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WO2009032840A1 - Composés de dmt-tic substitués par du fluor et leurs procédés d'utilisation - Google Patents

Composés de dmt-tic substitués par du fluor et leurs procédés d'utilisation Download PDF

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Publication number
WO2009032840A1
WO2009032840A1 PCT/US2008/075114 US2008075114W WO2009032840A1 WO 2009032840 A1 WO2009032840 A1 WO 2009032840A1 US 2008075114 W US2008075114 W US 2008075114W WO 2009032840 A1 WO2009032840 A1 WO 2009032840A1
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Prior art keywords
compound
salt
optical isomer
group
tissue
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PCT/US2008/075114
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English (en)
Inventor
Lawrence H. Lazarus
Gianfranco Balboni
Severo Salvadori
Xiaoyuan Chen
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
The Board Of Trustees Of The Leland Stanford Junior University
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Publication of WO2009032840A1 publication Critical patent/WO2009032840A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • PEPTIDES (DMT-TIC) FOR USE AS MYU- AND DELTA-OPIOID RECEPTOR PROBES IN
  • Imaging techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), and computed tomography (CT scan) provide non-destructive diagnostic examination of tissues or organs.
  • PET involves the acquisition of physiologic images based on the detection of positron radiation emitted from a radioactive substance administered to the patient.
  • the subsequent images of the human body developed with this technique are used to evaluate a variety of diseases, particularly cancer.
  • Targeted delivery of the radioactive substance to the tissue or organ has advantages such as excellent specificity and high binding affinity, and therefore, has received considerable attention from the industry. Accordingly, there is a desire for substances that target and deliver positron- emitting radionuclides to selected organs or tissues.
  • the present invention provides fluorine-substituted derivatives of Dmt-Tic (2',6'- dimethyl-L-tyrosine-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid peptide), for example, a compound of formula (I), optical isomer, or a pharmaceutically acceptable salt thereof:
  • the present invention also provides fluorine-substituted derivatives of methoxytyrosine-Tic and dimethoxytyrosine-Tic, for example, a compound of formula (III), optical isomer, or a pharmaceutically acceptable salt thereof:
  • the invention further provides a compound of formula (II), optical isomer, or pharmaceutically acceptable salt thereof:
  • composition comprising at least one compound of formula (I), (II) or (III) and a pharmaceutically acceptable carrier.
  • the Dmt-Tic pharmacophore binds, advantageously, with affinity to ⁇ -opioid and ⁇ -opioid receptors, which are found in certain cancers (e.g., lung, breast, and/or colorectal cancer).
  • the fluorine substituent is a radiolabel, 18 F.
  • the present invention further provides a method of locating a tumor comprising a ⁇ - or ⁇ -opioid receptor in a subject.
  • Figure 1 illustrates a method of synthesis of the compound BG- 137 in an embodiment of the invention.
  • Figure 2 illustrates a method of synthesis of the compound BG-139 in an embodiment of the invention.
  • the present invention provides agonists and antagonists of ⁇ -opioid and/or ⁇ - opioid receptors that do not pass the blood-brain barrier (BBB) and can be used to locate tumors that comprise ⁇ -opioid and/or ⁇ -opioid receptors.
  • BBB blood-brain barrier
  • the compounds of the invention are absorbed systemically.
  • the present invention is directed to the Dmt-Tic pharmacophore comprising a fluorine-substituent. More specifically, the present invention is directed to a compound of formula (I):
  • R 1 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, piperidinyl, pyrrolidinyl, pyrrolyl, and pyridinyl;
  • R 2 is one or more amino acid residues; and
  • R is selected from the group consisting of aryl, arylcarbonyl, arylalkylcarbonyl, aralkyloxycarbonyl, arylamido, aralkylamido, and heteroaryl, wherein the aryl, heteroaryl, or the "aryl" part of arylcarbonyl, arylalkylcarbonyl, aralkyloxycarbonyl, arylamido, and aralkylamido is substituted with one or more fluoro or trifluoromethyl groups; an optical isomer thereof; or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of amino, alkylamino, and dialkylamino.
  • R 2 is one or more amino acid residues, wherein an amino group of the amino acid is bonded to the 3-carboxyl group of the tetrahydroisoquinoline moiety; the amino group that is bonded to the 3-carboxyl group can be an alpha-amino group or another amino such as the side chain amino group of lysine.
  • the 3-carboxyl group is bonded to the amino group as an amide group.
  • at least one of the amino acid residues has an acidic functionality, such as -COOH or -CONH 2 . When more than one amino acid residue constitutes R , the residues are covalently bonded through amide bonds.
  • R 2 comprises 1-6 amino acid residues, preferably 1-3 amino acid residues, and more preferably 1-2 amino acid residues. Any suitable amino acid, natural or synthetic, can be employed. Typically, the one or more amino acid residues are selected from the group consisting of glycinyl, alaninyl, valinyl, leucinyl, isoleucinyl, phenylalaninyl, asparaginyl, glutaminyl, tryptophanyl, prolinyl, serinyl, threoninyl, tyrosinyl, hydroxyprolinyl, cysteinyl, cystinyl, methioninyl, aspartyl, glutamyl, lysinyl, argininyl, and histidinyl.
  • R 2 comprises one or more amino acid residues selected from the group consisting of phenylalaninyl, asparaginyl, glutaminyl, serinyl, and lysinyl, and more preferably phenylalaninyl and/or lysinyl.
  • the aryl part is substituted with one or more fluoro groups (preferably one) at any suitable ring position.
  • the fluoro group is the radiolabel, 18 F.
  • R 3 is selected from the group consisting of wherein n is 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6).
  • the aryl part is substituted with one or more trifluoromethyl groups (preferably one) at any suitable ring position.
  • the aryl part is substituted with one or more trifluoromethyl groups (preferably one) at any suitable ring position.
  • the aryl part is substituted with one or more trifluoromethyl groups (preferably one) at any suitable ring position.
  • R 'X trifluoromethyl group contains one, two, or three of the radiolabel, F.
  • R is selected from the group consisting of
  • R 3 is selected from the group consisting of 2-, 3-, or 4- fluorophenylcarbonyl, 2-, 3-, or 4-fiuorobenzylcarbonyl, 2-, 3-, or 4- fluorobenzyloxycarbonyl, 2-, 3-, or 4-fiuorophenylamido, 2-, 3-, or 4-fluorobenzylamido, and 4-, 5-, 6-, or 7-fluoro-l/i-benzimidazole-2-yl ("F-Bid").
  • R 3 is selected from the group consisting of 4-fluorophenylcarbonyl, 4-fluorobenzylcarbonyl, 4- fluorobenzyloxycarbonyl, 4-fluorophenylamido, 4-fluorobenzylamido, 5-fluoro-lH- benzimidazole-2-yl ("5F-Bid”), and 6-fluoro-lH-benzimidazole-2-yl ("6F-Bid”).
  • R 3 is 4-fluorophenylcarbonyl.
  • R is connected to R via any suitable group on R , e.g., a terminal amino or carboxy group on the amino acid residue of R .
  • R is connected via the amino group of the amino acid residue, either an alpha-amino group or a side chain amino group.
  • R 2 is lysinyl
  • R 3 is bonded to the amino group alpha to the carboxy group.
  • R could be bonded to the side chain amino group on lysinyl.
  • the compound of formula (I) can be chiral or achiral. If the compound is chiral, it can be the R enantiomer, the S enantiomer, or a mixture of both (including a racemic mixture). If more than one chiral center is present, the stereoisomers of the compound of formula (I) can be diastereomers of one another and can include a meso compound.
  • the present invention is directed to fluorine-substituted derivatives of methoxytyrosine-Tic and dimethoxytyrosine-Tic (2'-methoxy-L-tyrosine- l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid peptide, 6'-methoxy-L-tyrosine-l,2,3,4- tetrahydroisoquinoline-3-carboxylic acid peptide, and 2',6'-dimethoxy-L-tyrosine-l, 2,3,4- tetrahydroisoquinoline-3-carboxylic acid peptide), for example a compound of formula (III):
  • R 1 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, piperidinyl, pyrrolidinyl, pyrrolyl, and pyridinyl;
  • R 2 is one or more amino acid residues
  • R 3 is selected from the group consisting of aryl, arylcarbonyl, arylalkylcarbonyl, aralkyloxycarbonyl, arylamido, aralkylamido, and heteroaryl, wherein the aryl, heteroaryl, or the "aryl" part of arylcarbonyl, arylalkylcarbonyl, aralkyloxycarbonyl, arylamido, and aralkylamido is substituted with one or more fluoro or trifluoromethyl groups; an optical isomer thereof; or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of amino, alkylamino, and dialkylamino.
  • R 2 is one or more amino acid residues, wherein an amino group of the amino acid is bonded to the 3-carboxyl group of the tetrahydroisoquinoline moiety; the amino group that is bonded to the 3-carboxyl group can be an alpha-amino group or another amino such as the side chain amino group of lysine.
  • the 3-carboxyl group is bonded to the amino group as an amide group.
  • at least one of the amino acid residues has an acidic functionality, such as -COOH or -CONH 2 . When more than one amino acid residue constitutes R 2 , the residues are covalently bonded through amide bonds.
  • R 2 comprises 1-6 amino acid residues, preferably 1-3 amino acid residues, and more preferably 1-2 amino acid residues. Any suitable amino acid, natural or synthetic, can be employed. Typically, the one or more amino acid residues are selected from the group consisting of glycinyl, alaninyl, valinyl, leucinyl, isoleucinyl, phenylalaninyl, asparaginyl, glutaminyl, tryptophanyl, prolinyl, serinyl, threoninyl, tyrosinyl, hydroxyprolinyl, cysteinyl, cystinyl, methioninyl, aspartyl, glutamyl, lysinyl, argininyl, and histidinyl.
  • R 2 comprises one or more amino acid residues selected from the group consisting of phenylalaninyl, asparaginyl, glutaminyl, serinyl, and lysinyl, and more preferably phenylalaninyl and/or lysinyl.
  • the aryl part is substituted with one or more fluoro groups (preferably one) at any suitable ring position.
  • the fluoro group is the radiolabel, F.
  • R is selected from the group consisting of
  • n 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6).
  • the aryl part is substituted with one or more trifluoromethyl groups (preferably one) at any suitable ring position.
  • the trifluoromethyl group contains one, two, or three of the radiolabel, 18 F.
  • R 3 is selected from the group consisting of
  • R 3 is selected from the group consisting of 2-, 3-, or 4- fluorophenylcarbonyl, 2-, 3-, or 4-fluorobenzylcarbonyl, 2-, 3-, or 4- fluorobenzyloxycarbonyl, 2-, 3-, or 4-fluorophenylamido, 2-, 3-, or 4-fluorobenzylamido, and 4-, 5-, 6-, or 7-fluoro-l//-benzimidazole-2-yl ("F-Bid").
  • R 3 is selected from the group consisting of 4-fluorophenylcarbonyl, 4-fluorobenzylcarbonyl, 4- fluorobenzyloxycarbonyl, 4-fluorophenylarnido, 4-fluorobenzylamido, 5-fluoro-l//- benzimidazole-2-yl ("5F-Bid”), and 6-fluoro-lH-benzimidazole-2-yl ("6F-Bid”).
  • R 3 is 4-fluorophenylcarbonyl.
  • R 3 is connected to R 2 via any suitable group on R 2 , e.g., a terminal amino or carboxy group on the amino acid residue of R 2 .
  • R 3 is connected via the amino group of the amino acid residue, either an alpha-amino group or a side chain amino group.
  • R is lysinyl
  • R is bonded to the amino group alpha to the carboxy group.
  • R 3 could be bonded to the side chain amino group on lysinyl.
  • the compound of formula (III) can be chiral or achiral. If the compound is chiral, it can be the R enantiomer, the S enantiomer, or a mixture of both (including a racemic mixture). If more than one chiral center is present, the stereoisomers of the compound of formula (III) can be diastereomers of one another and can include a meso compound. [0028] In another embodiment, the invention is directed to fluorine-substituted derivatives of dermorphin, a ⁇ -selective opioid agonist, of the formula (II):
  • R 4 is one or more amino acid residues
  • R 5 is selected from the group consisting of aryl, arylcarbonyl, arylalkylcarbonyl, aralkyloxycarbonyl, arylamido, aralkylamido, and heteroaryl, wherein the aryl or heteroaryl group or the "aryl" part of arylcarbonyl, arylalkylcarbonyl, aralkyloxycarbonyl, arylamide, and aralkylamino is substituted with one or more fluoro or trifluoromethyl groups; an optical isomer thereof; or a pharmaceutically acceptable salt thereof.
  • R 4 comprises one or more amino acid residues, wherein an amino group of the amino acid is bonded to the carboxyl group of the prolinyl moiety; the amino group that is bonded to the carboxyl group of proline can be an alpha-amino group or another amino group such as the side chain amino group of lysine.
  • the carboxyl group is bonded to the amino group as an amide group.
  • at least one of the amino acid residues has an acidic functionality, such as -COOH or -CONH 2 . When more than one amino acid residue constitutes R 4 , the residues are covalently bonded through amide bonds.
  • R 4 comprises 1-6 amino acid residues, preferably 1-3 amino acid residues, and more preferably 1-2 amino acid residues. Any suitable amino acid, natural or synthetic, can be employed. Typically, the one or more amino acid residues are selected from the group consisting of glycinyl, alaninyl, valinyl, leucinyl, isoleucinyl, phenylalaninyl, asparaginyl, glutaminyl, tryptophanyl, prolinyl, serinyl, threoninyl, tyrosinyl, hydroxyprolinyl, cysteinyl, cystinyl, methioninyl, aspartyl, glutamyl, lysinyl, argininyl, and histidinyl.
  • R 4 comprises one or more amino acid residues selected from the group consisting of phenylalaninyl, asparaginyl, glutaminyl, serinyl, and lysinyl, and more preferably phenylalaninyl and/or lysinyl.
  • the aryl part is substituted with one or more fluoro groups (preferably one) at any suitable ring position.
  • the fluoro group is the radiolabel, 18 F.
  • R 5 is selected from the group consisting of
  • n 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6).
  • the aryl part is substituted with one or more trifluoromethyl groups (preferably one) at any suitable ring position.
  • the trifluoromethyl group contains one, two, or three of the radiolabel, F.
  • R is selected from the group consisting of
  • R is selected from the group consisting of 2-, 3-, or 4- fluorophenylcarbonyl, 2-, 3-, or 4-fluorobenzylcarbonyl, 2-, 3-, or 4- fluorobenzyloxycarbonyl, 2-, 3-, or 4-fluorophenylamido, 2-, 3-, or 4-fluorobenzylamido, and A-, 5-, 6-, or 7-fluoro-l/i-benzimidazole-2-yl ("F-Bid").
  • R 5 is selected from the group consisting of 4-fluorophenylcarbonyl, 4-fluorobenzylcarbonyl, 4- fluorobenzyloxycarbonyl, 4-fluorophenylamido, 4-fluorobenzylamido, 5-fluoro-l//- benzimidazole-2-yl ("5F-Bid”), and 6-ftuoro-lH-benzimidazole-2-yl ("6F-Bid”).
  • R 5 is 4-fluorophenylcarbonyl.
  • R 5 is connected to R 4 via any suitable group on R 4 , e.g., a terminal amino or carboxy group on the amino acid residue of R 4 .
  • R 5 is connected via the amino group of the amino acid residue, either alpha-amino group or side chain amino group.
  • R 4 is lysinyl, preferably R 5 is bonded to the amino group.
  • R 4 could be bonded to the alpha amino group on lysinyl.
  • the compound of formula (II) has a molecular weight greater than or equal to about 1,000 g/mol (e.g., 1,000 g/mol or higher, 1,100 g/mol or higher, 1,200 g/mol or higher, 1,500 g/mol or higher).
  • compounds of formula (II) can include a charged moiety at, for example, an amino (e.g., - NH 3 + ) or carboxy (e.g., -CO 2 " ) functionality at a functional pH such as 7.4.
  • the compound can function as a zwitterion or include a counterion such as a Group I or II cation (e.g., Na + , K + , Mg 2+ , or Ca 2+ ) or a Group VII anion (e.g., Bf, Cl " , or F).
  • a counterion such as a Group I or II cation (e.g., Na + , K + , Mg 2+ , or Ca 2+ ) or a Group VII anion (e.g., Bf, Cl " , or F).
  • alkyl implies a straight or branched alkyl moiety containing from, for example, 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • moieties include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, dodecanyl, and the like.
  • aryl refers to an unsubstituted or substituted aromatic carbocyclic moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like.
  • heteroaryl refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings.
  • Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
  • the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be aromatic, saturated, partially saturated, or unsaturated.
  • the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized.
  • Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
  • the heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
  • heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl (e.g., lH-benzimidazole-2-yl), triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, thienyl, isothiazolyl, quinolinyl, isoquinolinyl, thiazolyl, furyl, isoxazolyl, oxadiazolyl, and oxazolyl.
  • aralkyl refers to an alkyl group that is substituted with an aryl group.
  • the aryl and aralkyl groups are as described herein.
  • An example of an aralkyl group is benzyl.
  • arylcarbonyl and “arylalkylcarbonyl” refers to the group -C(O)R, in which R is an aryl or aralkyl group, respectively.
  • the aryl and aralkyl groups are as described herein.
  • An example of an arylcarbonyl group is phenylcarbonyl.
  • An example of arylalkylcarbonyl group is benzylcarbonyl.
  • aralkyloxycarbonyl refers to an aralkyloxy moiety bound to a carbonyl.
  • An example of an aralkyloxycarbonyl is benzyloxycarbonyl.
  • alkylamino refers to a group with one hydrogen and one alkyl group directly attached to a trivalent nitrogen atom.
  • dialkylamino refers to a group with two of the same or different alkyl groups directly attached to a trivalent nitrogen atom.
  • arylamido and aralkylamido refer to the groups -C(O)NHAr and -C(O)NH(CH 2 ) n Ar, respectively, in which Ar is an aryl group as described herein.
  • alkyl is as defined herein.
  • n is 1 to 6.
  • pharmaceutically acceptable salt is meant to include salts of the compound of formula (I) which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the free acid form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include alkali or alkaline earth metal salts, such as sodium, potassium, calcium, magnesium salts, or ammonium, organic amino, or a similar salt.
  • acid addition salts can be obtained by contacting the free base form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, trifluroacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, /7-toluenesulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1977)).
  • compounds of the present invention can contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the radiolabel is 18 F.
  • 18 F has a half-life (t*0 of 110 minutes, emits ⁇ + particles at an energy of 635 keV, and is 97% abundant.
  • F can be obtained from cyclotrons after bombardment of 18 O-enriched water with protons.
  • the enriched water containing H- 18 F can be neutralized with a base having a counter-ion that is any alkali metal (M), such as potassium or another monovalent ion, and the water can be evaporated off to give a residue of M- 18 F, which can be taken up in an organic solvent for further use.
  • M alkali metal
  • the counter- ion is selected to enable the fluoride ion to react rapidly in an organic phase with a halogen. Potassium is generally used as a counter-ion because it is cheaper than cesium. However, with carrier-free F, trivial amounts of counter-ion are required, and the counter-ion cost is minimal.
  • Cesium is useful as a counter ion since it is a larger ion with a more diffuse charge. Accordingly, cesium has looser ionic interactions with the small fluoride atom, and therefore does not interfere with the nucleophilic properties of the fluoride ion.
  • potassium is preferred to sodium, and, in general, the suitability of a Group Ia metal as a counter-ion in accordance with the present invention increases down the periodic table.
  • Group Ib reagents, such as silver also are useful as counter-ions.
  • organic phase transfer-type ions such as tetraalkylammonium salts, also can be used as counter-ions.
  • Fluoride salts can have a tendency to become hydrated and lose their nucleophilic character.
  • the labeling reaction is preferably performed under anhydrous conditions.
  • fluoride as potassium fluoride or as a complex with any of the other counter-ions discussed above
  • an organic solvent such as acetonitrile or tetrahydrofuran.
  • agents which bind to the counter-ion such as Kryptofix 2.2.2 (4,7,13, 16,21,24-hexaoxa-l,10-diazabicyclo[8.8.8]-hexacosane)
  • Kryptofix 2.2.2 4,7,13, 16,21,24-hexaoxa-l,10-diazabicyclo[8.8.8]-hexacosane
  • the present inventive compounds can be synthesized by any suitable method. See, for example, U.S. Patents 6,916,905 and 6,753,317, Modern Techniques of Peptide and Amino Acid Analysis, John Wiley & Sons, 1981; Bodansky, Principles of Peptide Synthesis, Springer Verlag, 1984).
  • compounds of formula (I) or (II) in accordance with embodiments of the invention can be made by starting from a protected amino acid residue (e.g., Lys) and further protecting it. Substituent R 3 is added and then the first protecting group on the amino acid residue can be selectively deprotected.
  • R 2 Next additional amino acid residues (R 2 ) are optionally added, then protected Tic is added, and then selectively deprotected. Protected Dmt is added next and then selectively deprotected. The first amino acid residue (R 2 ) can be further deprotected if necessary.
  • Compounds of formula (II) can be made from dermorphin. Once R 4 and R 5 have been prepared and coupled, as described above, the remaining peptide sequence can be added using known techniques. For the fluoro substituent on R 3 , the radiolabel 18 F can be used. Specific examples of synthesis methods of the present inventive compounds are set forth in the Examples herein.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I), (II), or (III), optical isomer, or salt thereof and a pharmaceutically acceptable carrier.
  • the composition is formulated for human administration.
  • Pharmaceutically acceptable carriers are well-known to those of ordinary skill in the art, as are suitable methods of administration. The choice of carrier will be determined, in part, by the particular method used to administer the composition.
  • routes of administering a composition are available, and, although more than one route can be used for administration, a particular route can provide a more immediate and more effective reaction than another route. Accordingly, there are a wide variety of suitable formulations of compositions that can be used in the present inventive methods.
  • a compound of the present invention can be made into a formulation suitable for parenteral administration, e.g., intravenal, subcutaneous, intraperitoneal, or dural administration.
  • a formulation can include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the formulations can be presented in unit dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneously injectable solutions and suspensions can be prepared from sterile powders, granules, and tablets, as described herein.
  • a formulation suitable for oral administration can consist of liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or fruit juice; capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solid or granules; solutions or suspensions in an aqueous liquid; and oil-in- water emulsions or water-in-oil emulsions.
  • diluents such as water, saline, or fruit juice
  • capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as solid or granules
  • solutions or suspensions in an aqueous liquid and oil-in- water emulsions or water-in-oil emulsions.
  • Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • a formulation suitable for oral administration can include lozenge forms, which can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • An aerosol formulation suitable for administration via inhalation also can be made.
  • the aerosol formulation can be placed into a pressurized acceptable propellant, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • a formulation suitable for topical application can be in the form of creams, ointments, or lotions.
  • a formulation for rectal administration can be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • a formulation suitable for vaginal administration can be presented as a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the dose administered to a subject, particularly a mammal (e.g., human), in the context of the methods of the present invention should be sufficient to produce and image and/or affect a response in the individual over a reasonable time frame.
  • the dose will be determined by the potency of the particular compound employed for agonizing/antagonizing the receptor, as well as the body weight and age of the individual.
  • the size of the dose also will be determined by the existence of any adverse side effects that may accompany the use of the particular compound employed. It is always desirable, whenever possible, to keep adverse side effects to a minimum.
  • the effective amount is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on interindividual differences in pharmacokinetics, drug distribution, and metabolism.
  • the "effective amount” can be defined, for example, as the blood or tissue level desired in the patient that corresponds to a concentration of one or more compounds according to the invention.
  • the "effective amount” for a given compound of the present invention also can vary when the composition of the present invention comprises another active agent or is used in combination with another composition comprising another active agent.
  • suitable animal models are available and have been widely implemented for evaluating the in vivo efficacy of such compounds. These models include the hot plate and tail-flick test (see, e.g., U.S. Patent 5,780,589). In vitro models are also available, examples of which are set forth in the Examples herein.
  • the dose of the compound of formula (I), (II), or (III), optical isomer or salt thereof desirably comprises about 0.1 mg per kilogram (kg) of the body weight of the mammal (mg/kg) to about 400 mg/kg (e.g., about 0.75 mg/kg, about 5 mg/kg, about 30 mg/kg, about 75 mg/kg, about 100 mg/kg, about 200 mg/kg, or about 300 mg/kg).
  • the dose of the compound of formula (I) or (II) comprises about 0.5 mg/kg to about 300 mg/kg (e.g., about 0.75 mg/kg, about 5 mg/kg, about 50 mg/kg, about 100 mg/kg, or about 200 mg/kg), about 10 mg/kg to about 200 mg/kg (e.g., about 25 mg/kg, about 75 mg/kg, or about 150 mg/kg), or about 50 mg/kg to about 100 mg/kg (e.g., about 60 mg/kg, about 70 mg/kg, or about 90 mg/kg).
  • antagonist refers to a compound that competes with an endogenous ⁇ -opioid or ⁇ -opioid ligand and inhibits ⁇ - or ⁇ -opioid signaling.
  • agonist refers to a compound that competes with the endogenous ⁇ - opioid or ⁇ -opioid ligand and activates or enhances ⁇ - or ⁇ -opioid signaling.
  • the present invention further provides a method of locating a ⁇ - and/or ⁇ -opioid receptor that is contained in a tissue or organ of a subject.
  • the method comprises the steps of: a) administering a radiolabeled compound of formula (I), (II), or (III), optical isomer or salt thereof to the subject,
  • the receptor is a ⁇ -opioid receptor.
  • a compound of formula (I) or (III), optical isomer or salt thereof preferably is administered.
  • the receptor is a ⁇ -opioid receptor.
  • a compound of formula (II), optical isomer or salt thereof preferably is administered.
  • the radiolabeled compound of formula (I), (I), or (III), optical isomer or salt thereof is administered in an amount effective to provide an image.
  • subject used herein includes animals such as humans, sheep, horses, cattle, pigs, monkeys, dogs, cats, rats, and mice.
  • the tissue or organ in the subject to be tested is any tissue or organ that is known to contain a ⁇ - and/or ⁇ -opioid receptor.
  • the tissue is peripheral to the brain.
  • Such tissues and organs include the entire organ or a tissue sample of a breast, an ovary, a salivary gland, a stomach, a kidney, a colon, a rectum, a cervix, a bladder, a head, a neck, including an esophagus, or the pulmonary system (e.g., a lung, trachea, nasal cavity, mouth, larynx, pharynx, and epiglottis).
  • the tissue is from the lung, colon, rectum, or breast. More preferably, the tissue is from the lung.
  • the tissue can also include a human cancer cell line known to contain a ⁇ - and/or ⁇ -opioid receptor.
  • Such cell lines include NCI-H 146 (small cell lung cancer, ⁇ -opioid receptor), NCI-Hl 87 (non-small cell lung cancer, ⁇ -opioid receptor), SHS Y5 Y (neuroblastoma, ⁇ - and ⁇ -opioid receptors), NS20Y (neuroblastoma, ⁇ -opioid receptor), SK- N-SH (neuroblastoma; ⁇ -opioid receptor), NG108-15 (neuroblastoma-glioma hybrid, ⁇ - opioid receptor), and T47D (breast cancer, ⁇ -opioid receptor).
  • Obtaining a diagnostic image of the tissue or organ in step b) typically comprises exposing the tissue or organ in the subject to an energy source, whereupon a diagnostic image of the tissue or organ is obtained.
  • the diagnostic image can be, for example, positron emission tomography (PET) image, a magnetic resonance image (MRI), a computerized tomography (CT) scan, single photon emission computed spectroscopy (SPECT) image, or the like.
  • PET positron emission tomography
  • MRI magnetic resonance image
  • CT computerized tomography
  • SPECT single photon emission computed spectroscopy
  • the diagnostic image can be an MRI.
  • the radiolabeled compound of formula (I), (II), or (III), optical isomer or salt thereof distributes in various concentrations to different tissues, and catalyzes the relaxation of protons in the tissues that have been excited by the absorption of radiofrequency energy from a magnetic resonance imager. This acceleration of the rate of relaxation of the excited protons provides for an image of different contrast when the subject is scanned with a magnetic resonance imager.
  • the magnetic resonance imager is used to record images at various times, generally either before and after administration of the 18 F labeled compound of formula (I), (II), or (III), or after administration only, and the differences in the images created by the presence of the radiolabeled compound of formula (I) or (II) in tissues are used in diagnosis.
  • Guidelines for performing imaging techniques can be found in Stark et al., Magnetic Resonance Imaging, Mosbey Year Book: St. Louis, 1992, hereby incorporated by reference.
  • Single Positron Emission Computed Tomography is a non-invasive imaging method to localize the position of a target such as a cancer metastasis, based on radioactive substances that emit gamma radiation when decaying.
  • a CT scan provides anatomical detail, such as size and location of the tumor or mass.
  • Digital geometry processing is used to generate a three-dimensional image of the internals of an object from a large series of two-dimensional X-ray images taken around a single axis of rotation.
  • CT produces a volume of data which can be manipulated, through a process known as windowing, in order to demonstrate various structures based on their ability to block the X-ray beam.
  • Combined techniques such as PET/CT and PET/MRI are suitable for use in the invention.
  • step b) comprises obtaining a positron emission tomography (PET) image of the tissue or organ.
  • PET is a non-invasive imaging method to localize the position of a target such as a cancer metastasis.
  • a positron-emitting radionuclide such as 1 F, is introduced, usually by injection, and accumulates in the target tissue or organ. As it decays it emits a positron, which promptly combines with a nearby electron resulting in the simultaneous emission of two identifiable gamma rays in opposite directions.
  • a PET scan can provide in vivo physiology such as metabolic detail (e.g., cellular activity) of the tumor or mass. The diagnosis is at a molecular level thereby providing detection of a tumor or mass at an early stage.
  • the present invention provides a method of measuring the quantity of a ⁇ - and/or ⁇ -opioid receptor that is contained in a tissue or organ of a subject.
  • the method comprises the steps of: a) administering a radiolabeled compound of formula (I), (II), or (III), optical isomer or salt thereof to the subject,
  • the receptor is a ⁇ -opioid receptor.
  • the receptor is a ⁇ -opioid receptor.
  • the radiolabeled compound of formula (I), (II), or (III), optical isomer or salt thereof is administered in an amount effective to provide an image.
  • the invention provides a method of locating a tumor comprising a ⁇ -opioid receptor in a mammal in need thereof comprising administering a compound of the formula selected from the group consisting of:
  • Crude compounds are purified by preparative reversed-phase HPLC (Waters Delta Prep 4000 system with Waters Prep LC 40 mm Assembly column Cl 8 (30 x 4 cm, 15 ⁇ m particle size)) and eluted at a flow rate of 20 mL/min with mobile phase solvent A (10% acetonitrile + 0.1% TFA in H 2 O, v/v), and a linear gradient from 10 to 60% solvent B (60%, acetonitrile + 0.1% TFA in H 2 O, v/v) in 30 min.
  • Analytical HPLC analyses are performed with a Beckman System Gold (Beckman ultrasphere ODS column, 250 x 4.6 mm, 5 ⁇ m particle size).
  • Analytical determinations and capacity factor (K') of the products that are used in HPLC in solvents A and B are programmed at flow rate of 1 mL/min with a linear gradient from 0 to 100% B in 25 min. Analogues have less than 1% impurities when monitored at 220 and 254 nm.
  • TLC is performed on precoated plates of silica gel F254 (Merck, Darmstadt, Germany): (A) l-butanol/AcOH/H 2 O (3:1:1, v/v/v); (B) CH 2 Cl 2 /toluene/methanol (17:1:2). Ninhydrin (1% ethanol, Merck), fluorescamine (Hoffman-La Roche) and chlorine spray reagents are used. Melting points are determined on a Kofler apparatus and are uncorrected. Optical rotations are assessed at 10 mg/mL in methanol with a Perkin-Elmer 241 polarimeter in a 10 cm water-jacketed cell.
  • Boc-Dmt-Tic-£-Lys(4-fluorobenzoyi)-OH is treated with TFA as reported for TFAH-Tic-£--Lys(Z)-OMe: yield 0.09 g (94%); Rf[A) 0.42; HPLC K 4.86; mp 149-151 °C; [Oc] 20 D -18.5; m/z 620 (M+H) + ; 1 H-NMR (DMSO-J 6 ) ⁇ 1.29-1.82 (m, 6H), 2.35 (s, 6H), 2.92- 3.20 (m, 6H), 3.95-4.92 (m, 5H), 6.29 (s, 2H), 6.96-7.93 (m, 8H).
  • Boc-Dmt-Tic-Phe-Lys(4-fluorobenzoyl)-OH is treated with TFA as reported for TFAH-Tic- ⁇ -Lys(Z)-OMe: yield 0.08 g (96%); Rf[A) 0.40; HPLC K' 2.87; mp 146-149 °C; [Ot] 20 D +31.1; m/z 161 (M+H) + ; 1 H-NMR (DMSO-Cf 6 ) ⁇ 1.29-1.78 (m, 6H), 2.35 (s, 6H), 2.92- 3.20 (m, 8H), 3.95-4.92 (m, 5H), 6.29 (s, 2H), 6.96-7.93 (m, 13H).
  • EXAMPLE 14 This example demonstrates a synthesis of the compound [ 18 F]fluoro-BG-139 in accordance with an embodiment of the invention.
  • BG-138 a compound of formula (II), in accordance with an embodiment of the invention.
  • Dermorphin is synthesized using Fmoc/t-butyl chemistry with a Syro XP multiple peptide synthesizer (MultiSynTech GmbH, Witten Germany).
  • Fmoc-Rink-amide MBHA resin (0.7 mmol/g, 0.150 g) is treated with 40% piperine/DMF and linked with: Fmoc- Lys(Dde)-OH, Fmoc-Pro-OH, Fmoc-Tyr( ⁇ u)-OH, Fmoc-Gly-OH, Fmoc-Phe-OH, Fmoc-D- AIa-OH, Boc-Tyr-OH (4 equiv.; 0.5 M in DMF) by using HOBt (5 equiv.; 0.78 M in DMF), DIC (7 equiv.; 1.09 M in DMF) as the coupling reagent.
  • the coupling reaction time is 1.5 h and piperidine (40%)/DMF is used to remove the Fmoc group at each step (20 min).
  • the peptide resin is washed with CH 2 Cl 2 and dried in vacuo to yield the protected Dermorphin resin.
  • the protected Dermorphin resin is treated with TFA/H 2 O/triethylsilane (9 : 0.5 :
  • This example demonstrates a method to determine the equilibrium receptor binding of compounds of formula (I) and (II) in accordance with an embodiment of the invention.
  • Opioid receptor affinities are determined under equilibrium conditions (2.5 h at room temperature) in a competition assay using brain P 2 synaptosomal membranes prepared from Sprague-Dawley rats (e.g., Lazarus et al., J. Med. Chem. 1991, 34, 1350-1355; Lazarus et al., Peptides 1993, 14, 21-28). Synaptosomes are preincubated to remove endogenous opioid peptides and stored at -80 °C in buffered 20% glycerol (Lazarus et al., J. Med. Chem. 1991, 34, 1350-1355; Lazarus et al., J Biol. Chem.
  • This example demonstrates the functional bioactivity of compounds of the invention in isolated organ preparations in accordance with an embodiment of the invention.
  • the isolated tissues are suspended in organ baths containing balanced salt solutions in a physiological buffer, pH 7.5.
  • Agonists are tested for the inhibition of electrically evoked contraction and expressed as IC 50 (nM) obtained from the dose-response curves.
  • the IC 50 values represent the mean ⁇ SE of five or six separate assays.
  • Delta-antagonist potencies in the MVD assay are determined against the ⁇ -agonist deltorphin-II; //-antagonism in the GPI assay uses the //-agonist endomorphin-2, and both are expressed as p ⁇ 2 determined using the Schild Plot (Arunlakshana et al., Br. J. Pharmcol. 1959, 14, 48-58).
  • Compounds from Examples 6 and 12 are tested in the electrically stimulated MVD and GPI assays for intrinsic functional bioactivity (Table 2).
  • aAgonist activity is expressed as IC 50 obtained from dose-response curves. These values represent the mean ⁇ SE for at least five to six fresh tissue samples.
  • pA 2 values of opioid antagonists against the agonists are determined by the method of Kosterlitz and Watt. ⁇ Br J. Pharmacol 1968, 33, 266-276).
  • Example 8 The compound of Example 8 is injected into normal mice for brain imaging. The total synthesis time is 120 min and the decay-corrected radiochemical yield of [ F]fluoro- BG-137 is about 30-32% decay starting from [ 18 F]SFB. [ 18 F]Fluoro-BG-137 shows no uptake in mouse brain as it does not cross the blood-brain barrier (BBB). [0106] An in vitro autoradiographic study is also performed by incubating normal rat brain slices with [ 18 F]fluoro-BG-137 without and with the presence of blocking ligands: BG- 137 and UFP-501 [N(Me) 2 -Dmt-Tic-OH].
  • the [ F]fluoro-BG-137 shows prominent uptake in the striatum, thalamus, and cortex, which are opioid rich regions. Significant blocking of the uptake by BG- 137 and UFP-501 indicates high specific binding of [ 18 F]fluoro-BG-137 to the ⁇ -opioid receptor.

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  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des composés de formule (I) ou leurs sels acceptables sur le plan pharmaceutique : formule (I) dans laquelle R1, R2 et R3 sont tels que décrits ici. La présente invention concerne également une composition pharmaceutique comprenant au moins un composé de formule (I) et un vecteur acceptable sur le plan pharmaceutique. La présente invention concerne aussi un procédé de localisation d'un récepteur aux opiacés µ et/ou δ contenu dans un tissu ou un organe.
PCT/US2008/075114 2007-09-05 2008-09-03 Composés de dmt-tic substitués par du fluor et leurs procédés d'utilisation WO2009032840A1 (fr)

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CN110194785A (zh) * 2016-04-21 2019-09-03 兰州大学 一种阿片和神经肽ff受体的多靶点肽类分子及其制备和应用
EP3807296A4 (fr) * 2018-06-14 2022-03-02 Dana-Farber Cancer Institute, Inc. Inhibiteurs peptidomimétiques de la peptidyl-prolyl cis/trans isomérase (pin1)

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Title
BALBONI ET AL: "Effect of Lysine at C-terminus of the Dmt-Tic Opioid Pharmacophore", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 18, 16 August 2006 (2006-08-16), pages 5610 - 5617, XP002511398 *
RAVERT ET AL: "PET imaging of opioid receptors in pain: progress and new directions", CURRENT PHARMACEUTICAL DESIGN, vol. 10, no. 7, 2004, XP002511399 *
RYU ET AL: "Synthesis of a Potent and Selective 18F-Labeled ?-Opioid Receptor Antagonist Derived from the Dmt-Tic Pharmacophore for Positron Emission Tomography Imaging", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 6, 1 March 2008 (2008-03-01), pages 1817 - 1823, XP002511400 *

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Publication number Priority date Publication date Assignee Title
CN110194785A (zh) * 2016-04-21 2019-09-03 兰州大学 一种阿片和神经肽ff受体的多靶点肽类分子及其制备和应用
CN110194785B (zh) * 2016-04-21 2023-02-24 上海天慈生命科学发展有限公司 一种阿片和神经肽ff受体的多靶点肽类分子及其制备和应用
EP3807296A4 (fr) * 2018-06-14 2022-03-02 Dana-Farber Cancer Institute, Inc. Inhibiteurs peptidomimétiques de la peptidyl-prolyl cis/trans isomérase (pin1)

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