was purified by passage through a silica gel column when elution with CHCl 3 /MeOH: 90/10.
  • A2058 cells derived from a brain metastasis of human malignant melanoma (Todaro et al. 1980 Proc. Natl. Acad. Sci. USA 77: 5258) were obtained from the National Institutes of Health. These cells were grown in DMEM2 medium (Dulbecco's modification of Eagle's medium, EMEM) supplemented with 10% fetal bovine serum and 0.03% L-glutamine.
  • DMEM2 medium Dulbecco's modification of Eagle's medium, EMEM
  • A2058 cells grown as described above, were harvested with calcium and magnesium free phosphate buffer (0.1 M) containing 0.02% EDTA. Cells were washed twice with ice-cold RPMI 1640 medium (Gibco) without glutamine and resuspended in the same medium. Carrier-free [ 125 I]PAB (0.1 ml) was added to eight aliquots of 0.1 ml test A2058 cells (1.5 X 10 6 cells in suspension). To observe competitive binding by non-radioactive IPAB, varying concentrations of non-radioactive IPAB were added in a volume of 0.1 ml. Cells were incubated at 37°C for 5 hr after addition of radioactive and
  • Fig. 1 illustrates that IPAB binds to human malignant melanoma cells with high affinity.
  • Fig. 1 shows the amount of nonradioactive IPAB needed to competitively inhibit binding of
  • IPAB was competitively inhibited by as little as 6.8 nM (i.e. K i is 6.8 nM).
  • A2058 cells derived from a brain metastasis of human malignant melanoma (Todaro et al. 1980 Proc. Natl. Acad. Sci. USA 77: 5258) are obtained from the National Institutes of Health. These cells are grown in DMEM2 medium (Dulbecco's modification of Eagle's medium, EMEM) supplemented with 10% fetal bovine serum and 0.03% L-glutamine.
  • DMEM2 medium Dulbecco's modification of Eagle's medium, EMEM
  • IPAB, B) and 125 I(2-piperidinylaminoethyl)4-iodobenzamide (D) is synthesized as described in Example 1.
  • Pharmacological antagonists and the corresponding receptors which are tested include SE2466-2 (i.e. sigma receptor antagonist), fluphenazine (sigma-1 at low concentrations and sigma-2 at high
  • A2058 cells grown as described above, are harvested with calcium and magnesium free phosphate buffer (0.1 M) containing 0.02% EDTA. Cells are washed twice with ice-cold RPMI 1640 medium (Gibco) without glutamine and resuspended in the same medium. Carrier-free [ 125 I]PAB (0.1 ml) is added to eight aliquots of 0.1 ml test A2058 cells (1.5 X 10 6 cells in suspension). To observe competitive binding by pharmacological
  • Antagonists with demonstrated binding specificity for cell surface sigma receptors e.g.
  • flupeenazine can act as competitive binding inhibitors of IPAB binding to malignant melanoma cells.
  • IPAB, B was synthesized as described in Example 1.
  • a sigma-1 binding assay was performed in guinea pig brain membranes and rat C6 glioma cells
  • a sigma-2 binding assay was performed in rat liver membranes in the presence of a sigma-2 selective ligand, [ 3 H]DTG, in the presence of dextrallorphan to mask sigma-1 sites.
  • IPAB IP-binding protein
  • guinea pig brain membranes 300-500 microgram protein
  • 3 nm [ 3 H]-(+)-pentazocine specific activity 52 Ci/mmol
  • the amount of non-specific binding was determined by the addition of 10 mM Tris-HCl, pH 8.0 followed by rapid filteration through glass filters using a Brandel Cell harvester (Gaithersburg, MD) . Filters were washed twice with ice-cold buffer. Prior to use, filters were soaked in 0.5% polyethyleneimine for about 30 min at 25° C.
  • rats liver membranes sigma-2) or C6 glioma cell homogenates were incubated with 3 nM [ 3 H]DTG (39.4 Ci/mmol) in the presence of 1 micromolar cold
  • IPAB unlabeled IPAB.
  • the amount of non-specific binding was determined by incubation of membranes in the presence of 5 micromolar haloperidol.
  • IPAB IPAB required to inhibit binding of sigma-1 and sigma-2 selective ligands by 50% (i.e. the IC 50 values) was derived using the computerized iterative curve-fitting program, GraphPAD. K i values were calculated from the IC 50 values using Cheng-Prusoff equation.
  • IPAB binds to cell surface sigma receptors with very high affinity.
  • A2058 tumor cells derived from a brain metastasis of human malignant melanoma (Todaro et al.
  • Non-small cell lung carcinoma cell lines NCI- 157, NCI-838 and NCI-1299 were obtained from the
  • the NCI-157 cell line is a squamous carcinoma cell line, while NCI-838 is an adenocarcinoma cell line and NCI-1299 is a large cell lung carcinoma cell.
  • Tumor cells were grown in DMEM2 medium
  • EMEM Eagle's medium
  • tumor cells were harvested using calcium and magnesium free PBS containing 0,02% EDTA. Suspension of 5 ⁇ 10 6 cells (viability greater than 95%) in 0.2 mL of medium were innoculated subcutaneously in female Balb/c nu/nu mice. After about two weeks, solid tumors of about 1 cm in diameter appeared in approximately 85% of all
  • mice with solid tumors having a diameter of about 1 cm were used for biodistribution studies.
  • mice (17-22 g) were injected intravenously with 0.2 ml of a saline solution
  • % injected dose/g (% ID/g) values were determined by comparison of tissue radioactivities with suitably diluted aliquots of the injected [ 125 I]PAB dose divided by the weight of the organ. The values obtained were normalized to a mouse weighing 20 g. The differences between [ 125 I]PAB and
  • Tables 1-3 illustrate the biodistribution of
  • mice receiving [ 125 I]PAB had more of this
  • concentration of [ 125 I]DAB was significantly higher than that of [ 125 I]PAB in non-cancerous blood, liver and intestinal tissues.
  • mice receiving [ 125 I]PAB had about four-fold more [ 125 I]PAB in their tumors than in their livers. In contrast mice receiving [ 125 I]DAB had only about half as much [ 125 I]DAB in their tumors as their livers.
  • [ 125 I]DAB are non-specifically localized in the liver.
  • Non-small cell lung carcinoma cell lines NCI-157, NCI-838 and NCI-1299 were obtained from the
  • the NCI-157 cell line is a squamous carcinoma cell line, while NCI-838 is an adenocarcinoma cell line and NCI-1299 is a large cell lung carcinoma cell.
  • Tumor cells were grown in DMEM2 medium
  • EMEM Eagle's medium
  • tumor cells were harvested using calcium and magnesium free PBS
  • mice (17-22 g) were injected intravenously with 0.2 ml of a saline solution
  • % injected dose/g (% ID/g) values were determined by comparison of tissue radioactivities with suitably diluted aliquots of the injected [ 125 I]PAB dose divided by the weight of the organ. The values obtained were normalized to a mouse weighing 20 g. Results
  • Tables 4-5 illustrate the biodistribution of [ 125 I]DAB and [ 125 I]PAB, respectively, in nude mice bearing human squamous cell carcinoma xenografts in the flank at one, six, and twenty-four hours after
  • mice receiving [ 125 I]PAB had more
  • [ 125 I]PAB in their tumors than any other tissue In contrast mice receiving [ 125 I]DAB had about six-fold more [ 125 I]DAB in their livers as their tumors. These data indicate that high levels of [ 125 I]DAB are non-specifically localized in the liver. These data also indicate that [ 125 I]DAB has less tumor specificity than [ 125 I]PAB.
  • Kidney 7.64 (0.35) 1.07 (0.16) 0.05 (0.00)
  • A2058 cells derived from a brain metastasis of human malignant melanoma (Todaro et. al. 1980 Proc. Natl. Acad. Sci. USA 77 : 5258) were obtained from the National Institutes of Health.
  • adenocarcinoma cell line NCI-838, was obtained from the National Cancer Institute. These cells were grown in
  • DMEM2 medium Dulbecco's modification of Eagle's medium, EMEM supplemented with 10% fetal bovine serum and 0.03% L-glutamine.
  • mice bearing human melanoma or non-small cell lung carcinoma xenograft tumors were injected intravenously with 0.2 ml of saline solution containing [ 131 I]PAB or [ 131 I]DAB (150-200 ⁇ Ci).
  • the animals were anesthetized with ketamine containing rompun before the imaging studies.
  • the images were obtained using a scintigraphic camera with a pin-hole collimator at 6 and 24 hr. post injection.
  • Figs. 2 and 3 provide scintigrams of nude mice implanted with human melanoma xenografts and treated with [ 131 I]PAB and [ 131 I]DAB, respectively.
  • IPAB is a significantly better diagnostic agent for tumor imaging than IDAB.
  • Fig. 4 provides a scintigram of a nude mouse implanted with a human adenocarcinoma xenograft 30 hrs. after injection of [ 131 I]PAB. These scintographic imaging studies easily visualized the implanted tumor at both 24 and 30 hrs. post-injection.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Cette invention concerne des composés ayant une affinité pour certaines cellules cancéreuses telles que celles des cancers du poumon, du côlon et du rein, des mélanomes malins, des gliomes, des neuroblastomes et des phéochromocytomes. Ces composés se lient également avec une forte spécificité aux récepteurs sigma de surface cellulaire et peuvent par conséquent être utilisés dans les techniques de visualisation de diagnostic de tous les tissus présentant une abondance de cellules ayant des récepteurs sigma. Les composés sont représentés par la formule (I) dans laquelle X représente un radionuclide; R2 représente -N(R3)2 ou un anneau hétérocyclique contenant de l'azote pentagonal ou hexagonal, facultativement substitué par au moins un groupe alkyle; les autres variables étant définies en page 5 du descriptif. Cette invention concerne également des procédés de visualisation de diagnostic et de détection et de traitement de tumeurs renfermant les cellules cancéreuses décrites ci-dessus.
PCT/US1993/004309 1993-05-06 1993-05-06 Composes destines a la visualisation et a la therapie du cancer WO1994026314A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002139503A CA2139503A1 (fr) 1993-05-06 1993-05-06 Composes pour le traitement et l'imagerie dans les cas de cancer
PCT/US1993/004309 WO1994026314A1 (fr) 1993-05-06 1993-05-06 Composes destines a la visualisation et a la therapie du cancer
JP6525353A JPH08510235A (ja) 1993-05-06 1993-05-06 癌の撮像及び治療用化合物
EP94930839A EP0650372A4 (fr) 1993-05-06 1993-05-06 Composes destines a la visualisation et a la therapie du cancer.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA002139503A CA2139503A1 (fr) 1993-05-06 1993-05-06 Composes pour le traitement et l'imagerie dans les cas de cancer
PCT/US1993/004309 WO1994026314A1 (fr) 1993-05-06 1993-05-06 Composes destines a la visualisation et a la therapie du cancer

Publications (1)

Publication Number Publication Date
WO1994026314A1 true WO1994026314A1 (fr) 1994-11-24

Family

ID=4154976

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/004309 WO1994026314A1 (fr) 1993-05-06 1993-05-06 Composes destines a la visualisation et a la therapie du cancer

Country Status (4)

Country Link
EP (1) EP0650372A4 (fr)
JP (1) JPH08510235A (fr)
CA (1) CA2139503A1 (fr)
WO (1) WO1994026314A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032968A1 (fr) * 1995-04-21 1996-10-24 John Christy S Composes pour l'imagerie cancerologique et le traitement du cancer
WO1996033186A1 (fr) * 1995-04-18 1996-10-24 Pharmacia & Upjohn S.P.A. Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4?
US5919934A (en) * 1997-02-19 1999-07-06 The George Washington University Compounds, compositions, and methods for cancer imaging and therapy
US5993777A (en) * 1993-05-06 1999-11-30 Research Corporation Technologies, Inc. Benzamide compounds for cancer imaging and therapy
US6517811B2 (en) 1993-05-06 2003-02-11 Research Corporation Technologies, Inc. Compounds for cancer imaging and therapy
WO2005089815A2 (fr) 2004-03-10 2005-09-29 Schering Ag Derives de benzamides radiohalogenes et leur utilisation dans le diagnostic et la therapie de tumeurs
US7947838B2 (en) 2003-07-31 2011-05-24 Washington University Radiolabelled benzamide analogues, their synthesis and use in diagnostic imaging
CN109721533A (zh) * 2017-10-27 2019-05-07 华中科技大学同济医学院附属协和医院 靶向黑色素瘤的显像剂及其制备方法与应用

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3591634A (en) * 1967-06-20 1971-07-06 Ile De France N-(tertiary amino-alkyl)-benzamides
US3891671A (en) * 1968-08-01 1975-06-24 Ile De France N-(2-pyrrolidyl or piperidyl alkyl)-4-hydroxy benzamides
US4360511A (en) * 1978-11-29 1982-11-23 Medi-Physics, Inc. Amines useful as brain imaging agents
US4430319A (en) * 1982-05-21 1984-02-07 State University Of New York Radioactive iodine labeled phenolic amines
US4584187A (en) * 1981-04-01 1986-04-22 Wieland Donald M Imaging agent and method of use
US4647446A (en) * 1982-08-18 1987-03-03 The Regents Of The University Of California Rapid brain scanning radiopharmaceutical
US4673686A (en) * 1978-01-20 1987-06-16 Societe D'etudes Scientifiques Et Industrielle De L'ile De France New substituted heterocyclic benzamides, methods of preparing them and their application as behavior modifiers
US4888353A (en) * 1986-02-28 1989-12-19 Erbamont, Inc. Carboxamides useful as antiemetic or antipsychotic agents
US4937260A (en) * 1982-09-09 1990-06-26 Astra Lakemedal Aktiebolag Benzamido-derivatives
US5122361A (en) * 1989-04-17 1992-06-16 Trustees Of The University Of Pennsylvania Dopamine receptor ligands and imaging agents
US5154913A (en) * 1987-11-19 1992-10-13 Vanderbilt University Radioiodinated benzamines method of their use as radioimaging agents
US5190741A (en) * 1989-02-14 1993-03-02 Institut National De La Sante Et De La Recherche Medicale (Inserm) Agents for diagnosing and treating melanomas, aromatic halogenated derivatives usable as such agents and their preparation

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3591634A (en) * 1967-06-20 1971-07-06 Ile De France N-(tertiary amino-alkyl)-benzamides
US3891671A (en) * 1968-08-01 1975-06-24 Ile De France N-(2-pyrrolidyl or piperidyl alkyl)-4-hydroxy benzamides
US4673686A (en) * 1978-01-20 1987-06-16 Societe D'etudes Scientifiques Et Industrielle De L'ile De France New substituted heterocyclic benzamides, methods of preparing them and their application as behavior modifiers
US4360511A (en) * 1978-11-29 1982-11-23 Medi-Physics, Inc. Amines useful as brain imaging agents
US4584187A (en) * 1981-04-01 1986-04-22 Wieland Donald M Imaging agent and method of use
US4430319A (en) * 1982-05-21 1984-02-07 State University Of New York Radioactive iodine labeled phenolic amines
US4647446A (en) * 1982-08-18 1987-03-03 The Regents Of The University Of California Rapid brain scanning radiopharmaceutical
US4937260A (en) * 1982-09-09 1990-06-26 Astra Lakemedal Aktiebolag Benzamido-derivatives
US4888353A (en) * 1986-02-28 1989-12-19 Erbamont, Inc. Carboxamides useful as antiemetic or antipsychotic agents
US5154913A (en) * 1987-11-19 1992-10-13 Vanderbilt University Radioiodinated benzamines method of their use as radioimaging agents
US5190741A (en) * 1989-02-14 1993-03-02 Institut National De La Sante Et De La Recherche Medicale (Inserm) Agents for diagnosing and treating melanomas, aromatic halogenated derivatives usable as such agents and their preparation
US5122361A (en) * 1989-04-17 1992-06-16 Trustees Of The University Of Pennsylvania Dopamine receptor ligands and imaging agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0650372A4 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5911970A (en) * 1993-05-06 1999-06-15 Research Corporation Technologies, Inc. Methods for cancer imaging and therapy using benzamine compounds
US5993777A (en) * 1993-05-06 1999-11-30 Research Corporation Technologies, Inc. Benzamide compounds for cancer imaging and therapy
US6015543A (en) * 1993-05-06 2000-01-18 Research Corporation Technologies, Inc. Benzamide compounds containing a heterocyclic ring for tumor imaging and therapy
US6447748B1 (en) 1993-05-06 2002-09-10 Research Corporation Technologies, Inc. Benzamide compounds for cancer imaging and therapy
US6517811B2 (en) 1993-05-06 2003-02-11 Research Corporation Technologies, Inc. Compounds for cancer imaging and therapy
WO1996033186A1 (fr) * 1995-04-18 1996-10-24 Pharmacia & Upjohn S.P.A. Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4?
WO1996032968A1 (fr) * 1995-04-21 1996-10-24 John Christy S Composes pour l'imagerie cancerologique et le traitement du cancer
US5919934A (en) * 1997-02-19 1999-07-06 The George Washington University Compounds, compositions, and methods for cancer imaging and therapy
US7947838B2 (en) 2003-07-31 2011-05-24 Washington University Radiolabelled benzamide analogues, their synthesis and use in diagnostic imaging
WO2005089815A2 (fr) 2004-03-10 2005-09-29 Schering Ag Derives de benzamides radiohalogenes et leur utilisation dans le diagnostic et la therapie de tumeurs
WO2005089815A3 (fr) * 2004-03-10 2006-06-15 Schering Ag Derives de benzamides radiohalogenes et leur utilisation dans le diagnostic et la therapie de tumeurs
CN109721533A (zh) * 2017-10-27 2019-05-07 华中科技大学同济医学院附属协和医院 靶向黑色素瘤的显像剂及其制备方法与应用

Also Published As

Publication number Publication date
JPH08510235A (ja) 1996-10-29
CA2139503A1 (fr) 1994-11-24
EP0650372A1 (fr) 1995-05-03
EP0650372A4 (fr) 1996-07-03

Similar Documents

Publication Publication Date Title
US6517811B2 (en) Compounds for cancer imaging and therapy
US6447748B1 (en) Benzamide compounds for cancer imaging and therapy
US5609849A (en) Serotonin (5-HT1A) receptor ligands and imaging agents
KR100451077B1 (ko) 도파민및세로토닌수송체리간드및영상화제
JP2020522478A (ja) 放射性医薬品、放射線造影剤及びそれらの使用
EP0445976B1 (fr) Antagonistes de CCK-A à émission de rayons gamma utilisés comme agents d'imagerie pancréatique
John et al. Synthesis, in vitro binding, and tissue distribution of radioiodinated 2-[125I] N-(N-benzylpiperidin-4-yl)-2-iodo benzamide, 2-[125I] BP: A potential σ receptor marker for human prostate tumors
Drews et al. Synthesis and biological evaluation of technetium (III) mixed-ligand complexes with high affinity for the cerebral 5-HT1A receptor and the alpha1-adrenergic receptor
US5919934A (en) Compounds, compositions, and methods for cancer imaging and therapy
WO1994026314A1 (fr) Composes destines a la visualisation et a la therapie du cancer
JP5186075B2 (ja) テクネチウム−９９ｍ及びレニウムで標識した小型作用剤及び腫瘍の画像化方法
US5993777A (en) Benzamide compounds for cancer imaging and therapy
JP4796301B2 (ja) テクネチウム−９９ｍ及びレニウムで標識した小型作用剤及び組織、臓器及び腫瘍の画像化方法
EP1867634B1 (fr) Ligand pour le transporteur d acetylcholine vesiculaire
John et al. Synthesis, in vitro validation and in vivo pharmacokinetics of [125I] N-[2-(4-iodophenyl) ethyl]-N-methyl-2-(1-piperidinyl) ethylamine: a high-affinity ligand for imaging sigma receptor positive tumors
John et al. An improved synthesis of [125I] N-(diethylaminoethyl)-4-iodobenzamide: a potential ligand for imaging malignant melanoma
JP2004501055A (ja) 低酸素の検出のために有用な化合物の製造
CA2475254A1 (fr) Composes therapeutiques
AU2013254326A1 (en) Labelled quinoxaline derivatives as multimodal radiopharmaceuticals and their precursors
EP0712315A1 (fr) Complexes radiometalliques se fixant dans les tissus hypoxiques
WO2016174496A1 (fr) Indicateurs radioactifs p-gp pour imagerie en tant que biomarqueurs de l'apparition de maladies neurodégénératives
Chumpradit et al. Preparation and biodistribution of 1-[2-(3-[125I] iodo-4-aminophenyl) ethyl]-4-[3-(trifluoromethyl) phenyl] piperazine and 1-[2-(3-[125I] iodo-4-azidophenyl) ethyl]-4-[3-(trifluoromethyl) phenyl] piperazine
Chen Synthesis of rhenium complexes as models for new sigma receptor imaging agents
Ashford The development and SAR of selective sigma-2 receptor ligands for the diagnosis of cancer
KR20210052435A (ko) 방사성 이미다조티아디아졸 유도체 화합물

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

WWE Wipo information: entry into national phase

Ref document number: 2139503

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1994930839

Country of ref document: EP

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWP Wipo information: published in national office

Ref document number: 1994930839

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1994930839

Country of ref document: EP